# Priya Life Science - Full Knowledge Base
This document contains the complete, unabridged technical knowledge base and glossary of Priya Life Science.

## Pharma Glossary

### ADR
Adverse Drug Reaction.
**Local Context:** A response to a medicinal product which is noxious and unintended, where a causal relationship between product and event is suspected.

### AE
Adverse Event.
**Local Context:** Any untoward medical occurrence in a patient or subject administered a drug. Reports are managed in the EU via EudraVigilance.

### ALCOA+
Data Integrity guidelines specifying that records must be Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available.
**Local Context:** Regulatory agencies like the HPRA place massive audit focus on ALCOA+ compliance to ensure patient safety and product quality.

### Annex 1
The section of the EU Good Manufacturing Practice (GMP) guidelines governing the manufacture of sterile medicinal products.
**Local Context:** A major revision of Annex 1 came into operation in August 2023, introducing stricter requirements for contamination control strategy (CCS).

### ASMF
Active Substance Master File.
**Local Context:** A submission to regulatory authorities providing confidential detailed information about the manufacture and control of an active substance (API).

### ATMP
Advanced Therapy Medicinal Product.
**Local Context:** Medicinal products based on gene therapy, somatic cell therapy, or tissue engineering. Evaluated centrally by the EMA Committee for Advanced Therapies (CAT).

### Audit Trail
A secure, computer-generated, time-stamped electronic record that allows for the reconstruction of the course of events relating to data entry or modification.
**Local Context:** Mandatory under EU GMP Annex 11 (Computerised Systems) to ensure data transparency.

### Benefit-Risk Balance
The relationship between the positive therapeutic effects of a product compared to its risks (safety issues).
**Local Context:** Regulators continuous evaluate this balance; a negative shift can lead to drug suspension or withdrawal.

### Bioprocess Operator
A technical specialist responsible for monitoring bioreactors, filtration systems, and cleanroom biomanufacturing lines.
**Local Context:** One of the most in-demand vocational roles in Ireland's biopharma hubs.

### Bioreactor
An engineered vessel or device that supports a biologically active environment for growing cells or organisms.
**Local Context:** Biologics hubs in Ireland (like Pfizer Grange Castle and Eli Lilly Limerick) utilize massive bioreactors for antibody production.

### Biosimilar
A biological medicine highly similar to another already approved biological medicine (the reference product).
**Local Context:** Regulated in Europe via strict comparative clinical and quality testing to establish therapeutic equivalence.

### Calibration
The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a standard.
**Local Context:** Calibration schedules must be strictly maintained and logged to avoid quality deviations.

### CAPA
Corrective and Preventive Action.
**Local Context:** A system used to investigate, root cause, and eliminate the recurrence of quality issues. Mandatory under EU GMP Chapter 1.

### CAR-T Therapy
Chimeric Antigen Receptor T-cell therapy. A type of immunotherapy where a patient's T cells are genetically engineered to target cancer cells.
**Local Context:** Classified as an ATMP in the EU, requiring complex vein-to-vein logistical tracking and specialized hospital validation.

### Cell Bank
A collection of ampoules containing a single pool of cells of uniform composition, stored under deep freeze conditions.
**Local Context:** Divided into Master Cell Bank (MCB) and Working Cell Bank (WCB) to ensure consistent cell culture starting materials.

### CEP
Certificate of Suitability.
**Local Context:** A certificate issued by the EDQM confirming that a substance complies with the monographs of the European Pharmacopoeia.

### cGMP
Current Good Manufacturing Practice.
**Local Context:** Regulations enforcing proper design, monitoring, and control of manufacturing facilities and processes. Audited directly by the HPRA.

### Change Control
A formal quality management system designed to propose, evaluate, review, and execute changes in equipment, processes, or materials.
**Local Context:** Required to prevent unauthorized modifications that could compromise the validated status of a manufacturing line.

### CHO Cells
Chinese Hamster Ovary cells.
**Local Context:** The mammalian cell line most commonly used in industrial biomanufacturing to produce recombinant therapeutic proteins.

### CIOMS
Council for International Organizations of Medical Sciences.
**Local Context:** An international body that publishes consensus guidelines for drug safety reporting formats (e.g., CIOMS I forms).

### CIP
Clean-in-Place.
**Local Context:** An automated method of cleaning the interior surfaces of pipes, vessels, process equipment, and filters without disassembly.

### CRA
Clinical Research Associate (Monitor).
**Local Context:** The professional responsible for monitoring trial sites to ensure compliance with the protocol, GCP guidelines, and regulatory requirements.

### CRF
Case Report Form.
**Local Context:** A printed, optical, or electronic document designed to record all of the protocol-required information on each trial subject.

### CRISPR
Clustered Regularly Interspaced Short Palindromic Repeats. A gene-editing technology allowing precise edits to genomic sequences.
**Local Context:** Used extensively in biotechnology R&D hubs in Dublin and Cork to research disease models.

### CRO
Contract Research Organisation.
**Local Context:** A company providing support services to the pharmaceutical and biotech industries, managing clinical trials on behalf of sponsors.

### CTA
Clinical Trial Application.
**Local Context:** The formal application requesting approval to conduct a clinical trial in the EU, now submitted via the Clinical Trials Information System (CTIS).

### CTD
Common Technical Document.
**Local Context:** The internationally agreed format for organizing applications (Modules 1-5) submitted to regulatory authorities.

### CTIS
Clinical Trials Information System.
**Local Context:** The single-entry portal managed by the EMA for submitting and evaluating clinical trials within the EU/EEA.

### CTR
Clinical Trials Regulation (EU No 536/2014).
**Local Context:** The harmonized EU regulation that entered into force in 2022, streamlining clinical trial approvals across the entire European Union.

### Deviation
An unplanned departure from an approved instruction, SOP, specification, or validation protocol during manufacturing or testing.
**Local Context:** All deviations must be documented, risk-assessed, and signed off by the Quality Unit before batch release.

### Double-Blind
A trial design where neither the subjects nor the investigators/medical staff know which treatment group patients are assigned to.
**Local Context:** Minimizes bias in reporting and clinical evaluation.

### Downstream Processing
The purification and recovery of product from cell culture fluid or biological harvests.
**Local Context:** Utilizes filtration, chromatography, and viral inactivation steps to isolate pure proteins.

### DSUR
Development Safety Update Report.
**Local Context:** The safety report submitted annually by sponsors during the clinical trial/development phase of an investigational drug.

### E-E-A-T
Experience, Expertise, Authoritativeness, and Trustworthiness. Google's core search quality evaluation framework.
**Local Context:** Crucial ranking signal for life science publications in Ireland aiming to rank on Google search for medical and regulatory guidance.

### eCTD
Electronic Common Technical Document.
**Local Context:** The electronic version of the CTD format, mandatory for all EMA submissions and most national submissions in Europe.

### ELISA
Enzyme-Linked Immunosorbent Assay. An analytical biochemistry assay that uses a solid-phase enzyme immunoassay to detect the presence of a ligand.
**Local Context:** Frequently used by Quality Control labs in Ireland for checking antibody concentration and purity.

### EMA
European Medicines Agency.
**Local Context:** The EU body responsible for the scientific evaluation, supervision, and safety monitoring of medicines. Relocated from London to Amsterdam in 2019.

### Embargo
A request or agreement that information provided in a press release should not be published by the media until a designated date and time.
**Local Context:** Commonly used when distributing clinical trial phase results or regulatory approval announcements in advance to trusted journalists.

### EudraVigilance
The central European database managed by the EMA to collect and monitor suspected adverse reactions to medicines.
**Local Context:** All marketing authorization holders in Ireland must integrate their safety databases with EudraVigilance.

### Expression System
The combination of an expression vector and its host cell used to produce a target recombinant protein.
**Local Context:** Includes mammalian (CHO), bacterial (E. coli), and yeast (S. cerevisiae) systems.

### FDA
Food and Drug Administration (United States).
**Local Context:** The US federal agency regulating food, drugs, and medical devices. HPRA-regulated Irish manufacturing sites exporting to the US are regularly audited by the FDA.

### GAMP 5
Good Automated Manufacturing Practice version 5. A risk-based approach to compliant GxP computerized systems.
**Local Context:** The global standard used by QA departments in Ireland to validate software and automated systems.

### GCP
Good Clinical Practice.
**Local Context:** An international ethical and quality standard for designing, conducting, and reporting clinical trials involving human subjects.

### GLP-1
Glucagon-like peptide-1 receptor agonists. A class of biological drugs used to treat type 2 diabetes and obesity.
**Local Context:** Major manufacturing plants in Ireland are expanding lines to support high global demands for these peptides.

### Grade A
The high-risk cleanroom grade for aseptic operations, requiring laminar flow and near-zero particle counts.
**Local Context:** Regulated under EU GMP Annex 1, requiring active microbial and physical monitoring during all filling processes.

### Grade B
The background environment cleanroom grade for Grade A zones in aseptic preparation and filling.
**Local Context:** Requires strict personnel gowning and gown validation before entering.

### Grade C
Cleanroom grade used for less critical stages of manufacturing, such as preparation of solutions to be filtered.
**Local Context:** Requires controlled access and cleanroom clothing standards.

### Grade D
Cleanroom grade used for handling less critical materials and equipment cleaning operations.
**Local Context:** Acts as the entry barrier cleanroom classification in most Irish biopharma plants.

### Host Cell Proteins
Proteins produced by the host cell line during recombinant protein expression that must be purified out of the final product.
**Local Context:** Monitored as critical process impurities under EU pharmacopoeia specifications.

### HPRA
Health Products Regulatory Authority.
**Local Context:** The state agency responsible for regulating medicines, medical devices, and other health products in Ireland. Formerly known as the Irish Medicines Board (IMB).

### HVAC
Heating, Ventilation, and Air Conditioning.
**Local Context:** Cleanroom air handling systems that control temperature, humidity, and particle counts, using HEPA filters to prevent product contamination.

### ICF
Informed Consent Form.
**Local Context:** The documentation demonstrating that a subject has voluntarily confirmed their willingness to participate in a trial after being fully informed.

### ICH
International Council for Harmonisation.
**Local Context:** The global body bringing together regulators and industry to standardize technical requirements for pharmaceutical development (e.g., Q8, Q9, Q10).

### ICSR
Individual Case Safety Report.
**Local Context:** The standard electronic format used to report a single suspected adverse reaction case associated with a medicine.

### IMP
Investigational Medicinal Product.
**Local Context:** An active ingredient or placebo being tested or used as a reference in a clinical trial. IMPs must be manufactured under strict EU GMP Volume 4 requirements.

### Investigator Brochure
The comprehensive compilation of clinical and non-clinical data on the investigational products under study.
**Local Context:** Must be updated annually by the sponsor and provided to principal investigators.

### LIMS
Laboratory Information Management System.
**Local Context:** Software-based laboratory system that manages sample tracking, test results, instrument integration, and regulatory reporting.

### LSO
Local Safety Officer.
**Local Context:** The designated pharmacovigilance contact in a specific country, responsible for national reporting and communication with the local regulator (HPRA).

### Lyophilisation
Freeze-drying. A low-temperature dehydration process that involves freezing the product, lowering pressure, then removing ice by sublimation.
**Local Context:** Highly utilized in Ireland for packaging and stabilizing delicate protein and biologic therapies.

### MAA
Marketing Authorization Application.
**Local Context:** The application submitted to the EMA or national authorities (like the HPRA) to market a drug within the European Economic Area (EEA).

### MedDRA
Medical Dictionary for Regulatory Activities.
**Local Context:** The global standard medical terminology used to classify adverse event reports and medical diagnoses.

### Media Fill
A process simulation test where a sterile microbiological growth medium is run through the manufacturing line to validate aseptic status.
**Local Context:** An essential operational requirement audited strictly by HPRA inspectors to verify cleanroom sterility.

### Media Relations
The process of coordinating and building relationships with journalists, editors, and industry publications to secure organic media coverage.
**Local Context:** Irish biotechs build media relations with trade publications like FierceBiotech and regional platforms like Priya Life Science to attract venture capital.

### Monoclonal Antibody
Monoclonal Antibody (mAb). Laboratory-produced molecules engineered to serve as substitute antibodies that can restore, enhance, or mimic the immune system.
**Local Context:** Form the cornerstone of biopharmaceutical manufacturing in Ireland, representing blockbuster treatments like pembrolizumab or adalimumab.

### mRNA Vaccine
A vaccine using messenger RNA to instruct cells to produce a protein that triggers an immune response.
**Local Context:** Revolutionized drug delivery during the pandemic, leading to significant investment in lipid nanoparticle (LNP) tech in Ireland.

### NREC
National Research Ethics Committees of Ireland.
**Local Context:** The consolidated Irish ethics review body providing single national ethical opinions for clinical trials and medical devices.

### OOS
Out of Specification.
**Local Context:** Test results that fall outside the specifications or acceptance criteria established in drug applications or official pharmacopoeias.

### OOT
Out of Trend.
**Local Context:** A stability or release test result that is within the specification limit but is an atypical outlier compared to previous historical batch data.

### Orphan Drug
A medicine developed to treat rare medical conditions that would not be profitable to produce without government assistance or market exclusivity.
**Local Context:** In the EU, orphan designation grants 10 years of market exclusivity upon approval to encourage rare disease R&D.

### PAES
Post-Authorisation Efficacy Study.
**Local Context:** A clinical trial required to address efficacy questions that could not be resolved before marketing authorization.

### PASS
Post-Authorisation Safety Study.
**Local Context:** A study carried out after a medicine is authorized to identify, characterize, or quantify a safety hazard or evaluate risk management effectiveness.

### PAT
Process Analytical Technology.
**Local Context:** A system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes.

### Phase I
First-in-human clinical testing, typically performed in a small cohort of healthy volunteers (20-100) to evaluate safety and tolerability.
**Local Context:** LSO and REC approval is mandatory prior to recruitment.

### Phase II
Therapeutic exploratory testing in a cohort of patient volunteers (100-500) to assess efficacy, dosing ranges, and safety.
**Local Context:** Conducted across major teaching hospitals in Ireland under principal investigators.

### Phase III
Therapeutic confirmatory testing in large, diverse patient populations (1,000-5,000) to confirm clinical efficacy and monitor adverse reactions.
**Local Context:** Data from Phase III forms the bulk of the marketing authorization application (MAA).

### Phase IV
Post-marketing surveillance studies conducted after a medicine is authorized, evaluating long-term safety and real-world effectiveness.
**Local Context:** Often mandated by the EMA as part of post-authorization safety commitments.

### PIL
Package Leaflet.
**Local Context:** The leaflet included in the medicine box containing information for patients. It must align exactly with the approved SmPC in local languages.

### PIP
Paediatric Investigation Plan.
**Local Context:** A research and development plan to ensure that necessary data on the safety and efficacy of a medicine in children are gathered.

### Placebo
An inactive substance designed to look identical to the active investigational drug, used as a control in trials.
**Local Context:** Used to isolate the clinical effect of the active pharmaceutical ingredient.

### Plasmid
A small, circular, double-stranded DNA molecule that is distinct from a cell's chromosomal DNA, commonly used as a vector in gene cloning.
**Local Context:** Quality control departments validate plasmids for purity and sequence identity before bioprocess scale-up.

### PSUR
Periodic Safety Update Report.
**Local Context:** A pharmacovigilance document providing an evaluation of the risk-benefit balance of a medicine, submitted at defined time points post-approval.

### Public Relations
The strategic practice of managing and disseminating information from an individual or organization to the public to construct a favorable reputation.
**Local Context:** For life science firms in Ireland, PR campaigns are regulated by HPRA codes to avoid off-label promotional violations.

### QA
Quality Assurance.
**Local Context:** The wide-ranging concept covering all matters that individually or collectively influence the quality of a product, ensuring it is fit for its intended use.

### QC
Quality Control.
**Local Context:** The part of GMP concerned with sampling, specifications, and testing, ensuring that the necessary and relevant tests are actually carried out.

### QP
Qualified Person.
**Local Context:** A legally mandated role in the EU/EEA. The QP certifies that each batch of medicinal products has been manufactured in accordance with GMP and the marketing authorization.

### QPPV
Qualified Person Responsible for Pharmacovigilance.
**Local Context:** An EU-mandated executive responsible for the establishment and maintenance of the safety database and system for a marketing authorization holder.

### Qualification
The process of testing equipment, utilities, or systems to ensure they work correctly (divided into Installation, Operational, and Performance Qualification).
**Local Context:** Qualification (IQ/OQ/PQ) is the precursor to overall process validation.

### REC
Research Ethics Committee.
**Local Context:** The local or national board of experts reviewing trial protocols to protect the rights, safety, and well-being of trial subjects.

### Recombinant DNA
DNA molecules formed by laboratory methods of genetic recombination to bring together genetic material from multiple sources.
**Local Context:** Used to engineer host cell lines (like CHO cells) for therapeutic protein synthesis.

### RMP
Risk Management Plan.
**Local Context:** A detailed description of the risk management system required in the EU for identifying and minimizing the safety risks of a medicine.

### RP
Responsible Person.
**Local Context:** The person designated at a pharmaceutical wholesale distribution site to ensure that GDP (Good Distribution Practice) requirements are met.

### SAE
Serious Adverse Event.
**Local Context:** An event resulting in death, life-threatening situation, hospitalization, persistent disability, or congenital anomaly.

### Scientific Advice
Formal meetings where developers discuss clinical, non-clinical, or quality testing plans with regulators before submitting marketing applications.
**Local Context:** HPRA offers Scientific Advice to Irish life science startups and academic research teams to streamline development.

### Serialization
The process of printing unique 2D barcodes and serial numbers on medicine packages for trace-and-track validation.
**Local Context:** Mandated in the EU by the Falsified Medicines Directive (FMD) to secure the distribution supply chain.

### Signal Detection
The systematic search for new risks or safety changes by looking at adverse event database trends.
**Local Context:** EMA mandates ongoing signal detection using global healthcare registry databases.

### Single-Use Technology
Disposable manufacturing equipment components (such as bags and connectors) used in place of traditional stainless steel.
**Local Context:** Reduces cross-contamination risks and cleaning validation requirements in biopharma facilities.

### SIP
Sterilize-in-Place / Steam-in-Place.
**Local Context:** An automated thermal method of sterilizing process lines and bioreactors using saturated steam without disassembling the system.

### SmPC
Summary of Product Characteristics.
**Local Context:** The official document approved by regulators outlining how a medicine should be used safely, forming the basis for the Package Leaflet (PIL).

### SOP
Standard Operating Procedure.
**Local Context:** Step-by-step instructions compiled by an organization to help workers carry out complex routine operations safely and consistently.

### Thought Leadership
The practice of expressing authoritative, original ideas and commentary in a specialized field to establish expertise and credibility.
**Local Context:** Highly utilized by Quality Assurance and Regulatory directors on LinkedIn to build site and personal authority.

### Transfection
The process of deliberately introducing nucleic acids into eukaryotic cells to alter their genetic makeup.
**Local Context:** Crucial step in developing host cell lines for recombinant biomanufacturing.

### Upstream Processing
The initial stages of bioprocessing including cell line selection, media preparation, cell inoculation, and growth in bioreactors.
**Local Context:** Focuses on optimizing yields before cell harvest and purification.

### Validation
Documented evidence providing a high degree of assurance that a specific process, method, or system will consistently produce a product meeting specifications.
**Local Context:** Essential for all manufacturing equipment and analytical methods in Ireland.

### Variations
Changes made to the parameters of an approved marketing authorization after a medicine is on the market.
**Local Context:** Categorized into Type IA (minor, do not require approval), Type IB (minor, require validation), and Type II (major scientific assessment required).

### WFI
Water for Injection.
**Local Context:** High-purity water used as an excipient or vehicle for parenterals. Under EU pharmacopoeia rules, WFI must meet strict microbial and chemical limits.


## Sterile GMP Knowledge Hub Documents

### Document: FDA 21CFR 211 Complete (FDA)

# 21 CFR Parts 210 & 211 — Current Good Manufacturing Practice for Finished Pharmaceuticals: FDA Baseline CGMP Regulations: Organization, Facilities, Production Controls, Laboratory, and Records

## Subpart 0: Overview: Scope, Dual Compliance & Regulatory Architecture (§§ 210.1–211.3)

# Section 0: Overview — Scope, Dual Compliance & Regulatory Architecture

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

        

**Federal Food, Drug, and Cosmetic Act (FDCA) — Adulteration Provision:**

        

            "A drug shall be deemed to be adulterated… if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess."
              
*— FDCA §501(a)(2)(B), 21 U.S.C. §351(a)(2)(B)*
        

        

This provision is the ultimate enforcement anchor for all CGMP requirements. Any drug product that deviates from CGMP is deemed adulterated under federal law — regardless of whether it actually caused patient harm.

        

---

        

**21 CFR 210.1 — Status of Current Good Manufacturing Practice Regulations:**

        

"(a) The regulations set forth in this part and in parts 211 through 226 and parts 600 through 680 of this chapter contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength, and meets the quality and purity characteristics that it purports or is represented to possess."

        

"(b) The failure to comply with any regulation set forth in this part and in parts 211 through 226 and parts 600 through 680 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action."

        

---

        

**21 CFR 210.2 — Applicability of Current Good Manufacturing Practice Regulations:**

        

"(a) The regulations in this part and in parts 211 through 226 and parts 600 through 680 of this chapter as they may pertain to a drug; (1) apply to all persons who are manufacturers, packers, or holders of such drug marketed in the United States; (2) apply to all drugs…"

        

"(b) Where a person engages in only some operations subject to the regulations in this part, parts 211 through 226 and parts 600 through 680 of this chapter, such person shall comply with the regulations governing those operations."

        

"(c) An investigational drug for use in a Phase 1 study… is subject to legal requirements of the act relating to the safety of the drug product… [The regulations in part 211 do not apply to the manufacture of such investigational drug for human use, except where the investigational drug has been made available for a Phase 2 or Phase 3 investigation…]"

        

---

        

**21 CFR 210.3 — Definitions:**

        

The following definitions apply to Parts 210 through 226 and Parts 600 through 680 unless the context otherwise requires:

        
            Batch
            A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. *(§210.3(b)(2))*

            Lot
            A batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. *(§210.3(b)(10))*

            Lot number, control number, or batch number
            Any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of drug product or other material can be determined. *(§210.3(b)(11))*

            Component
            Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product. *(§210.3(b)(3))*

            Drug product
            A finished dosage form, for example, tablet, capsule, solution, etc., that contains an active drug ingredient generally, but not necessarily, in association with inactive ingredients. The term also includes a finished dosage form that does not contain an active ingredient but is intended to be used as a placebo. *(§210.3(b)(4))*

            Drug substance
            An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or other animals. The term includes those parts of the molecule that impart the activity and may be modified to form salts, esters, or other noncovalent derivatives used as formulated intermediates. Drug substance does not include intermediates used in the synthesis of such ingredient. *(§210.3(b)(7))*

            Fiber
            Any particulate contaminant with a length at least three times greater than its width. *(§210.3(b)(8))*

            Non-fiber releasing filter
            Any filter, which after any appropriate pretreatment such as washing or flushing, will not release fibers into the component or drug product that is being filtered. All filters composed of asbestos are deemed to be fiber releasing filters. *(§210.3(b)(13))*

            In-process material
            Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product. *(§210.3(b)(9))*

            Strength
            (1) The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or (2) The potency, that is, the therapeutic activity of the drug product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference to a standard). *(§210.3(b)(16))*

            Theoretical yield
            The quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular drug product, based upon the quantity of components to be used, in the absence of any loss or error in actual production. *(§210.3(b)(17))*

            Actual yield
            The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular drug product. *(§210.3(b)(1))*

            Percentage of theoretical yield
            The ratio of the actual yield (at any appropriate phase of manufacture, processing, or packing of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage. *(§210.3(b)(14))*

            Active ingredient
            Any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect. *(§210.3(b)(7) — see also drug substance definition)*

            Inactive ingredient
            Any component other than an active ingredient. *(§210.3(b)(8) cross-reference)*

            Acceptance criteria
            Numerical limits, ranges, or other criteria for acceptance of the results of analytical procedures. While this specific term is defined in ICH Q6A and referenced throughout Part 211 (particularly §§211.160, 211.165, 211.194), Part 210.3 provides the foundational framework under which specification criteria are understood. Acceptance criteria must be established, documented, and consistently applied. *(see §211.160(b))*

            Expiration date / Expiry
            The date placed on the label of a drug product designating the time during which a batch of the product is expected to remain within the approved shelf life specifications if stored under defined conditions, and after which it must not be used. Part 211 §211.137 requires expiration dating for drug products. Expiration dating is a prerequisite for certain yield calculations and retention period determinations under §211.180(b). *(§211.137)*

            Representative sample
            A sample that consists of a number of units that are drawn based on rational criteria, such as random sampling and intended to assure that the sample accurately portrays the material being sampled. *(§210.3(b)(15))*
        

        

**Additional Definitions Cross-Referenced in Part 211 (not in §210.3, but important for operational context):**

        

            
- **Quality control unit (QU)** — defined by function in §211.22: "a unit that has the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products…"

            
- **Out-of-specification (OOS) result** — not in Part 211 text, but addressed in FDA's 2006 OOS Guidance; test result falling outside established specifications (§211.165) or acceptance criteria triggers investigation under §211.192 / §211.194

            
- **Process validation** — not defined in Part 211, but the concept underlies §§211.100, 211.110, 211.113; defined in FDA's 2011 Process Validation Guidance as collecting and evaluating data from process design through commercial production to establish scientific evidence that a process is capable of consistently delivering a quality product

## Subpart 1: Subparts A–B: Organization, Personnel & QC Unit (§§ 211.1–211.68) (§§ 211.22–211.34)

# Section 1: Subparts A–B: Organization, Personnel & QC Unit

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

        

**§ 211.22(a)** — There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

        

**§ 211.22(b)** — Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.

        

**§ 211.22(c)** — The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.

        

**§ 211.22(d)** — Adequate laboratory facilities for the testing and approval (or rejection) of drug products shall be available to the quality control unit. The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.

        

**Operational meaning of "written procedures shall be followed" (§211.22(d)):** This clause is deceptively important. It is not enough to have written QCU SOPs — those SOPs must actually be followed in practice. FDA inspectors look for consistency between stated procedure and actual practice. Examples of noncompliance: a written procedure says QCU must review all batch records within 48 hours of completion, but batch records are routinely reviewed weeks later; a SOP mandates QCU signature on all change control approvals, but unsigned change controls are found in files. Gaps between written procedure and practice frequently become Warning Letter content, not merely 483 observations.

        

            "The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company."
              
*— 21 CFR §211.22(a), contract manufacturing clause*
        

        

**Subpart A General Scope — §211.1(a)**: The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products (excluding positron emission tomography drugs) for administration to humans or animals. The failure to comply with any regulation in 21 CFR Part 211 causes a drug product to be adulterated under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.

        

**§211.3 — Definitions**: Key terms include: batch (a specific quantity of a drug or other material that is intended to have uniform character and quality); lot (a batch or a specific identified portion of a batch); component (any ingredient intended for use in the manufacture of a drug product); drug product container (any object that holds the drug product); quality control unit (any person or organizational element designated by the firm to be responsible for the duties relating to quality control).

        

**Adulteration consequence of §211.1(a):** The link between CGMP failure and drug adulteration is not merely administrative. Under Section 501(a)(2)(B) of the FD&C Act, a drug product manufactured, processed, packed, or held in conditions that do not conform to CGMP is deemed adulterated — regardless of whether the product itself has any measurable quality defect. This means a drug can be removed from the market, subjected to a recall, and trigger criminal liability for responsible persons, even if laboratory testing shows it meets all specifications. CGMP compliance is not optional because it produces good products; it is legally mandatory because its absence makes the product legally adulterated.

        

**§210 vs §211 — the regulatory relationship:** 21 CFR Part 210 establishes the general CGMP framework and the consequence of non-compliance (adulteration). 21 CFR Part 211 provides the detailed operational requirements. Part 210 §210.2(a) states that the failure to comply with Part 211 constitutes a failure to comply with Part 210 as well — so both parts are triggered together in any enforcement action. Understanding this dual-part structure is important when reading FDA Warning Letters, which may cite both §210 and §211 violations arising from the same observation.

## Subpart 2: Subparts C–D: Buildings, Facilities & Equipment (§§ 211.42–211.72) (§§ 211.42–211.72)

# Section 2: Subparts C–D: Buildings, Facilities & Equipment

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

        

**§ 211.42(a)** — Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.

        

**§ 211.42(b)** — Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.

        

**§ 211.42(c)** — Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mix-ups during the course of the following procedures:

        

            
- (1) Receipt, identification, storage, and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;

            
- (2) Holding of rejected components, drug product containers, closures, and labeling before disposition;

            
- (3) Storage of released components, drug product containers, closures, and labeling;

            
- (4) Storage of in-process materials;

            
- (5) Manufacturing and processing operations;

            
- (6) Packaging and labeling operations;

            
- (7) Quarantine storage before release of drug products;

            
- (8) Storage of drug products after release;

            
- (9) Control and laboratory operations;

            
- (10) Aseptic processing, which includes as appropriate:
                

                    
    - (i) Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable;

                    
    - (ii) Temperature and humidity controls;

                    
    - (iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar;

                    
    - (iv) A system for monitoring environmental conditions;

                    
    - (v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions;

                    
    - (vi) A system for maintaining any equipment used to control the aseptic conditions.

                

            

        

        

**§ 211.42(d)** — Operations relating to the manufacture, processing, and packing of penicillin shall be performed in facilities separate from those used for other drug products for human use.

        

            "An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar."
              
*— 21 CFR §211.42(c)(10)(iii), the CGMP legal basis for HEPA in aseptic areas*

## Subpart 3: Subparts E–F: Components, Production Controls & Sterile Operations (§§ 211.80–211.115) (§§ 211.80–211.115)

# Section 3: Subparts E–F: Components, Production Controls & Sterile Operations

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

        

**§ 211.80 General requirements.**  

        There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.

        

**§ 211.82 Receipt and storage of untested components, drug product containers, and closures.**

        

(a) Upon receipt and before testing or examination, each lot of components, drug product containers, and closures shall be quarantined until tested or examined, as appropriate, and released for use.

        

(b) Components, drug product containers, and closures shall be stored under quarantine until they have been tested or examined, as appropriate, and released. Storage within the area used for components, drug product containers, and closures that have been released is permissible if the components are adequately identified as to their status.

        

**§ 211.84 Testing and approval or rejection of components, drug product containers, and closures.**

        

(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.

        

(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels, and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by §211.170.

        

(c) Samples shall be examined and tested as follows:

        

            
- (1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.

            
- (2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test methods at appropriate intervals.

            
- (3) Containers and closures shall be tested for conformity with all appropriate written specifications.

            
- (4) When appropriate, components shall be microscopically examined.

            
- (5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.

        

        

(d) Any lot of components, drug product containers, or closures that meets the appropriate written specifications of identity, strength, quality, and purity may be approved and released for use. Any lot of such material that does not meet such specifications shall be rejected.

        

            "At least one test shall be conducted to verify the identity of each component of a drug product."
              
*— 21 CFR §211.84(c)(1), the 100% identity testing requirement*
        

        

**§ 211.86 Use of approved components, drug product containers, and closures.**  

        Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.

        

**§ 211.87 Retesting of approved components, drug product containers, and closures.**  

        Components, drug product containers, and closures shall be retested or reexamined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit in accordance with §211.84 as necessary, e.g., after storage for long periods or after exposure to air, heat, or other conditions that might adversely affect the component, drug product container, or closure.

        

**§ 211.89 Rejected components, drug product containers, and closures.**  

        Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

## Subpart 4: Subparts G–H: Packaging, Labeling & Distribution (§§ 211.122–211.150) (§§ 211.122–211.150)

# Section 4: Subparts G–H: Packaging, Labeling & Distribution

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

## Regulatory Text

        

**§ 211.122(a)** There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.

        

**§ 211.122(b)** Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.

        

**§ 211.122(c)** Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.

        

**§ 211.122(d)** Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents shall be stored separately with suitable identification. Access to the storage area shall be limited to authorized personnel.

        

**§ 211.122(e)** Obsolete and outdated labels, labeling, and other packaging materials shall be destroyed.

        

**§ 211.122(f)** Use of gang-printed labeling for different drug products, or different strengths or net contents of the same drug product, is prohibited unless the labeling from gang-printed sheets is adequately differentiated by size, shape, or color.

        

**§ 211.122(g)** If cut labeling is used, it is subject to the following labeling identity requirements:

        

            
1. Separate storage areas or physical segregation of labels from labeling for different drug products, or for different strengths or net contents of the same drug product, to prevent mix-ups.

            
2. Identification of the drug product, strength, quantity of contents, and lot or control number of the drug product for which the labeling is intended on the containers of cut labeling.

        

        

**Labeling defined under 21 CFR 201.1 (for context):**

        

            
- Container labels (primary and secondary)

            
- Package inserts / prescribing information

            
- Carton labeling

            
- Patient medication guides

            
- Any written, printed, or graphic matter accompanying a drug product

        

        

            "Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product." — 21 CFR § 211.122(a)

## Subpart 5: Subparts I–K: Laboratory Controls, Records & Complaint Files (§§ 211.160–211.208) (§§ 211.160–211.208)

# Section 5: Subparts I–K: Laboratory Controls, Records & Complaint Files

    

    

21 CFR Parts 210 & 211 — Drug CGMP for Finished Pharmaceuticals | eCFR current as of April 2026

    

        

**§211.160(a) — General requirements:** The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.

        

**§211.160(b) — Laboratory controls shall include:**

        

            
- **(1)** Determination of conformance to applicable written specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products.

            
- **(2)** Determination of conformance to written specifications and a description of sampling and testing procedures and, where appropriate, methodological limitations for in-process materials and drug products. The sampling and testing procedures shall include the kind and number of tests; such procedures shall assure that batches of drug products meet specifications.

            
- **(3)** The establishment of the accuracy, sensitivity, specificity, and reproducibility of test methods used. Such validation and documentation may be accomplished in accordance with §211.194(a)(2).

            
- **(4)** The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.

        

        

**§211.165 — Testing and release for distribution:**

        

**(a)** For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, pending the results of such testing.

        

**(b)** There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms.

        

**(c)** Any sampling and testing plans shall be described in written procedures that shall include the method of sampling and the number of units per batch to be tested; such written procedure shall be followed.

        

**(d)** Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or rejection levels.

        

**(e)** The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with §211.194(a)(2). Appropriate controls shall be used to validate results of each test method.

        

**(f)** Drug products failing to meet established standards or specifications and any other relevant quality criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.

        

            "The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications… shall be recorded and justified."
              
*— 21 CFR §211.160(a)*

---

### Document: FDA 21CFR 820 Complete (FDA)

# 21 CFR Part 820 — Quality Management System Regulation (QMSR): FDA Quality System Requirements for Medical Device Manufacturers — 2024 QMSR Final Rule Aligned with ISO 13485:2016

## Section 0: Overview — QMSR Transition & 2024 Final Rule (§820.1 + FDA Final Rule Preamble)

# Section 0: Overview — QMSR Transition & 2024 Final Rule

    

    

21 CFR Part 820 — Quality Management System Regulation (QMSR) | FDA | eCFR current (effective Feb 2, 2026)

    

        

**Background — FDA Quality System Regulation Amendments (Final Rule, Feb 2, 2024):**

        

            "FDA is amending the device current good manufacturing practice (CGMP) requirements of the Quality System Regulation (QSR), which are codified in 21 CFR part 820. The agency is revising part 820 to incorporate by reference the international consensus standard ISO 13485:2016, Medical devices – Quality management systems – Requirements for regulatory purposes. FDA also is making other revisions to part 820 to align with the incorporated standard. This final rule renames part 820 the Quality Management System Regulation (QMSR)."
              
*— 89 FR 7496, Feb 2, 2024 (Docket No. FDA-2019-N-1947)*
        

        

**Historical Background — QSR (Quality System Regulation, 1996):**

        

The original QSR took effect on June 1, 1997. It was FDA's first comprehensive quality system standard for medical device manufacturers and was modeled on ISO 9001 (1987 version). Over the following decades, ISO 13485 emerged as the global benchmark — adopted by the EU (IVDR/MDR), Canada (CMDCAS), Japan (JPAL), and most competent authorities worldwide. This created a dual-compliance burden: U.S. manufacturers had to maintain both an FDA QSR system AND an ISO 13485 QMS simultaneously.

        

**21 CFR § 820.1 — Scope (QMSR, effective Feb 2, 2026):**

        

            "(a) The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The requirements in this part are intended to ensure that finished devices will be safe and effective and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act (the act). This part establishes basic requirements applicable to manufacturers of finished devices. If a manufacturer engages in only some operations subject to the requirements in this part, and not in others, that manufacturer need only comply with those requirements applicable to the operations in which it is engaged."
              
*— 21 CFR § 820.1(a) (paraphrased from QMSR final rule; verify against current eCFR)*
        

        

"(b) FDA does not intend this part to apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to use appropriate provisions of this regulation as guidance."

        

---

        

**Why FDA Changed the Rule — Stated Rationale:**

        

            
- **Global harmonization:** Align U.S. requirements with international standard already adopted by most competent authorities.

            
- **Reduce duplicative burden:** Manufacturers certified to ISO 13485 will have substantially overlapping QMS documentation; QMSR eliminates the need to maintain two parallel systems.

            
- **Leverage modern quality concepts:** ISO 13485:2016 incorporates risk-based thinking, lifecycle management, and software-specific provisions absent from the 1996 QSR.

            
- **FDA enforcement alignment:** FDA can inspect against ISO 13485 clauses, providing a common framework recognized by inspectors globally (MDSAP).

        

        

            "By incorporating ISO 13485 by reference, FDA is able to leverage the work of a consensus standards organization and provide requirements that are consistent with an internationally recognized QMS standard. This will reduce the compliance burden for manufacturers that maintain a quality management system consistent with ISO 13485."
              
*— FDA preamble, 89 FR 7496 (Feb 2, 2024)*

## Section 1: §820.1–820.3 — Scope, Applicability & Definitions (§§ 820.1–820.3)

# Section 1: §820.1–820.3 — Scope, Applicability & Definitions

    

    

21 CFR Part 820 — QMSR | FDA | §§ 820.1–820.3 | eCFR current as of April 2026

    

        

**§820.1(a) — General**

        

**(1)** Current good manufacturing practice (CGMP) requirements are set forth in this quality system regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The requirements in this part are intended to ensure that finished devices will be safe and effective and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act (the act). This part establishes basic requirements applicable to manufacturers of finished medical devices.

        

**(2)** If a manufacturer engages in only some operations subject to the requirements in this part, and not in others, that manufacturer need only comply with those requirements applicable to the operations in which it is engaged.

        

**(3)** With respect to class I devices, design controls apply only to those devices listed in §820.30(a)(2). This regulation does not apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to use appropriate provisions of this regulation as guidance. Manufacturers of human blood and blood components are not subject to this part, but are subject to part 606 of this chapter.

        

**§820.1(b) — Responsibility of manufacturers**  

        Each manufacturer shall be responsible for establishing and maintaining an adequate quality system with the organizational structure, responsibilities, procedures, processes, and adequate resources for assuring that devices will be safe and effective and otherwise in compliance with this part.

        

**§820.1(c) — Applicability**  

        The quality system regulation applies to any finished device manufacturer who imports, exports, repackages, or relabels a device. A manufacturer of a finished medical device must comply with this part regardless of where the device is manufactured.

        

**§820.1(d) — Foreign manufacturers**  

        If a manufacturer who offers devices for import into the United States refuses to permit or allow the completion of a Food and Drug Administration inspection of the foreign facility for the purpose of determining compliance with this part, it shall appear for purposes of section 801(a) of the act, that the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, or servicing of any devices produced at such facility that are offered for import into the United States do not conform to the requirements of section 520(f) of the act and this part and that the devices manufactured at that facility are adulterated.

        

**§820.1(e) — Exemptions or variances**  

        Any person who wishes to petition for an exemption or variance from any device quality system requirement is subject to the requirements of section 520(f)(2) of the act. Petitions for an exemption or variance shall be submitted according to the procedures set forth in §10.30 of this chapter, the FDA's administrative procedures. Guidance documents on the exemption procedures are available from CDRH.

        

            "Each manufacturer shall be responsible for establishing and maintaining an adequate quality system…for assuring that devices will be safe and effective."
              
*— 21 CFR §820.1(b)*

## Section 2: §820.4 — QMS Requirements & ISO 13485 Integration (§820.4 + ISO 13485:2016 §§4–6)

# Section 2: §820.4 — QMS Requirements & ISO 13485 Integration

    

    

21 CFR Part 820 — QMSR | FDA | §820.4 + ISO 13485:2016 §§4–6

    
    

        

## Subsection 1 — §820.4: QMS Requirements (Regulatory Text)

            

                

#### §820.4 — Quality Management System Requirements

                

*Text effective February 2, 2026 (21 CFR Part 820 QMSR Final Rule)*

                

Each manufacturer subject to this part must establish, implement, and maintain a quality management system that meets the requirements of ISO 13485:2016, *Medical devices — Quality management systems — Requirements for regulatory purposes*, incorporated by reference in §820.1(b), as supplemented by the requirements in Appendix A of this part.

            

            

### What "Incorporated by Reference" Means Legally

            

Under the Administrative Procedure Act (5 U.S.C. 552(a)) and 1 CFR Part 51, when FDA incorporates a document by reference into the Code of Federal Regulations, that document carries the full legal force of federal regulation. Compliance with ISO 13485:2016 is therefore not voluntary guidance — it is a federal legal requirement for all manufacturers subject to 21 CFR Part 820.

            

The Office of the Federal Register publishes availability notices when standards are incorporated. Manufacturers must use the specific version cited in §820.1(b) — ISO 13485:2016 — regardless of whether newer versions of the standard are released.

            

### Scope of Application

            

§820.4 applies to manufacturers of finished devices intended for commercial distribution in the United States. The term "manufacturer" is defined in §820.3 and includes any person who designs, manufactures, fabricates, assembles, or processes a finished device. Contract manufacturers (CDMOs), specification developers, and repackagers are all potentially subject depending on their role.

            

### Structure: ISO 13485 + Appendix A

            

The QMSR operates as a two-layer framework:

            

                
- **Layer 1 — ISO 13485:2016:** The baseline QMS standard providing all general requirements for documentation, management responsibility, resources, product realization, and measurement/analysis/improvement.

                
- **Layer 2 — Appendix A:** FDA-specific supplemental requirements that either modify ISO 13485 provisions or add requirements that have no ISO 13485 equivalent. Where Appendix A and ISO 13485 differ, Appendix A controls.

            

        

        

            

## — §820.4

            

                

#### QMSR

                

                

            

            

                

#### Incorporation by Reference

                

                

                

                    

                    

                    

                

            

            

                

#### +

                

                

            

            

                

#### ISO 13485

                

            

        

    

    
    
    
    

        

            

## Subsection 2 — ISO 13485:2016 Sections 4, 5, and 6

            

### Section 4 — Quality Management System

            

**4.1 General Requirements:** The organization shall establish, document, implement, and maintain a QMS and maintain its effectiveness in accordance with the requirements of the standard. The organization shall document its QMS in a manner that ensures the ability of devices and services to meet requirements and to facilitate improvement of the QMS.

            

**4.2 Documentation Requirements:**

            

                
- **4.2.1 General:** QMS documentation shall include a documented quality policy and quality objectives; a quality manual; documented procedures required by the standard; documents needed to ensure the effective planning, operation, and control of processes; records required by the standard; and any other documentation specified by applicable regulatory requirements.

                
- **4.2.2 Quality Manual:** Must include the scope of the QMS with justification for any exclusions; documented procedures or references to them; a description of the interaction between QMS processes; and a description of the structure of the documentation used in the QMS.

                
- **4.2.3 Medical Device File (Technical File/DHF):** Each device or family of devices must have a dedicated medical device file that includes documents providing a description of the device, its intended use, labeling, and specifications; procedures and records relevant to the device including design and development, production, testing, and post-market activities.

                
- **4.2.4 Control of Documents:** Procedures for approving documents for adequacy, reviewing/updating and re-approving, identifying changes and revision status, ensuring current versions at point of use, ensuring readability, identifying external documents, and preventing unintended use of obsolete documents.

                
- **4.2.5 Control of Records:** Records established to provide evidence of conformity and effective operation of the QMS shall be controlled. Retention period must be at least equivalent to the lifetime of the device as defined by the manufacturer, but not less than 2 years from the date of product release by the manufacturer, or as specified by applicable regulatory requirements.

            

            

### Section 5 — Management Responsibility

            

**5.1 Management Commitment:** Top management shall provide evidence of its commitment to development and implementation of the QMS and maintaining its effectiveness by communicating regulatory requirements, establishing quality policy and objectives, conducting management reviews, and ensuring availability of resources.

            

**5.3 Quality Policy:** Top management shall ensure the quality policy is appropriate to the organization's purpose; includes a commitment to comply with requirements and to maintain the effectiveness of the QMS; provides a framework for quality objectives; is communicated and understood at appropriate levels; and is reviewed for continuing suitability.

            

**5.4 Planning:** 5.4.1 Quality objectives must be established at relevant functions and levels, be measurable, consistent with the quality policy, and include those needed to meet product requirements. 5.4.2 Quality management system planning must maintain the integrity of the QMS when changes are planned and implemented.

            

**5.5 Responsibility, Authority, and Communication:** Top management shall define and communicate responsibilities and authorities. A management representative must be appointed with authority and responsibility for ensuring QMS processes are established and maintained, reporting on QMS performance, and promoting awareness of applicable regulatory requirements and QMS requirements throughout the organization.

            

**5.6 Management Review:** Top management shall review the QMS at planned intervals to ensure its continuing suitability, adequacy, and effectiveness. Records of management reviews shall be maintained.

            

Management review **inputs** must include: feedback, complaint handling, reporting to regulatory authorities, audit results, monitoring and measurement of processes and products, corrective and preventive actions, follow-up actions from previous reviews, changes that could affect the QMS, and recommendations for improvement.

            

Management review **outputs** must include decisions and actions related to: improvement needed to maintain the suitability, adequacy, and effectiveness of the QMS; improvement of product related to customer requirements; and resource needs.

            

### Section 6 — Resource Management

            

**6.1 Provision of Resources:** The organization shall determine and provide the resources needed to implement and maintain the QMS, maintain its effectiveness, and meet applicable regulatory requirements and customer requirements.

            

**6.2 Human Resources:** Personnel performing work affecting product quality shall be competent based on appropriate education, training, skills, and experience. The organization shall determine the necessary competence, provide training or take other actions to achieve necessary competence, evaluate the effectiveness of actions taken, ensure personnel are aware of the relevance and importance of their activities, and maintain appropriate records of education, training, skills, and experience.

            

**6.3 Infrastructure:** The organization shall determine, provide, and maintain infrastructure needed to achieve product conformity. Infrastructure includes buildings, workspace, and associated utilities; process equipment (hardware and software); and supporting services such as information systems.

            

**6.4 Work Environment and Contamination Control:** The organization shall determine and manage the work environment needed to achieve conformity to product requirements. Requirements include documented requirements for health, cleanliness, clothing of personnel if contact with product or work environment could adversely affect product quality. Arrangements for controlling contaminated or potentially contaminated products shall be documented to prevent contamination of other products, the work environment, or personnel.

        

        

            

## — ISO 13485 §4–6

            

                

#### ISO 13485 §4–6 QMS

                

                

                    

                    

                    

                    

                    

                    

                

                

            

            

                

#### §4.2

                

                

                    

                    

                    

                    

                

                

            

            

                

#### vs ——

                
                    
                        
                        
                        
                    
| | (Controlled Document) | (Record) |
| --- | --- | --- |
                    
                        
                        
                        
                    
                    
                        
                        
                        
                    
                    
                        
                        
                        
                    
                    
                        
                        
                        
                    
| | / | |
                    
                        
                        
                        
                    
| | SOPWI | CAPA |
                

            

            

                

#### 

                

                

                    

                    

                    

                

                

            

            

                

#### §6.2

                

                

                    

                    

                    

                    

                

                

            

            

                

#### §6.4 ——

                

                

                    

                    

                    

                

                

            

        

    

    
    
    
    

        

            

## Subsection 3 — Document Control & Record Retention Requirements

            

### ISO 13485 §4.2.4 — Control of Documents

            

A documented procedure shall be established to define the controls needed for:

            

                
- Approving documents for adequacy prior to issue

                
- Reviewing and updating as necessary and re-approving documents

                
- Ensuring that changes and the current revision status of documents are identified

                
- Ensuring that relevant versions of applicable documents are available at points of use

                
- Ensuring that documents remain legible and readily identifiable

                
- Ensuring that documents of external origin are identified and their distribution controlled

                
- Preventing the unintended use of obsolete documents, and applying suitable identification to them if they are retained for any purpose

            

            

The organization shall prevent the deterioration or loss of documents. Changes to documents shall be reviewed and approved either by the original approving function or another designated function that has access to pertinent background information upon which to base its decisions.

            

### ISO 13485 §4.2.5 — Control of Records

            

Records shall be established and maintained to provide evidence of conformity to requirements and of the effective operation of the QMS. Records shall remain legible, readily identifiable, and retrievable. A documented procedure shall be established to define the controls needed for:

            

                
- Identification of records

                
- Storage and protection of records

                
- Retrieval of records

                
- Retention time of records

                
- Disposition of records

            

            

The organization shall retain records for at least the period equivalent to the lifetime of the medical device as defined by the organization, but not less than 2 years from the date of product release by the manufacturer, or as otherwise specified by applicable regulatory requirements.

            

### FDA Retention Requirement (Appendix A / QMSR)

            

FDA's record retention requirement for device history records (DHRs), device master records (DMRs), and quality system records is more specific than ISO 13485's baseline. Under the QMSR, records must be retained for a period equivalent to the design and expected life of the device, but in no case less than 2 years from the date of release of the device for commercial distribution by the manufacturer.

            

The practical calculation: identify the expected lifetime of the device (e.g., a reusable surgical instrument with 10-year expected service life), add 2 years, and that is the minimum retention period. For many implantable devices with long service lives (cardiac pacemakers, orthopedic implants), this calculation can extend retention requirements to 15–25+ years.

        

        

            

## —

            

                

#### §4.2.4

                

                

                    

                    

                    

                    

                    

                    

                    

                

            

            

                

#### 

                

                

```

```

                

                

            

            

                

#### Distribution Control

                

                

                    

                    

                    

                

            

            

                

#### FDA 483 ——

                

                    

                    

                    

                    

                    

                

            

        

    

    
    
    
    

        

            

## Subsection 4 — FDA Appendix A: FDA-Specific Additions and Modifications

            

Appendix A to 21 CFR Part 820 contains FDA-specific requirements that supplement ISO 13485:2016. These fall into two categories: (1) requirements that modify or clarify how ISO 13485 provisions apply in the US context, and (2) requirements with no ISO 13485 equivalent that reflect longstanding FDA regulatory priorities.

            

### Design Controls — Mandatory Under FDA, Optional Under ISO 13485

            

ISO 13485:2016 §7.3 permits manufacturers to exclude design and development requirements if the design and development of medical devices is performed by an outside party or if the design is well established and documented. This exclusion is permissible under the international standard for manufacturers that only produce to customer-owned designs.

            

FDA's Appendix A removes this option for manufacturers subject to §820.4. Design controls are mandatory for all manufacturers of Class II and Class III devices, and for Class I devices with design specifications. A specification developer or US agent who holds the device master record cannot claim ISO 13485 §7.3 exclusion under QMSR. This is one of the most significant FDA additions.

            

### Complaint Handling — Cross-Reference to §820.198

            

While ISO 13485 §8.2.2 addresses feedback and §8.5.1 addresses complaint handling in general terms, FDA Appendix A requires compliance with the specific requirements of §820.198, which mandates:

            

                
- A formally designated unit responsible for receiving, reviewing, and evaluating complaints

                
- Written procedures for complaint handling

                
- Evaluation of every complaint to determine whether a MDR report is required under 21 CFR Part 803

                
- Complaint records to be kept at the manufacturing establishment

                
- Specific content requirements for complaint records including the device name, lot/control number, date received, name/address of complainant, nature of complaint, and investigation results

            

            

### MDR (Medical Device Reporting) Cross-References

            

Appendix A establishes explicit cross-references between QMSR quality system activities and the MDR reporting obligations under 21 CFR Part 803. The QMS must include procedures that identify when events associated with marketed devices constitute reportable events, and that ensure timely reporting within the applicable MDR timeframes (30-day for non-malfunction serious injury/death; 5-day for MDR-reportable events requiring immediate action).

            

### Language Requirements

            

For devices distributed in the United States, records, labeling, and submissions required under QMSR must be in the English language or have English translations available. This supplements ISO 13485, which does not specify a language requirement. A company whose operational language is not English must ensure English-language versions of device history records, complaint files, and quality records are accessible to FDA investigators during inspections.

            

### Correction and Removal Reporting — Cross-Reference to 21 CFR Part 806

            

Appendix A establishes that CAPA activities under ISO 13485 §8.5.2 and §8.5.3 must interface with field correction and removal reporting obligations under 21 CFR Part 806. Where a CAPA involves a device already distributed, the QMS must trigger evaluation of whether a §806 report is required.

        

        

            

## — Appendix A FDA

            

                

#### ISO 13485

                

                

                    

                    

                    

                    

                    

                

            

            

                

#### CDMO

                

                

                

                    

                    

                    

                

            

            

                

#### §820.198 ——

                

                

                    

                    

                    

                    

                    

                    

                    

                    

                

                

            

            

                

#### Appendix A FDA

                

                

            

        

    

    
    
    
    

        

            

## Subsection 5 — Comparison: ISO 13485 §5/§6 vs. Old QSR §820.20

            

The original QSR (1996/2002 Quality System Regulation) had a self-contained §820.20 addressing management responsibility. The QMSR replaces those provisions by incorporating ISO 13485 §5 and §6. The table below maps old §820.20 provisions to their QMSR equivalents.

            
                
                    
                        
                        
                        
                    
| Old QSR §820.20 Provision | QMSR / ISO 13485:2016 Equivalent | Change Summary |
| --- | --- | --- |
                
                
                    
                        ****
                        
                        
                    
| §820.20(a) — Quality policy: Top management shall establish a quality policy | ISO 13485 §5.1 + §5.3 | Substantially similar; ISO 13485 adds requirement that quality policy provide a framework for quality objectives |
                    
                        ****
                        
                        
                    
| §820.20(b)(1) — Organizational structure: Organizational chart and responsibility/authority | ISO 13485 §5.5.1 | Essentially identical; ISO 13485 uses "defined and communicated" language |
                    
                        ****
                        
                        
                    
| §820.20(b)(2) — Management representative with authority over QS | ISO 13485 §5.5.2 | ISO 13485 adds explicit requirement to promote awareness of applicable regulatory requirements |
                    
                        ****
                        
                        
                    
| §820.20(b)(3) — Adequate resources (personnel, equipment) | ISO 13485 §6.1 + §6.2 + §6.3 | ISO 13485 significantly expands this — adds competence assessment, training effectiveness evaluation, infrastructure maintenance, work environment management |
                    
                        ****
                        
                        
                    
| §820.20(c) — Management review at defined intervals with defined records | ISO 13485 §5.6 | ISO 13485 specifies mandatory inputs and outputs; old QSR was less prescriptive on content |
                    
                        ****
                        
                        
                    
| §820.20(d) — Quality planning: quality plans, quality objectives | ISO 13485 §5.4 | Essentially equivalent; ISO 13485 adds requirement for QMS planning to maintain integrity during changes |
                    
                        ****
                        
                        
                    
| §820.20(e) — Quality system procedures established and maintained | ISO 13485 §4.1 + §4.2 | ISO 13485 adds Medical Device File requirement (§4.2.3) and is more explicit about documentation hierarchy |
                    
                        **
                        
                        
                    
| No equivalent in old QSR §820.20 | ISO 13485 §6.4 — Work environment and contamination control | New explicit requirement for documenting work environment requirements and contamination control arrangements |
                
            

            

### What Stayed the Same

            

The fundamental obligations of management responsibility did not change materially: top management must be engaged, there must be a management representative, resources must be adequate, management reviews must occur, and quality policies and objectives must be established. The QMSR adopted these existing requirements wholesale via ISO 13485.

            

### What Changed — Key Additions

            

                
- **More prescriptive management review:** ISO 13485 §5.6 specifies exactly what inputs must be reviewed and what outputs must be produced — more rigorous than old §820.20(c)

                
- **Competence evaluation:** Old §820.20 required "adequate" personnel; ISO 13485 §6.2 requires formal competence determination, training, effectiveness evaluation, and records

                
- **Work environment:** Old QSR addressed this in §820.70(c); ISO 13485 §6.4 consolidates it under resource management

                
- **Medical Device File:** New concept under ISO 13485 §4.2.3 — each device or device family must have a dedicated file aggregating all relevant QMS documents and records

            

        

        

            

## —

            

                

#### QSR

                

                

                    

                    

                    

                    

                

            

            

                

#### /

                

                

                

                

                    

                    

                    

                    

                    

                    

                    

                    

                    

                

                

                

                    

                    

                    

                

            

            

                

#### ISO 13485 §4.2.3 Medical Device File——

                

                

                    

                    

                    

                    

                    

                

                

            

            

                

## Application Scenario — CDMO ISO 13485 to QMSR Gap Analysis

            

                

#### Scenario: Contract Sterile Device CDMO — ISO 13485 Certified, Entering US Market

                

**Background:** SterileMed Manufacturing (hypothetical) is a contract manufacturer based in Singapore. It holds ISO 13485:2016 certification from a Notified Body. Its client base includes EU and Japanese OEMs. It has been approached by a US Class II device company to manufacture their sterile single-use laparoscopic instruments under a Supply Agreement. This will be the CDMO's first US-distributed product.

                

**QMSR Compliance Gap Analysis — Actions Required:**

                

**1. Design Controls Assessment**

                

SterileMed's ISO 13485 certification excludes §7.3 because all device designs are customer-supplied. Under QMSR Appendix A, this exclusion is not permitted. Action required: determine the scope of design responsibility. If SterileMed only manufactures to customer-locked specifications without modification, it may argue it is not performing design and development under the QMSR definition. However, if it specifies any manufacturing process parameters that affect design outputs, it must establish design controls. Recommend: negotiate a Design Control Matrix with the US client defining where each party's responsibility begins and ends; document this in the Quality Agreement.

                

**2. Complaint Handling Upgrade to §820.198**

                

SterileMed's existing complaint procedure meets ISO 13485 §8.2.2 but lacks: (a) a formal unit designated for US complaint handling; (b) a documented MDR evaluation step for each US complaint; (c) specific record content fields required by §820.198. Action required: revise complaint procedure to add MDR evaluation logic tree, define responsible US-designated unit (can be the client company under Quality Agreement), align complaint record format with §820.198 requirements.

                

**3. English Language Records**

                

SterileMed's quality records are maintained in English and Mandarin Chinese. For FDA inspection purposes, English versions must be the primary accessible versions. Action required: confirm all Device History Records, CAPA records, complaint files, and management review records are available in English; ensure FDA investigators have access during US inspections.

                

**4. MDR Cross-Reference in QMS Procedures**

                

No existing procedure connects ISO 13485 §8.5 CAPA activities to US MDR reporting timelines. Action required: add a procedure step (or new procedure) that routes US complaint-related CAPAs through a 21 CFR Part 803 evaluation; establish 30-day and 5-day MDR clocks in the QMS.

                

**5. Record Retention Adjustment**

                

SterileMed currently retains records for device lifetime + 2 years per ISO 13485. For the US product (single-use instruments, 3-year shelf life), FDA formula yields: 3 years (device lifetime) + 2 years = minimum 5 years from release. Current retention policy likely already meets this. Action required: verify retention calculation for each product type; if any product has a device lifetime exceeding current ISO-driven retention periods, update retention schedule.

            

        

        

            

## — CDMO

            

                

#### ISO 13485  QMSR

                

                

                    

                    

                    

                    

                    

                

            

            

                

#### Quality Agreement CDMO

                

                

                    

                    

                    

                    

                    

                    

                

                

            

            

                

#### FDA ——§820.4

                

                

                    

                    

                    

                    

                    

                    

                    

                    

                    

                    

                

            

        

    

    
    
    
    

        

            

## Section Summary — Key Takeaways

            

                

#### Core Points — §820.4 and ISO 13485 Integration

                

                    
- **§820.4 is brief but comprehensive:** Manufacturers must meet ISO 13485:2016 (incorporated by reference with legal force) plus FDA Appendix A supplements. The entire QMSR regulatory framework flows from this single provision.

                    
- **ISO 13485 §4 (Documentation):** Four-tier document hierarchy; controlled documents require version management, approval, and distribution control; records require retention for device lifetime + 2 years minimum under FDA rules.

                    
- **ISO 13485 §5 (Management):** Top management accountability is formalized — quality policy, objectives, management representative, and especially management review with prescribed inputs and outputs. This is substantially more prescriptive than the old QSR.

                    
- **ISO 13485 §6 (Resources):** Competence-based training with effectiveness evaluation; infrastructure maintenance; work environment and contamination control documentation.

                    
- **Appendix A FDA additions:** Design controls cannot be excluded; complaint handling must meet §820.198 detail level including MDR evaluation; MDR and Part 806 cross-references must be built into QMS procedures; English language records must be available.

                    
- **Document vs. Record distinction:** Documents guide future action (mutable, version-controlled); records evidence past action (immutable, retention-controlled). Treating records as documents or vice versa is a common 483 finding.

                

            

        

        

            

## 

            

                

#### §820.4 + ISO 13485

                

                    

                    

                    

                    

                    

                    

                

            

            

                

####

## Section 3: Design Controls & Product Realization (FDA Additions) (ISO 13485:2016 §7 + FDA Appendix A additions)

# Section 3: Design Controls & Product Realization (FDA Additions)

    

    

21 CFR Part 820 — QMSR | FDA | ISO 13485:2016 §7 + FDA Appendix A additions

    

## Regulatory Text

        

**ISO 13485:2016 §7.3.1 — Design and Development General**  

        The organization shall document procedures for design and development. *Note: Design and development controls may be excluded when justified. See §4.2.2.*

        

**21 CFR Part 820 Appendix A (QMSR FDA-Specific Requirements) — Design Controls**  

        Notwithstanding any exclusion permitted under ISO 13485:2016 §7.3, manufacturers of finished devices subject to this part that are Class II or Class III devices, or Class I devices listed in §820.30(a)(2), shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met.

        

**§820.30(a) — Design and development planning (legacy text, now codified via ISO §7.3.2)**  

        (1) Each manufacturer of any class III or class II device, and the class I devices listed in paragraph (a)(2) of this section, shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met.

        

**§820.30(b) — Design and development planning**  

        Each manufacturer shall establish and maintain plans that describe or reference the design and development activities and define responsibility for implementation. The plans shall identify and describe the interfaces with different groups or activities that provide, or result in, input to the design and development process. The plans shall be reviewed, updated, and approved as design and development evolves.

        

**§820.30(c) — Design inputs**  

        Each manufacturer shall establish and maintain procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient. The procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements. The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s).

        

**§820.30(d) — Design outputs**  

        Each manufacturer shall establish and maintain procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements. Design output procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are essential for the proper functioning of the device are identified. Design output shall be documented, reviewed, and approved before release.

        

**§820.30(e) — Design review**  

        Each manufacturer shall establish and maintain procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device's design development. The procedures shall ensure that participants at each design review include representatives of all functions concerned with the design stage being reviewed, as well as an individual(s) who does not have direct responsibility for the design stage being reviewed, when practicable. The results of a design review, including identification of the design, the date, and the individual(s) performing the review, shall be documented in the DHF.

        

**§820.30(f) — Design verification**  

        Each manufacturer shall establish and maintain procedures for verifying the device design. Design verification shall confirm that the design output meets the design input requirements. The results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, shall be documented in the DHF.

        

**§820.30(g) — Design validation**  

        Each manufacturer shall establish and maintain procedures for validating the device design. Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions. Design validation shall include software validation and risk analysis, where appropriate. The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF.

        

**§820.30(h) — Design transfer**  

        Each manufacturer shall establish and maintain procedures to ensure that the device design is correctly translated into production specifications. These specifications shall be part of the device master record. Where a device design is transferred to an outside manufacturer, the receiving manufacturer must have access to the relevant design history file.

        

**§820.30(i) — Design changes**  

        Each manufacturer shall establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation.

        

**§820.30(j) — Design History File (DHF)**  

        Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the requirements of this part.

        

            "Design validation shall be performed under defined operating conditions on initial production units… and shall include testing of production units under actual or simulated use conditions."
              
*— 21 CFR §820.30(g), now incorporated via ISO 13485:2016 §7.3.7 + FDA Appendix A*

## Section 4: CAPA, Nonconforming Product, Complaint Files & Records (ISO 13485:2016 §8 + §820.198 + MDR cross-references)

# Section 4: CAPA, Nonconforming Product, Complaint Files & Records

    

    

21 CFR Part 820 — QMSR | FDA | ISO 13485:2016 §8 + §820.198 + MDR cross-references

    

        

**Regulatory Basis:** ISO 13485:2016 §8.3 / 21 CFR Part 820 QMSR incorporates ISO 13485 by reference. The organization shall ensure that product which does not conform to product requirements is identified and controlled to prevent its unintended use or delivery.

        

**Core Requirements:**

        

            
- **Identification:** Nonconforming product must be clearly identified — labeling, tags, physical segregation, system flags in electronic batch records.

            
- **Segregation:** Physical or system-based quarantine from conforming product. Separate holding areas with controlled access. The purpose is unambiguous — prevent mix-up, prevent inadvertent release.

            
- **Documentation:** Written records describing the nonconformity, the product involved, quantities, dates discovered, and the disposition decision with rationale.

        

        

**Disposition Decisions (§8.3.3):**

        

            
- **Rework:** Processing to bring product into conformance with specification. Requires written rework procedure, re-testing per the original acceptance criteria, and documentation that rework was performed. Rework must be evaluated for adverse effect on product.

            
- **Scrap / Destruction:** Final disposition for product that cannot be reworked or accepted. Destruction must be documented — quantity, method, personnel, date.

            
- **Use-as-Is (Deviation/Concession):** Acceptance of nonconforming product under a documented concession. Requires risk-based justification demonstrating the nonconformity does not affect safety, effectiveness, or essential performance. Customer or regulatory notification may be required. Cannot be used for safety-critical nonconformities.

            
- **Return to Supplier:** For incoming material nonconformities — documented return with supplier notification and quarantine until resolution.

        

        

**Re-verification After Rework (§8.3.4):** Product that has been reworked shall be re-inspected or re-tested against original acceptance criteria. The re-inspection results shall be documented in the DHR (Device History Record).

        

**Advisory Notice Considerations:** If a nonconformity is discovered in distributed (released) product, the organization must evaluate:

        

            
- Does it constitute a malfunction that could cause or contribute to serious injury if it recurs?  MDR evaluation required (21 CFR Part 803)

            
- Does the nonconformity affect a significant number of devices?  Field Correction / Recall consideration (21 CFR Part 806)

            
- Is an Advisory Notice to users required (ISO 13485 §8.3.4)?

        

        

**Linkage to CAPA:** A single nonconformity event may be handled as a deviation. However, if trend analysis reveals a pattern (same nonconformity type recurring), this must trigger a CAPA to address the systemic root cause. ISO 13485 §8.3  §8.5.2 linkage is mandatory and must be documented.

---

### Document: FDA 21CFR Biologics Complete (FDA)

# 21 CFR Subchapter F — Biologics (Parts 600–680): FDA Regulatory Framework for Biological Products: Licensing, Manufacturing Standards, and Lot Release Requirements

21 CFR SUBCHAPTER F — BIOLOGICS (PARTS 600–680)
Title 21, Code of Federal Regulations
Center for Biologics Evaluation and Research (CBER), FDA
Source: eCFR / Cornell LII / GovInfo — current as of April 2026

OVERVIEW AND SCOPE

21 CFR Subchapter F (Parts 600–680) is FDA's regulatory framework for biological products throughout their lifecycle — from licensing through manufacturing, testing, and postmarket reporting. This applies to vaccines, blood products, plasma-derived therapies, allergenic substances, and certain diagnostic materials. Biological products regulated under section 351 of the Public Health Service Act (PHS Act) must also comply with applicable provisions of 21 CFR Parts 210 and 211 (drug CGMPs).

Parts in Subchapter F:
- Part 600: Biological Products: General (establishment controls, deviation management, postmarket responsibilities)
- Part 601: Licensing (BLA applications, supplements, controlled change management)
- Part 610: General Biological Products Standards (safety, purity, potency, identity, labeling, lot release)
- Part 606: Current Good Manufacturing Practice for Blood and Blood Components
- Part 607: Establishment Registration and Product Listing for Blood Products
- Part 630: Requirements for Blood and Blood Products (donor eligibility)
- Part 640: Additional Standards for Blood and Blood Components (labeling, storage, identity)
- Part 660: Additional Standards for Diagnostic Substances for Laboratory Tests
- Part 680: Additional Standards for Miscellaneous Products (allergenics)

PART 600 — BIOLOGICAL PRODUCTS: GENERAL

Subpart A — General Provisions

Section 600.2 Mailing Addresses
All submissions referenced in Parts 600–680 must be sent to the Director of the Center for Biologics Evaluation and Research (CBER) or Center for Drug Evaluation and Research (CDER), depending on product type.

Section 600.3 Definitions
Key definitions used throughout Subchapter F:

(a) Act — The Public Health Service Act (58 Stat. 682), approved July 1, 1944.
(b) Secretary — The Secretary of Health and Human Services and delegated officers/employees.
(c) Commissioner of Food and Drugs — The FDA Commissioner.
(d) Center for Biologics Evaluation and Research — FDA's CBER division.
(e) State — A State, District of Columbia, Puerto Rico, or Virgin Islands.
(f) Possession — Includes Puerto Rico and Virgin Islands.
(g) Products — Encompasses biological products and trivalent organic arsenicals.
(h) Biological product — "A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings." A protein is any alpha amino acid polymer with a specific, defined sequence greater than 40 amino acids in size.
(i) Trivalent organic arsenicals — Arsphenamine derivatives applicable to disease prevention/treatment in humans.
(j) Applicable to prevention/treatment/cure — Includes diagnostic use via administration or application.
(k) Proper name — The licensed product designation on packaging.
(l) Dating period — Period where product can reasonably yield specific results.
(m) Expiration date — Calendar date/time marking the dating period's end.
(n) Standards — Specifications and procedures for establishments or manufacturing.
(o) Continued — Applied to product safety, purity, potency during dating period.
(p) Safety — "The relative freedom from harmful effect to persons...when prudently administered..."
(q) Sterility — Freedom from viable contaminating microorganisms (per § 610.12).
(r) Purity — Relative freedom from extraneous matter, moisture, volatile/pyrogenic substances.
(s) Potency — "The specific ability or capacity of the product...to effect a given result."
(t) Manufacturer — Legal entities engaged in licensed product manufacture or license applicants assuming compliance responsibility.
(u) Manufacture — Steps in product propagation including "filling, testing, labeling, packaging, and storage."
(v) Location — Buildings, equipment, animals, and personnel within manufacturer's designated area.
(w) Establishment — Same meaning as "facility" per Public Health Service Act § 351.
(x) Lot — "That quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel."
(y) Filling — Final containers identical and filled from same bulk lot without integrity-affecting changes.
(z) Process — Manufacturing steps affecting product safety, purity, or potency.
(aa) Selling agent or distributor — Persons distributing licensed products other than retail.
(bb) Container — "The immediate unit, bottle, vial, ampule, tube, or other receptacle containing the product."
(cc) Package — Immediate carton, wrapper, and labeling with enclosed container contents.
(dd) Label — "Any written, printed, or graphic matter on the container or package."
(ee) Radioactive biological product — Products labeled with or intended for radionuclide labeling.
(ff) Amendment — Submission revising/modifying pending license applications.
(gg) Supplement — Request approving changes in approved license applications.
(hh) Distributed — Biological product leaving manufacturer's control.
(ii) Control — Responsibility for maintaining continued product safety, purity, potency, and regulatory compliance.
(jj) Assess the effects of the change — Evaluating manufacturing changes on product identity, strength, quality, purity, and potency.
(kk) Specification — "The quality standard (i.e., tests, analytical procedures, and acceptance criteria)."
(ll) Complete response letter — FDA communication describing deficiencies in license applications.
(mm) Resubmission — Applicant submission addressing all complete response letter deficiencies.

Subpart B — Establishment Standards

Section 600.10 Personnel
Personnel must possess "capabilities commensurate with their assigned functions, a thorough understanding of the manufacturing operations" they perform, and receive proper training. Facilities must include professionally trained persons necessary for competent performance of all manufacturing processes.

Restriction categories:
(b) Personnel qualifications — Training and experience requirements for all manufacturing staff.
(c)(1) Product safety — Individuals whose presence could "affect adversely the safety and purity of a product" face exclusion from manufacturing areas during active production.
(c)(2) Sterile operations — Those performing sterile work must don "clean or sterilized protective clothing and devices" sufficient to prevent product contamination.
(c)(3) Pathogenic work — Personnel handling human pathogens or spore-forming microorganisms, or caring for animals, must either be excluded from other manufacturing areas or change outer garments and footwear before entering such spaces.
(c)(4) Live vaccine areas — The strictest rules apply here. Personnel cannot enter live vaccine areas after working with other infectious agents the same day. Only essential personnel are permitted during active work. Street clothing must be replaced with laboratory attire. Animal care workers cannot contact other animals during their shift.

Section 600.11 Physical Establishment, Equipment, Animals, and Care
Physical establishment, equipment, animals, and care must be adequate for licensed product manufacturing, including appropriate environmental controls, sanitation programs, and maintenance of equipment in a condition that will prevent contamination.

Section 600.12 Records
"Records shall be made, concurrently with the performance, of each step in the manufacture and distribution of products, in such a manner that at any time successive steps in the manufacture and distribution of any lot may be traced by an inspector."

Key requirements:
- Records must be legible and indelible
- Must identify the person immediately responsible
- Include dates of the various steps
- Be as detailed as necessary for clear understanding by one experienced in product manufacture
- Records must include all relevant information for lot traceability

Section 600.13 Retention Samples
Retain sufficient quantities from each lot of each product released for distribution to permit reexamination and retesting if needed. Retention samples must be maintained under conditions that will maintain product integrity.

Section 600.14 Reporting of Biological Product Deviations by Licensed Manufacturers
Who must report: Licensed manufacturers holding a biological product license who had control over the product when the deviation occurred. This applies even when manufacturing steps are contracted to others, provided procedures exist for receiving information about deviations and adverse events.

Exceptions:
- In vitro diagnostic product manufacturers (report under Part 803)
- Blood and blood component manufacturers (report under § 606.171)
- Source plasma manufacturers reporting deviations during plasma manufacture (report under § 606.171)

What must be reported: Events associated with manufacturing, testing, processing, packing, labeling, storage, holding, or distribution if the event:
- Represents a deviation from CGMP, applicable regulations, specifications, or established standards
- Represents an unexpected or unforeseeable event affecting safety, purity, or potency
- Occurs in your facility or contracted facilities
- Involves a distributed biological product

Reporting timeline: "You should report a biological product deviation as soon as possible but you must report at a date not to exceed 45-calendar days from the date you acquire information reasonably suggesting that a reportable event has occurred."

Submission: Form FDA-3486, submitted to CBER or CDER depending on product type.

Section 600.15 Temperatures During Shipment
Products requiring refrigeration must be maintained at appropriate temperatures during shipment. Biological products must arrive at distribution facilities in a condition consistent with requirements for maintaining product safety, purity, and potency.

Subpart C — Establishment Inspection

Section 600.20 Inspectors
Authorized representatives of the Secretary may access and inspect any licensed establishment. Manufacturers must permit and facilitate inspection.

Section 600.21 Time of Inspection
Establishments may be inspected at reasonable times during normal business hours and at other times when warranted by the circumstances.

Section 600.22 [Reserved]

Subpart D — Reporting of Adverse Experiences

Section 600.80 Postmarketing Reporting of Adverse Experiences
Biological product license holders must promptly review and report adverse experiences from all sources — commercial marketing, postmarketing studies, scientific literature, and foreign data.

15-Day Alert Reports: Must report "serious and unexpected" adverse experiences "as soon as possible but no later than 15 calendar days from initial receipt of the information."

Periodic Reports:
- Quarterly for 3 years from license issuance, then annually
- Submitted within 30 days (quarterly) or 60 days (annual) of reporting period close

Required information — Nonvaccine products: Patient data, adverse experience details, suspect product information, reporter identification, and applicant contact details must be included in Individual Case Safety Reports (ICSRs).

Required information — Vaccine products: Patient name, address, vaccination dates, facility details, and healthcare provider information are mandated.

Electronic submission: All safety reports must be submitted electronically per FDA guidance.
Record retention: Adverse experience records must be maintained for 10 years.
Exemptions: Whole blood, blood components, and in vitro diagnostic products are excluded.
Privacy: Patient names and addresses should be coded for nonvaccine products; vaccine data become part of CDC surveillance systems.

Section 600.81 Distribution Reports
License holders must submit distribution reports containing the quantity of each product distributed in the United States during the reporting period.

Section 600.82 Notification of Permanent Discontinuance or Manufacturing Interruption
Manufacturers must notify FDA when permanently discontinuing manufacture or when manufacturing is interrupted in a manner that is likely to disrupt supply.

Section 600.90 Waivers
FDA may grant waivers to specific requirements upon written request with adequate justification.

PART 601 — LICENSING

Subpart A — General Provisions

Section 601.2 Biologics License Application Requirements
Manufacturers must submit applications to the Director of CBER or CDER. Applications require:
- Data from nonclinical laboratory and clinical studies demonstrating product meets safety, purity, and potency requirements
- Statements on compliance with parts 58 (nonclinical labs) and 56 (institutional review boards)
- Manufacturing methods and stability data
- Product samples and representative lot test results
- Label specimens and container information
- All manufacturing location addresses
- Financial disclosure statements per part 54
- Environmental assessment or categorical exclusion claim

Special categories exempt from certain requirements (§§ 600.10–600.13, 610.53, 610.62):
- Therapeutic DNA plasmid products
- Synthetic peptide products (40 or fewer amino acids)
- Monoclonal antibodies for in vivo use
- Recombinant DNA-derived therapeutic products

Withdrawal reporting: License holders must report product withdrawals within 30 working days, including holder name, product name, BLA number, National Drug Code, and expected withdrawal date.

Master files: Generally, biologics applications cannot incorporate drug substance information by reference, with limited exceptions for legacy applications and non-biological combination product components.

Section 601.4 Licenses — Issuance and Denial
FDA will issue a license when the application demonstrates compliance with applicable requirements. FDA may deny a license application if requirements are not met.

Section 601.6 Suspension of License
FDA may suspend a biologics license if continued manufacturing presents an imminent hazard to public health.

Section 601.7 Revocation of License
FDA may revoke a biologics license for cause, including failure to maintain manufacturing standards, fraudulent application, or safety/purity/potency failures.

Section 601.8 Misbranding
A biological product is misbranded if its label or labeling is false or misleading in any particular.

Section 601.9 Licenses — Products; Procedures
Describes procedures for licensing biologics manufactured at multiple locations, by multiple manufacturers, or under cooperative manufacturing arrangements.

Subpart C — Biologics Licensing

Section 601.12 Changes to an Approved Application
Holders of approved applications must describe and report all changes using supplements or annual reports:

(a) Major changes — require Prior Approval Supplement (PAS) before distribution. Include changes that have a substantial potential to have an adverse effect on safety or effectiveness.
(b) Moderate changes — require Supplement — Changes Being Effected (CBE) or CBE-30 before or 30 days prior to distribution.
(c) Minor changes — can be reported in annual report (Changes in Annual Report, CAR).

Section 601.14 Regulatory Submissions in Electronic Format
Electronic submissions to CBER are required for biologics license applications.

Section 601.20 Biologics Licenses — Issuance
License issuance is contingent on FDA inspection of the manufacturing facility and documentation that manufacturing standards are met.

Section 601.25 Review Procedures
FDA review procedures for biologics license applications including standard and priority reviews.

Section 601.26 Acceptance Review for Combination Products with a Biological Product Primary Mode of Action
Acceptance review procedures for combination products.

Section 601.27 Pediatric Studies
Requirements for conducting pediatric studies and reporting results.

Section 601.28 Annual Reports
License holders must submit annual reports containing information about changes to the product, manufacturing, and labeling since the last annual report.

Section 601.29 Withdrawal of Application
Applicants may withdraw pending applications.

Subpart D — Diagnostic Radiopharmaceuticals

Sections 601.30–601.35 — Standards specific to diagnostic radiopharmaceutical products, including imaging agents labeled with radioisotopes.

Subpart E — Accelerated Approval

Sections 601.40–601.46 — Accelerated approval pathway for biological products for serious or life-threatening illnesses based on a surrogate endpoint or intermediate clinical endpoint reasonably likely to predict clinical benefit. Post-approval studies are required to verify clinical benefit.

Subpart F — Confidentiality of Information

Sections 601.50–601.51 — Trade secret and proprietary data protections for information submitted in biologics license applications.

Subpart G — Postmarketing Studies

Section 601.70 — Requirements for postmarketing studies committed to as a condition of approval. Includes annual status reporting.

Subpart H — Approval When Human Efficacy Studies Are Not Ethical or Feasible

Sections 601.90–601.95 — The "Animal Rule" — allows approval based on animal model efficacy data when human efficacy trials are not feasible (e.g., chemical or biological threat agents). Rigorous manufacturing standards apply.

PART 610 — GENERAL BIOLOGICAL PRODUCTS STANDARDS

Subpart A — Release Requirements

Section 610.1 Required Tests
No product may be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. The following standards apply to all biological products unless otherwise specified.

Section 610.2 Release of Products: Failure to Meet Standards
Products failing to meet applicable standards may not be released. FDA must be notified and product must be quarantined or destroyed per applicable procedures.

Subpart B — General Provisions (Test Requirements)

Section 610.9 Equivalent Methods and Processes
Modifications to required test methods or manufacturing processes are permitted only when:
(a) The applicant presents evidence through a license application or supplement demonstrating "the modification will provide assurances of the safety, purity, potency, and effectiveness" equal to or greater than the original specified method.
(b) Written approval is obtained from the Director of CBER or CDER.

Section 610.10 Potency
"Tests for potency shall consist of either in vitro or in vivo tests, or both, which have been specifically designed for each product so as to indicate its potency in a manner adequate to satisfy the interpretation of potency given by the definition in § 600.3(s) of this chapter."

Key requirements:
- Test type options: in vitro, in vivo, or combined testing
- Product-specific design: each biological product requires customized testing protocols
- Tests must align with the potency definition in § 600.3(s): "The specific ability or capacity of the product to effect a given result"
- Limits of potency shall be set forth in the standards for each product

Section 610.11 General Safety
Each lot of biological product must be tested for general safety. A product fails general safety requirements if it contains harmful or toxic substances not related to its intended use.

Section 610.12 Sterility
Manufacturers must perform sterility testing of each lot of each biological product's final container material or other material as approved in the biologics license application.

Test validation: The sterility test must be "validated to demonstrate that the test is capable of reliably and consistently detecting the presence of viable contaminating microorganisms."

Written procedures required:
- Test method description
- Sampling methodology
- Lot acceptance/rejection specifications
- Sample considerations: lot size, manufacturing duration, container configuration, inhibitor/preservative concentrations, appropriate product dilution factors

Testing methods:
- Culture-based methods: specified media composition, growth-promotion testing, and incubation conditions required
- Non-culture-based methods: defined test parameters, acceptance criteria, and controls required

Repeat testing: If initial tests detect microorganisms, one repeat test is permitted only if laboratory error or faulty materials caused the positive result.

Exceptions: Certain products (whole blood, vaccines, reagents) are exempt. The FDA Director may waive requirements if route of administration or preparation method precludes sterility concerns.

Section 610.13 Purity
Each lot of biological product must be "free of extraneous material except that which is unavoidable in the manufacturing process" as approved in the biologics license application.

(a) Residual moisture testing: Each dried product lot must undergo testing for residual moisture and meet established limits per approved methods. The CBER Director may exempt this test if unnecessary for product safety, purity, and potency.

(b) Pyrogenic substances testing: All final containers intended for injection must be tested for pyrogenic substances via intravenous rabbit injection. Exemptions apply to certain products including vaccines, plasma, and diagnostic substances.

Section 610.14 Identity
"The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations" are complete.

Test specificity: The identity test must be "specific for each product in a manner that will adequately identify it as the product designated on final container and package labels and circulars, and distinguish it from any other product being processed in the same laboratory."

Acceptable methods for establishing identity:
- Physical or chemical characteristics of the product
- Inspection by macroscopic or microscopic methods
- Specific cultural tests
- In vitro or in vivo immunological tests

Section 610.15 Constituent Materials
Constituent materials used in manufacturing, including media, diluents, and adjuvants, must meet established standards and not adversely affect product safety, purity, or potency.

Section 610.16 Conformity with Standards
Each lot must conform to applicable standards for the product as established in the biologics license application.

Section 610.17 Jurisdictional Blood Requirements
Where applicable, blood used in manufacturing must meet applicable donor eligibility requirements.

Section 610.18 Cultures
Storage and maintenance: Cultures must be "stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics" while ensuring contamination-free conditions.

Identity and verification: Each culture requires clear source identification. New stock preparations need complete strain identification; seed lots must have lot numbers and preparation dates. "Periodic tests shall be performed as often as necessary to verify the integrity of the strain characteristics and freedom from extraneous organisms," with results documented.

Cell lines requirements: Cell lines used in manufacturing must be:
- Identified by history
- Described regarding cytogenetic characteristics and tumorigenicity
- Characterized for in vitro growth traits and life potential
- Tested for detectable microbial agents

The Director of CBER or CDER may require additional safety, purity, and potency tests. Primary cell cultures not subcultivated or subcultivated minimally are exempt.

Records: Appropriate records "shall be prepared and maintained as required" per 21 CFR §§ 211.188 and 211.194.

Subpart E — Testing Requirements for Relevant Transfusion-Transmitted Infections

Sections 610.39–610.48
Testing requirements for transfusion-transmitted infections applicable to blood and blood components. Each unit must be tested for specified infectious disease markers (HIV, HCV, HBV, syphilis, etc.) using FDA-licensed or approved tests. Reactive test results require quarantine and notification procedures.

Subpart F — Dating Period Limitations

Section 610.50 Selling, Barter, or Exchange
No product may be sold, bartered, or exchanged after its expiration date.

Section 610.53 Dating Periods for Specific Products
Dating periods (expiration dating) are established for individual biological products through the license application. Products must be labeled with expiration dates and may not be distributed beyond the established dating period unless additional testing demonstrates continued conformance.

Subpart G — Labeling Standards

Section 610.60 Container Label
Biological product containers capable of bearing a complete label must display:
1. Product name (proper designation)
2. Manufacturer information (name, address, and license number)
3. Lot identification (lot number or equivalent identifier)
4. Expiration date
5. Dosage (recommended individual dose for multi-dose containers)
6. Prescription designation ("Rx only" statement for prescription biologicals)
7. Medication Guide required statement per 21 CFR 208.24(d) when applicable

Alternative label scenarios:
- Package label (§ b): If container lacks packaging, all package label requirements transfer to the container itself
- Partial labels (§ c): For containers with space limitations, include minimum information: product name, lot identification, manufacturer name, and recommended dose. These must be placed within outer packaging containing full package label details
- No container label (§ d): Unlabelable containers may omit label information if enclosed in properly labeled outer packaging
- Visual inspection (§ e): A sufficient uncovered container area must remain accessible along the full length or circumference to permit content inspection

Section 610.61 Package Label
The package label must include all information required on the container label plus:
- Number of containers in the package (if multiple)
- Volume of product in container
- Storage temperature requirements
- Diluent information if applicable
- Name and address of the distributor if different from manufacturer
- Statement of ingredients where required

Section 610.62 Proper Name; Distinguishing Name
The proper name of the product must appear prominently on the label and be the name used throughout all labeling.

Section 610.63 Lot Number
The lot number must be a unique identifier traceable to manufacturing history of that specific lot.

Section 610.64 Expiration Date
The expiration date must appear in an unambiguous format and must correlate with the dating period established in the license.

Section 610.65 Recommended Storage Temperature
The label must state the required storage temperature to maintain product safety, purity, and potency throughout the dating period.

Section 610.67 Labeling Changes
Changes to labeling must be approved per 21 CFR 601.12 prior to implementation.

Section 610.68 Exemptions and Alternatives
FDA may grant exemptions to specific labeling requirements upon written request with adequate justification.

PARTS 606, 607, 630, 640, 660, AND 680 — SPECIALTY PRODUCT REQUIREMENTS

Part 606 — Current Good Manufacturing Practice for Blood and Blood Components
Establishes CGMP requirements specific to blood and blood component manufacturing. Includes requirements for personnel, equipment, supplies, facilities, laboratory controls, distribution, and production and process controls. Blood deviation reporting under § 606.171 is analogous to § 600.14 for other biological products.

Part 607 — Establishment Registration and Product Listing for Manufacturers of Human Blood and Blood Products
Registration requirements for blood establishments with FDA. Manufacturers must register and list their products biannually.

Part 630 — Requirements for Blood and Blood Products
Establishes donor eligibility requirements and testing procedures for blood and blood components. Includes requirements for donor screening, deferral, and reinstatement. All donors must be tested for specified transfusion-transmitted infections before collected blood is used.

Part 640 — Additional Standards for Human Blood and Blood Components
Additional product-specific standards for various blood components (Whole Blood, Red Blood Cells, Platelets, Fresh Frozen Plasma, Cryoprecipitate, etc.) covering filling, labeling, storage, dating, and identity requirements.

Part 660 — Additional Standards for Diagnostic Substances for Laboratory Tests
Standards for diagnostic substances used in laboratory testing, including antigen and antibody reagents. Requirements for identity, purity, potency, and labeling specific to diagnostic applications. Method validation and defensible analytical decision-making requirements.

Part 680 — Additional Standards for Miscellaneous Products
Additional standards for allergenic products (allergy testing and immunotherapy), including standardized identity, controlled labeling, and manufacturing evidence requirements. Allergen extracts must meet identity, potency, and safety standards.

APPLICABILITY TO STERILE BIOLOGICS CDMO OPERATIONS

For a contract development and manufacturing organization (CDMO) involved in sterile biologics fill-finish:

Primary applicable regulations:
- Part 600 (establishment standards, deviation reporting, adverse experience reporting) applies in full
- Part 601 (licensing) applies to the product license holder; CDMO must support BLA compliance through contract manufacturing agreements and quality agreements
- Part 610 (general standards) — sterility (610.12), purity (610.13), identity (610.14), potency (610.10), and labeling (610.60–610.68) standards apply to every lot released

CDMO-specific considerations:
- Deviation reporting (600.14) applies to the license holder, but CDMO must have systems to detect deviations and notify license holders within timeframes supporting the 45-day reporting window
- Manufacturing changes (601.12) must be coordinated with license holders — CDMO-initiated changes require sponsor approval before implementation
- Quality agreements must define responsibilities for lot release testing, deviation investigation, CAPA, and regulatory reporting
- Records (600.12) maintained by the CDMO must support license holder's traceability requirements
- Sterility testing (610.12) validation must be product-specific and approved in the BLA — CDMO must validate for each product
- Identity testing (610.14) must distinguish products manufactured in the same laboratory — particularly important in multi-product facilities

---

### Document: FDA 21CFR Part11 Complete (FDA)

# 21 CFR Part 11 — Electronic Records; Electronic Signatures: FDA Requirements for Electronic Records and Electronic Signatures in Regulated Industries

21 CFR PART 11 — ELECTRONIC RECORDS; ELECTRONIC SIGNATURES
Source: eCFR / Cornell LII (current through April 2026)
URL: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-11

================================================================================
OVERVIEW AND REGULATORY CONTEXT
================================================================================

21 CFR Part 11 was promulgated by the FDA in 1997 (62 FR 13430) and establishes
criteria under which the agency considers electronic records and electronic
signatures trustworthy, reliable, and generally equivalent to paper records and
handwritten signatures executed on paper. It applies to all FDA-regulated
industries: pharmaceuticals, biologics, medical devices, food, cosmetics, and
tobacco.

The regulation responds to the rapid adoption of computerized systems in regulated
industries during the 1990s. Before Part 11, no clear federal standard existed for
the acceptability of electronic records as alternatives to paper records required
by FDA regulations.

FDA 2003 GUIDANCE ON SCOPE AND APPLICATION
In August 2003, FDA issued a guidance document "21 CFR Part 11; Electronic
Records; Electronic Signatures — Scope and Application" which significantly
narrowed the agency's enforcement focus. Key points:

1. PREDICATE RULE CONCEPT: Part 11 applies only to electronic records that FDA
   regulations require to be maintained or submitted and where the regulated
   entity chooses to use electronic records instead of paper records. The
   underlying FDA regulation requiring the record is called the "predicate rule"
   (e.g., 21 CFR 211.68 — computers in drug manufacturing; 21 CFR 211.186 —
   master production and control records; 21 CFR 211.188 — batch production
   records).

2. ENFORCEMENT DISCRETION: FDA exercises enforcement discretion regarding
   certain Part 11 requirements for:
   - Legacy systems installed before Part 11's effective date (August 20, 1997)
     if those systems use paper as the official record supplemented by
     electronic records
   - Validation requirements for legacy systems that are compliant in all
     other aspects

3. WHAT PART 11 DOES NOT REQUIRE: Part 11 does NOT mandate that any entity
   use electronic records or electronic signatures. It only governs the
   standards IF electronic records/signatures are used.

4. RISK-BASED APPROACH: FDA encourages a risk-based approach to Part 11
   compliance. Not all predicate rule records carry equal risk. The investment
   in controls should be commensurate with the risk to product quality and
   patient safety.

PART 11 AND ALCOA+
Part 11's requirements align directly with ALCOA+ data integrity principles:
- Attributable: §11.10(g) authority checks; §11.50 signature manifestations
- Legible: §11.10(b) ability to generate readable copies
- Contemporaneous: §11.10(e) time-stamped audit trails
- Original: §11.10(e) computer-generated audit trails (not user-modifiable)
- Accurate: §11.10(a) system validation

The "+" elements (Complete, Consistent, Enduring, Available) are addressed by:
- Complete/Consistent: §11.10(e) audit trail captures ALL operator actions
- Enduring: §11.10(c) records protected for retention period
- Available: §11.10(b) copies available for FDA review/inspection

CDMO RELEVANCE
In a pharmaceutical CDMO context, Part 11 applies to:
- Electronic Batch Records (eBR): replacing paper batch manufacturing records
  required by 21 CFR 211.188
- LIMS (Laboratory Information Management Systems): electronic lab data
  required by 21 CFR 211.194
- SCADA/DCS (Supervisory Control and Data Acquisition / Distributed Control
  Systems): process control data required by 21 CFR 211.68
- Building Management Systems (BMS): environmental monitoring temperature/
  humidity data for sterile manufacturing
- Computer-assisted manufacturing equipment: automated dispensing systems,
  in-line inspection systems, automated visual inspection
- MES (Manufacturing Execution Systems): electronic work instructions and
  confirmations

================================================================================
SUBPART A — GENERAL PROVISIONS
§§ 11.1 — 11.3
================================================================================

§ 11.1 SCOPE

(a) The regulations in this part set forth the criteria under which the agency
considers electronic records, electronic signatures, and handwritten signatures
executed to electronic records to be trustworthy, reliable, and generally
equivalent to paper records and handwritten signatures executed on paper.

(b) This part applies to records in electronic form that are created, modified,
maintained, archived, retrieved, or transmitted, under any requirements set forth
in agency regulations. This part also applies to electronic records submitted to
the agency under requirements of the Federal Food, Drug, and Cosmetic Act and
the Public Health Service Act, even if such records are not specifically
identified in agency regulations. However, this part does not apply to paper
records that are, or have been, transmitted by electronic means.

(c) Where electronic signatures and their associated electronic records meet the
requirements of this part, the agency will consider the electronic signatures
to be equivalent to full handwritten signatures, initials, and other general
signings as required by agency regulations, unless specifically excepted by
regulation(s) effective on or after August 20, 1997.

(d) Electronic records that meet the requirements of this part may be used in
lieu of paper records, in accordance with § 11.2, unless paper records are
specifically required.

(e) Computer systems (including hardware and software), controls, and attendant
documentation maintained under this part shall be readily available for, and
subject to, FDA inspection.

KEY INTERPRETATION: §11.1 does not apply to paper records simply transmitted
electronically (e.g., a scanned PDF of a paper record sent by email). The
electronic record must itself be created, modified, maintained, or archived
in electronic form.

§ 11.2 IMPLEMENTATION

(a) For records required to be maintained but not submitted to the agency,
persons may use electronic records in lieu of paper records or electronic
signatures in lieu of traditional signatures, in whole or in part, provided
that the requirements of this part are met.

(b) For records submitted to the agency, persons may use electronic records
in lieu of paper records or electronic signatures in lieu of traditional
signatures, in whole or in part, provided that:
   (1) The requirements of this part are met; and
   (2) The document or parts of a document to be submitted have been identified
       in public docket No. 92S-0251 as being the type of submission the agency
       accepts in electronic form. This docket will identify specifically what
       types of documents or parts of documents are acceptable for electronic
       submission. The agency will periodically publish in the Federal Register
       a list of the types of documents it will accept electronically.

§ 11.3 DEFINITIONS

As used in this part:

(a) Act means the Federal Food, Drug, and Cosmetic Act (sec. 201-903 of the
act (21 U.S.C. 321-394)).

(b) Agency means the Food and Drug Administration.

(c) Biometric means a method of verifying an individual's identity based on
measurement of the individual's physical feature(s) or repeatable action(s)
where those features and/or actions are both unique to that individual and
measurable.

(d) Closed system means an environment in which system access is controlled
by persons who are responsible for the content of electronic records that are
on the system.

EXAMPLE: A dedicated pharmaceutical manufacturing control system (DCS/SCADA)
where only authorized company personnel can access and whose access is managed
by the company's IT/quality team is a closed system. The company controls
both who can log in and what records are stored.

(e) Digital signature means an electronic signature based upon cryptographic
methods of originator authentication, computed by using a set of rules and a
set of parameters such that the identity of the signer and the integrity of
the data can be verified.

NOTE: Digital signatures (using cryptography like RSA or ECDSA) are a
SUBSET of electronic signatures. Not all electronic signatures are digital
signatures. PKI-based systems use digital signatures.

(f) Electronic record means any combination of text, graphics, data, audio,
pictorial, or other information representation in digital form that is created,
modified, maintained, archived, retrieved, or distributed by a computer system.

(g) Electronic signature means a computer data compilation of any symbol or
series of symbols executed, adopted, or authorized by an individual to be the
legally binding equivalent of the individual's handwritten signature.

(h) Handwritten signature means the scripted name or legal mark of an individual
handwritten by that individual and executed or adopted with the present
intention to authenticate a writing in an electronic form. The act of signing
with a writing or marking instrument such as a pen or stylus is preserved.
The scripted name or legal mark, while conventionally applied to paper, may
also be applied to other devices that capture the name or mark.

(i) Open system means an environment in which system access is not controlled
by persons who are responsible for the content of electronic records that are
on the system.

EXAMPLE: A cloud-based system accessed over the public internet, or a
third-party hosted system where the cloud provider (not the pharmaceutical
company) controls system access, is an open system. Email systems are open
systems. Systems accessed via public telecommunication infrastructure are
open systems.

OPEN vs CLOSED SYSTEM KEY DISTINCTION:
The determining factor is NOT the technology (internet vs intranet) but
WHO controls access. If the persons responsible for the electronic records
control system access  CLOSED. If access is controlled by others OPEN.

================================================================================
SUBPART B — ELECTRONIC RECORDS
§§ 11.10 — 11.30
================================================================================

§ 11.10 CONTROLS FOR CLOSED SYSTEMS

Persons who use closed systems to create, modify, maintain, or transmit
electronic records shall employ procedures and controls designed to ensure
the authenticity, integrity, and, when appropriate, the confidentiality of
electronic records, and to ensure that the signer cannot readily repudiate
the signed record as not genuine. Such procedures and controls shall include
the following:

(a) VALIDATION
Validation of systems to ensure accuracy, reliability, consistent intended
performance, and the ability to discern invalid or altered records.

Validation Scope: This encompasses Installation Qualification (IQ),
Operational Qualification (OQ), and Performance Qualification (PQ). The
depth of validation should be commensurate with risk. Systems that create,
modify, or maintain records that support product release decisions require
rigorous validation.

FDA 2003 Guidance interpretation: For legacy systems (predating August 1997),
FDA exercises enforcement discretion on validation requirements provided the
system otherwise meets Part 11. New systems must be fully validated.

Computer System Validation (CSV) requirements under §11.10(a):
- Written validation plan (VMP or CVMP)
- URS (User Requirements Specification)
- FS (Functional Specification) / DS (Design Specification)
- IQ/OQ/PQ protocols and reports
- Traceability matrix linking requirements to test scripts
- Periodic revalidation when changes occur (change control)

(b) READABLE COPIES
The ability to generate accurate and complete copies of records in both human
readable and electronic form suitable for inspection, review, and copying by
the agency.

This requirement ensures that if FDA inspectors arrive on-site, they can
receive complete, accurate, human-readable copies of all electronic records.
Systems must export records to formats accessible to the agency (PDF, CSV,
printed copies). Data migration to new systems must preserve readability of
archived records.

(c) PROTECTION OF RECORDS
Protection of records to enable their accurate and ready retrieval throughout
the records retention period.

Records must be protected from:
- Unauthorized alteration or deletion
- Data corruption from hardware failure
- Loss from disaster (backup/disaster recovery requirements)
- Degradation of storage media over time

Retention periods are defined by predicate rules (e.g., 21 CFR 211.180 —
drug records must be retained at least 1 year after drug expiry, typically
2-3 years minimum for most pharmaceutical records, up to lifetime for
biologics).

(d) LIMITING SYSTEM ACCESS
Limiting system access to authorized individuals.

Access controls implementation:
- Role-based access control (RBAC) — users assigned roles with defined
  permissions matching their job function and training
- Individual user accounts — no shared/generic accounts (except emergency
  access with appropriate controls and documentation)
- User access reviews — periodic review of user accounts and permissions
- Deprovisioning — timely removal of access when personnel change roles or leave
- Physical access controls for workstations running regulated systems

The prohibition on shared accounts is a common FDA 483 observation: "Shared
usernames/passwords observed in [LIMS/DCS/eBR system]."

(e) AUDIT TRAILS
Secure, computer-generated, time-stamped audit trails to independently record
the date and time of operator entries and actions that create, modify, or delete
electronic records. Record changes shall not obscure previously recorded
information. Such audit trail documentation shall be retained for a period at
least as long as that required for the subject electronic records and shall be
available for agency review and copying.

CRITICAL ELEMENTS OF §11.10(e) AUDIT TRAILS:
1. SECURE: Audit trails cannot be turned off, modified, or deleted by system
   users. Only system administrators with documented authorization can adjust
   audit trail settings, and such changes must themselves be logged.
2. COMPUTER-GENERATED: The system automatically creates audit entries — they
   are NOT manually entered by users. This is the core distinction from paper-
   based records where an operator writes in a logbook.
3. TIME-STAMPED: Each entry records the date and time, which should be
   synchronized to a reliable time source (network time protocol — NTP).
   Time zone documentation is important for multi-site systems.
4. INDEPENDENTLY RECORDING: The audit trail records actions independent of
   the data record itself. Audit trails cannot be part of the same file that
   can be edited.
5. CREATE/MODIFY/DELETE: ALL three operations must be captured, not just
   modifications. This means the audit trail should record:
   - Original entry (with timestamp and user ID)
   - Any change (old value  new value, reason for change, timestamp, user)
   - Any deletion (original value, reason, timestamp, user)
6. NOT OBSCURING: Changed records must show BOTH old and new values. A system
   that simply overwrites old data with new data WITHOUT capturing the original
   value does NOT meet §11.10(e).
7. RETAINED AS LONG AS THE RECORD: If a batch record must be retained for
   3 years, the audit trail for that batch record must also be retained for
   3 years.
8. AVAILABLE FOR FDA REVIEW: FDA inspectors must be able to access and copy
   audit trails during inspections.

COMMON AUDIT TRAIL DEFICIENCIES (FDA 483 OBSERVATIONS):
- Audit trail not enabled or incomplete (not capturing all events)
- Audit trail can be modified by non-privileged users
- Old values not captured (only new value recorded)
- Reason for change not required or captured
- Audit trail retention shorter than record retention period
- Audit trail not reviewed as part of quality oversight

(f) OPERATIONAL SYSTEM CHECKS
Use of operational system checks to enforce permitted sequencing of steps and
events, as appropriate.

This controls the workflow sequence in electronic systems. For example:
- In an eBR system, an operator cannot sign the "product dispensed" step
  before the "formulation complete" step
- In a LIMS, results cannot be approved before all required tests are entered
- In a DCS, a sterilization cycle cannot be released before all critical
  parameters (time, temperature, pressure) are verified within specification

(g) AUTHORITY CHECKS
Use of authority checks to ensure that only authorized individuals can use
the system, electronically sign a record, access the operation or computer
system input or output device, alter a record, or perform the operation at issue.

Authority checks go beyond access controls (§11.10d) to specifically govern:
- WHO can perform electronic signatures (only persons with validated signing
  authority in the system)
- WHO can approve specific records (e.g., only QC manager can approve
  certificate of analysis)
- WHO can modify approved records (e.g., only QA can make post-approval
  amendments with justification)

(h) DEVICE CHECKS
Use of device checks to determine, as appropriate, the validity of the source
of data input or operational instruction.

Device checks ensure that:
- Input devices (scales, pH meters, analytical instruments) are calibrated
  and verified
- Data from automated systems is validated as coming from authorized,
  functioning instruments
- Checksums or other validation methods verify data integrity during
  transmission from instruments to systems

(i) EDUCATION, TRAINING AND EXPERIENCE
Determination that persons who develop, maintain, or use electronic record/
electronic signature systems have the education, training, and experience to
perform their assigned tasks.

This mirrors 21 CFR 211.68 training requirements but specifically for computer
systems. Training must be:
- Role-specific (what the person needs to know for their specific system role)
- Documented (training records are themselves electronic records if kept in
  an LMS or HRIS)
- Current (retraining required when system changes)

(j) WRITTEN POLICIES
The establishment of, and adherence to, written policies that hold individuals
accountable and responsible for actions initiated under their electronic
signatures.

This creates the legal/administrative framework ensuring that electronic
signatures carry the same accountability weight as handwritten signatures.
SOPs must:
- Define what constitutes an electronic signature at the company
- Specify prohibited actions (sharing credentials, signing for others)
- Establish consequences for misuse (disciplinary action)
- Reference the FDA letter requirement in §11.100(c)

(k) USE OF APPROPRIATE CONTROLS FOR SYSTEMS DOCUMENTATION
Use of appropriate controls over systems documentation including:
   (1) Adequate controls over the distribution of, access to, and use of
       documentation for system operation and maintenance.
   (2) Revision and change control procedures to maintain an audit trail
       that identifies the date of, and the nature of, changes to systems
       documentation, and the individuals making the change.

Systems documentation includes:
- System Administrator Manuals
- User manuals and SOPs
- Validation documents (IQ/OQ/PQ reports)
- Computer System Validation Package

These documents must be controlled under the company's document management
system (DMS), itself typically a Part 11 compliant system.

§ 11.30 CONTROLS FOR OPEN SYSTEMS

Persons who use open systems to create, modify, maintain, or transmit electronic
records shall employ procedures and controls designed to ensure the authenticity,
integrity, and, as appropriate, the confidentiality of electronic records from
the point of their creation to the point of their receipt.

Open systems require ALL controls in §11.10 PLUS additional safeguards:
- Document encryption using appropriate encryption methods to ensure data
  cannot be read during transmission by unauthorized parties
- Use of appropriate digital signature standards (e.g., FDA-recognized
  cryptographic standards) when additional security is needed
- Additional physical security for workstations and transmission endpoints

WHY OPEN SYSTEMS NEED MORE CONTROLS:
In a closed system, the company controls who has access — physical and
logical access controls are sufficient. In an open system (accessible via
public networks), records can be intercepted during transmission. Encryption
protects confidentiality. Digital signatures protect integrity (any alteration
of the transmitted record would invalidate the digital signature).

PRACTICAL EXAMPLE: A CRO submitting clinical data to a sponsor via a cloud
platform. The CRO cannot fully control access to the cloud infrastructure
(managed by AWS, Azure, etc.) — this is an open system. The data submission
must be encrypted and digitally signed to meet §11.30.

================================================================================
SUBPART C — ELECTRONIC SIGNATURES
§§ 11.50 — 11.300
================================================================================

§ 11.50 SIGNATURE MANIFESTATIONS

(a) Signed electronic records shall contain information associated with the
signing that clearly indicates all of the following:
   (1) The printed name of the signer;
   (2) The date and time when the signature was executed; and
   (3) The meaning (such as review, approval, responsibility, or authorship)
       associated with the signature.

(b) The items identified in paragraphs (a)(1), (a)(2), and (a)(3) of this
section shall be subject to the same controls as for electronic records and
shall be included as part of any human readable form of the electronic record
(such as electronic display or printout).

THREE MANDATORY ELEMENTS OF §11.50 SIGNATURE MANIFESTATIONS:
1. PRINTED NAME: The full name of the signer — not just a user ID or employee
   number. The name must be human-readable.
2. DATE AND TIME: Timestamp of signature execution — not the date the record
   was created, but the exact date and time the signature was applied. This
   must be automatic (computer-generated), not manually entered by the signer.
3. MEANING: The purpose of the signature must be stated explicitly:
   - "Reviewed by" — for QC analysts reviewing test data
   - "Approved by" — for QA managers approving batch records
   - "Authored by" — for operators entering data
   - "Verified by" — for second-person verification steps

COMMON DEFICIENCIES:
- System displays only user ID (not printed name) in audit trail
- Date/time is manually entered by the signer (not computer-generated)
- Meaning is generic ("signed") rather than specific ("approved for release")
- Signature manifestation not included in printed/exported copies of records

§ 11.70 SIGNATURE/RECORD LINKING

Electronic signatures and handwritten signatures executed to electronic records
shall be linked to their respective electronic records to ensure that the
signatures cannot be excised, copied, or otherwise transferred to falsify an
electronic record by ordinary means.

ANTI-FALSIFICATION PURPOSE:
§11.70 prevents what is called "signature cut-and-paste" fraud: extracting
a valid electronic signature from a legitimate record and inserting it into
a falsified record. Technical implementations include:
- Cryptographic binding: The signature is computed over the record content
  (like a digital signature/hash). Any modification to the record invalidates
  the signature.
- Database linking: The signature record contains an immutable foreign key
  reference to the specific version of the electronic record (identified by
  a hash or unique record ID).
- Time-lock: Once signed, the record is frozen — no edits allowed without
  going through an amendment workflow that requires re-signature.

FDA INSPECTION FOCUS: Inspectors may test this by asking: "If I print this
batch record, can the signature block be cut and pasted into another document?"
The system design must make this technically impossible or detectable.

§ 11.100 GENERAL REQUIREMENTS FOR ELECTRONIC SIGNATURES

(a) Each electronic signature shall be unique to one individual and shall not
be reused by, or reassigned to, anyone else.

UNIQUENESS PRINCIPLE: One electronic signature (the combination of user ID,
password, and/or biometric) maps to exactly one person. No sharing, no
delegation. This is why shared accounts are fundamentally incompatible with
Part 11 — if two people share an ID/password, the signature is not unique to
one individual.

(b) Before an organization establishes, assigns, certifies, or otherwise
sanctions an individual's electronic signature, or any element of such
electronic signature, the organization shall verify the identity of the
individual.

IDENTITY VERIFICATION: The company must verify who a person is before
assigning them an electronic signature. Acceptable methods:
- Government-issued photo ID verification during onboarding/HR process
- Biometric enrollment process (fingerprint, iris scan)
- In-person verification by HR or Supervisor

This requirement means "provisioning" an account requires documented identity
verification — not just completing a form.

(c) Persons using electronic signatures shall, prior to or at the time of
such use, certify to the agency in writing that the electronic signatures in
their system are intended to be the legally binding equivalent of traditional
handwritten signatures. Upon agency request, such certification shall be
submitted in paper form with a traditional signature to the docket established
by the agency for such purposes.

FDA LETTER REQUIREMENT: §11.100(c) requires companies to submit a letter to
FDA certifying that their electronic signatures are legally binding equivalents
of handwritten signatures. This is typically a one-time submission per company
(not per system or per user), sent to:
FDA Office of Regional Operations (ORO), Docket No. 92S-0251.

(d) If an individual is using electronic signatures in a way not in compliance
with this paragraph, the electronic signature is not considered to be the
equivalent of a traditional handwritten signature.

§ 11.200 ELECTRONIC SIGNATURE COMPONENTS AND CONTROLS

(a) Electronic signatures that are not based upon biometrics shall:
   (1) Employ at least two distinct identification components such as an
       identification code and password.

   (2) Be used only by their genuine owners; and

   (3) Be administered and executed to ensure that attempted use of an
       individual's electronic signature by anyone other than its genuine
       owner requires collaboration of two or more individuals.

WHEN BOTH COMPONENTS ARE REQUIRED (NON-BIOMETRIC):
- First use in a single work session: Must use BOTH identification components
  (ID code + password)
- Subsequent uses in a continuous session: At least one component must be
  used (e.g., just re-entering the password is sufficient)
- For non-continuous sessions (new login, session timeout/expiry): Must use
  BOTH components again

PRACTICAL IMPLEMENTATION:
- Standard login: username + password (both components)
- Within-session re-authentication for signing: password only (one component)
- After session timeout: username + password again (both components)
- Some systems add a third factor (MFA) for enhanced security — this exceeds
  Part 11 minimum requirements

(b) Electronic signatures based upon biometrics shall be designed to ensure
that they cannot be used by anyone other than their genuine owners.

BIOMETRIC ELECTRONIC SIGNATURES:
Biometrics (fingerprint, retinal scan, facial recognition, voice recognition)
are inherently individual — you cannot transfer your fingerprint to another
person. Therefore, the two-component requirement of (a) does not apply to
biometric signatures. Instead, the system design must ensure:
- The biometric template cannot be spoofed (anti-spoofing measures)
- False acceptance rate (FAR) is sufficiently low for the risk level
- Biometric data storage is secure

§ 11.300 CONTROLS FOR IDENTIFICATION CODES/PASSWORDS

Persons who use electronic signatures based upon use of identification codes in
combination with passwords shall employ controls to ensure their security and
integrity. Such controls shall include:

(a) Maintaining the uniqueness of each combined identification code and password,
such that no two individuals have the same combination of identification code
and password.

(b) Ensuring that identification code and password issuances are periodically
checked, recalled, or revised (e.g., to cover such events as password aging,
with appropriate token revisions as necessary).

PASSWORD MANAGEMENT REQUIREMENTS:
- Password expiration policy (typical: 90 days maximum)
- Password complexity requirements (length, character types)
- Prevention of password reuse (password history)
- Account lockout after failed attempts (prevent brute force)
- These are not explicitly stated in the regulation but are expected as
  "controls to ensure security and integrity"

(c) Following loss management procedures to electronically de-authorize lost,
stolen, missing, or otherwise potentially compromised tokens, cards, and other
devices that bear or generate identification code or password information, and
to issue temporary or permanent replacements using suitable, rigorous controls.

LOST/STOLEN CREDENTIAL RESPONSE:
- Immediate reporting procedure when credentials are lost or stolen
- Immediate account deactivation/disabling upon report
- Issuance of new credentials with identity re-verification
- Documentation of the incident and response
- These procedures must be defined in SOPs and followed consistently

(d) Use of transaction safeguards to prevent unauthorized use of passwords
and/or identification codes, and to detect and report in an immediate and
urgent manner any attempts at their unauthorized use to the system security
unit, and, as appropriate, to organizational management.

TRANSACTION SAFEGUARDS:
- Failed login attempt monitoring and alerting
- Account lockout after N failed attempts (N typically 3-5)
- Real-time alerts to system security personnel when lockout occurs
- Intrusion detection for patterns suggesting unauthorized access attempts
- Logging of all authentication attempts (successful and failed)

(e) Initial and periodic testing of devices, such as tokens or cards, that
bear or generate identification code or password information to ensure that
they function properly and have not been altered in a unauthorized manner.

TOKEN/DEVICE TESTING:
For systems using hardware tokens (RSA SecurID, smart cards, USB security
keys), these devices must be:
- Tested on initial issuance to verify they work as intended
- Periodically tested to verify continued function
- Inspected for signs of tampering or unauthorized modification

================================================================================
CROSS-REFERENCE: PART 11 AND OTHER FDA REGULATIONS
================================================================================

PREDICATE RULES — KEY CROSS-REFERENCES:

21 CFR 211.68 (Automatic, Mechanical, and Electronic Equipment):
- Requires validation of computerized systems used in drug manufacturing
- Establishes that computer printouts of data shall be checked against
  original data
- Part 11 elaborates on what "validation" means for systems creating
  electronic records

21 CFR 211.186 (Master Production and Control Records):
- Requires master batch records; if maintained electronically, Part 11 applies
- Electronic master production records must meet §11.10 controls

21 CFR 211.188 (Batch Production and Control Records):
- Batch records are the primary CDMO document — eBRs must meet Part 11
- Every entry in an eBR is an electronic record under Part 11
- Every signature in an eBR is an electronic signature

21 CFR 211.194 (Laboratory Records):
- LIMS-generated analytical records are electronic records under Part 11
- Instrument data files (HPLC, UV-Vis, GC) are electronic records
- Original raw data files must be retained (§11.10c)

21 CFR 211.180 (General Requirements for Records and Reports):
- Sets record retention periods
- Part 11 §11.10(c) and (e) reference retention periods defined here

================================================================================
COMPUTER SYSTEM VALIDATION (CSV) FRAMEWORK
================================================================================

§11.10(a) requires validation but does not define the validation methodology.
Industry has adopted the GAMP 5 (Good Automated Manufacturing Practice)
framework published by ISPE:

GAMP 5 CATEGORIES OF SOFTWARE:
- Category 1: Infrastructure software (OS, databases) — minimal validation
- Category 3: Non-configured software (commercial off-the-shelf, no custom
  configuration) — vendor assessment + testing
- Category 4: Configured software (LIMS, ERP, DCS with configured workflows)
  — full CSV with IQ/OQ/PQ
- Category 5: Custom software (bespoke applications) — full development
  lifecycle validation

CSV LIFECYCLE DOCUMENTS FOR PART 11 COMPLIANCE:
1. Computer System Validation Master Plan (CVMP)
2. User Requirements Specification (URS)
3. Functional Requirements Specification (FRS)
4. Design Specification (DS)
5. Vendor Assessment / Supplier Qualification
6. Installation Qualification (IQ) Protocol and Report
7. Operational Qualification (OQ) Protocol and Report
8. Performance Qualification (PQ) Protocol and Report
9. Traceability Matrix
10. Summary Validation Report
11. System Release for Use (sign-off)
12. Periodic Review procedure
13. Change Control procedure

CRITICAL VALIDATION REQUIREMENTS FOR PART 11 SYSTEMS:
- Audit trail function specifically tested (turned on, immutable, captures
  all required events with correct user ID, timestamp, old/new values)
- Access control tested (verify unauthorized users cannot access restricted
  functions)
- Signature requirements tested (verify printed name, date/time, meaning
  appear correctly)
- Signature linking tested (verify signature cannot be detached from record)
- Backup and recovery tested
- Data export/reporting tested (verify complete, accurate copies for FDA)

================================================================================
FDA INSPECTION READINESS FOR PART 11
================================================================================

TYPICAL FDA INSPECTION QUESTIONS FOR PART 11:

1. "Show me your audit trail for this batch record"
   - Inspector will check: Is it enabled? Does it capture all required events?
   - Are old values captured? Is the reason for change documented?

2. "Who has administrator access to this system?"
   - Verifying that administrator access is limited and controlled
   - Checking that admin actions are also logged

3. "Can you generate a complete copy of this batch record for me?"
   - Testing §11.10(b) — readability and completeness of exported copies

4. "What is your process when an employee leaves the company?"
   - Checking timely deprovisioning under §11.10(d)

5. "Show me the validation documentation for this system"
   - Checking §11.10(a) — full IQ/OQ/PQ package

6. "What is your SOD [Separation of Duties] for this system?"
   - Checking §11.10(g) — authority checks and role separation

7. "Show me your password policy and password reset procedure"
   - Checking §11.300 — password management controls

COMMON PART 11 FDA 483 OBSERVATIONS (REAL EXAMPLES):
1. "Audit trail was not enabled on [system name]"
2. "The system allows users to modify data without capturing the reason for
   change and original data"
3. "User accounts are shared between multiple personnel"
4. "The audit trail does not capture deleted records"
5. "Personnel training records for the computerized system are incomplete"
6. "No written policies holding individuals accountable for their electronic
   signatures"
7. "The electronic signature does not display the printed name of the signer"
8. "System administrator passwords are not periodically changed"
9. "No procedure exists for reporting lost or compromised access credentials"
10. "Backup and recovery procedures have not been tested"

================================================================================
FREQUENTLY CONFUSED CONCEPTS
================================================================================

Q: Does Part 11 require electronic records?
A: NO. Part 11 only applies if a company CHOOSES to use electronic records
   for records that predicate rules require to be maintained.

Q: Does Part 11 apply to ALL computer systems?
A: NO. Only to systems that CREATE, MODIFY, MAINTAIN, ARCHIVE, RETRIEVE,
   or TRANSMIT records required by predicate FDA regulations. A general
   purpose email system used for non-regulated communications is not a
   Part 11 system (though if used to transmit regulated records, those
   records and that transmission would be subject to Part 11).

Q: What is the difference between an electronic signature and a digital signature?
A: Digital signatures use public key cryptography (PKI) and are a subset of
   electronic signatures. An electronic signature can be as simple as an
   ID+password combination. A digital signature is a specific cryptographic
   technique. Part 11 requires electronic signatures; digital signatures
   are required for open systems (§11.30) when additional security is needed.

Q: Can you use biometrics alone (without password) for signing?
A: YES. §11.200(b) states that biometric signatures must be designed to
   ensure only genuine owners can use them — the two-component requirement
   applies only to non-biometric signatures.

Q: How long must audit trails be retained?
A: At least as long as the associated electronic record (§11.10e). The
   retention period is set by the predicate rule for each record type.

Q: Must FDA be notified before implementing a Part 11 system?
A: Only §11.100(c) requires FDA notification — a one-time written certification
   that electronic signatures are intended to be legally binding. This is not
   a per-system notification but a company-level declaration.

---

### Document: FDA 21CFR Part312 Complete (FDA)

# 21 CFR Part 312 — Investigational New Drug Applications (IND): FDA Requirements for Investigational New Drug Applications: Sponsor Obligations, CMC Requirements, and CDMO Manufacturing Responsibilities

## Section 0: Overview — IND Purpose, Exemptions & CDMO Relevance (§§ 312.1–312.10)

# Section 0: Overview — IND Purpose, Exemptions & CDMO Relevance

    

    

21 CFR Part 312 — Investigational New Drug Applications (IND) | FDA | §§ 312.1–312.10

    

        

**Statutory Basis:** Section 505(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) prohibits the interstate shipment of any drug intended for investigational use in humans unless the sponsor has an effective Investigational New Drug Application on file with FDA. This is the foundational legal hook that makes Part 312 operative.

        

**Purpose of the IND:** The IND exists to give FDA the opportunity to review safety data and study protocols before clinical trials begin. Its twin purposes are:

        

            
1. Ensuring adequate preclinical data exists to support the proposed human studies (safety threshold), and

            
2. Ensuring adequate human subject protections are in place (ethical threshold).

        

        

**How the IND becomes effective:** An IND is not approved by FDA — it becomes *effective* automatically **30 calendar days** after FDA receives a complete submission, unless FDA places the study on clinical hold within that window. A clinical hold is an order from FDA to delay or suspend a proposed or ongoing clinical investigation.

        

            "A sponsor may begin a clinical investigation 30 days after FDA receives the IND, or on earlier notification by FDA that the investigation may begin." — 21 CFR §312.40(b)
        

        

**Two principal IND types:**

        

            
- **Commercial IND:** Sponsor is a pharmaceutical or biotechnology company; the ultimate goal is submission of a New Drug Application (NDA) or Biologics License Application (BLA). Full IND with complete CMC, pharmacology, and clinical protocol sections required.

            
- **Research (Investigator) IND:** Sponsor-investigator is typically an academic physician or institution; no commercial intent. FDA applies somewhat reduced expectations, but the IND must still meet Part 312 requirements.

## Section 1: Subpart A — IND Types, Phase Definitions & General Requirements (§§ 312.1–312.22)

# Section 1: Subpart A — IND Types, Phase Definitions & General Requirements

    

    

21 CFR Part 312 — IND Applications | FDA | §§ 312.1–312.22

    

### Topics Covered

## Section 2: §312.23 — IND Content: CMC Section & Manufacturing Requirements (§312.23(a)(7) — CMC section)

# Section 2: §312.23 — IND Content: CMC Section & Manufacturing Requirements

    

    

21 CFR Part 312 — IND Applications | FDA | §312.23(a)(7) — CMC section

    

### Topics Covered

## Section 3: Subpart C — Sponsor Responsibilities: Amendments, Annual Reports & Safety Reporting (§§ 312.30–312.33)

# Section 3: Subpart C — Sponsor Responsibilities: Amendments, Annual Reports & Safety Reporting

    

    

21 CFR Part 312 — IND Applications | FDA | §§ 312.30–312.33

    

        

**§ 312.30 Protocol amendments.**

        

A sponsor shall submit a protocol amendment describing any change in a Phase 1 protocol that significantly affects the safety of subjects. A sponsor shall submit a protocol amendment describing any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study. Examples of changes requiring a protocol amendment include:

        

            
- Any increase in drug dosage or duration of exposure of individual research subjects beyond that in the current protocol

            
- Any significant increase in the number of research subjects

            
- The addition of a new test article

            
- The addition of a new clinical investigator or research site

            
- A significant change in the study design (e.g., adding or dropping control groups)

        

        

**New Protocol Amendments**

        

A sponsor who adds a new protocol after the IND goes into effect shall submit the new protocol to FDA as a protocol amendment. The sponsor may begin the clinical investigation on the date the amendment is submitted to FDA unless the sponsor has received a clinical hold or is conducting a Phase 1 investigation, in which case FDA's 30-day review period applies before enrollment begins.

        

**Three Categories of Protocol Amendments**

        

            
1. **New Protocol Amendment:** Adding an entirely new clinical study (e.g., adding Phase 2 study to an existing Phase 1 IND). The new protocol must be submitted before any subjects are enrolled in the new study.

            
2. **Protocol Change Amendment:** Modifying an existing protocol — changing dose, duration of exposure, patient population, endpoints, or study design elements that affect subject safety or scientific quality.

            
3. **New Investigator Amendment:** Adding a new investigator or clinical site to the study. Must include a signed Form FDA 1572 (Statement of Investigator) and curriculum vitae.

        

        

**When FDA Prior Approval (30-Day Wait) is Required:**

        

            
- Any change that represents a significant increase in risk to subjects

            
- Adding a new indication to the IND

            
- Phase 1 protocols: sponsor must wait 30 days after submitting the protocol amendment before initiating the study, unless FDA notifies that study may proceed earlier

        

        

**Notify Within 30 Days (Information Amendment):**

        

            
- Minor changes that do not significantly affect subject safety, scope, or scientific quality

            
- Administrative changes (e.g., sponsor contact information update)

            
- Changes already reflected in other amendments submitted concurrently

        

        

            "A sponsor shall submit a protocol amendment describing any change in a Phase 2 or 3 protocol that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study."
              
*— 21 CFR §312.30(b)*

## Section 4: Subpart D — Investigator Responsibilities, GMP Obligations & CDMO Manufacturing Controls (§§ 312.50–312.70)

# Section 4: Subpart D — Investigator Responsibilities, GMP Obligations & CDMO Manufacturing Controls

    

    

21 CFR Part 312 — IND Applications | FDA | §§ 312.50–312.70

    

## Regulatory Text & Analysis

        

**§312.50 — General Sponsor Responsibilities**

        

Sponsors are responsible for selecting qualified investigators and providing each investigator with the information needed to conduct an investigation properly, for ensuring proper monitoring of the investigation(s), for ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, for maintaining an effective IND with respect to the investigations, and for ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug.

        

**§312.51 — Transfer of Obligations to a Contract Research Organization (CRO)**

        

A sponsor may transfer responsibility for any or all of the sponsor's obligations under this part to a contract research organization. Any such transfer shall be described in writing. If not all obligations are transferred, the writing is required to describe each obligation being assumed by the CRO. A CRO that assumes any obligation of a sponsor shall comply with the specific regulations applicable to that obligation and shall be subject to the same regulatory action as a sponsor for failure to comply with any obligation assumed under this part. **The sponsor retains ultimate responsibility for all transferred obligations that the CRO fails to fulfill.**

        

**§312.52 — Use of Contract Research Organizations**

        

If a sponsor uses a CRO, the sponsor shall transfer in writing each obligation being assumed by the CRO. The FDA may inspect the CRO to determine whether it is in compliance with the regulations applicable to the obligations assumed and whether it is performing the obligations that were transferred to it.

        

            "A contract research organization that assumes any obligation of a sponsor shall comply with the specific regulations applicable to that obligation and shall be subject to the same regulatory action as a sponsor for failure to comply."
              
*— 21 CFR §312.52(b)*
        

        

**§312.53 — Selecting Investigators and Monitors**

        

Before permitting an investigator to begin participation in an investigation, the sponsor shall obtain the following:

        

            
- A signed Form FDA 1572 — Statement of Investigator — from each investigator

            
- A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation

            
- A protocol describing the clinical study to be conducted by the investigator

            
- Financial disclosure information if required under 21 CFR Part 54

        

        

The sponsor must also select a monitor who is qualified by training and experience to monitor the progress of the investigation.

---

### Document: FDA 21CFR Part4 Complete (FDA)

# 21 CFR Part 4 — Regulation of Combination Products: FDA Jurisdiction Assignment, PMOA Determination, and CGMP Dual Compliance for Combination Products

## Section 0: Overview — What Are Combination Products & Why Part 4 Matters (§4.1 + FDA guidance context)

# Section 0: Overview — What Are Combination Products & Why Part 4 Matters

    

    

21 CFR Part 4 — Regulation of Combination Products | FDA | eCFR current

    
    

        

## What Are Combination Products? —

                

Statutory definition, four product types, and real-world examples

            

        

        

            

                

                    

Regulatory Text & Summary (English)

                    

### Statutory Definition

                    

Under **FD&C Act §3(g)** (21 U.S.C. §353(g)), the term **"combination product"** includes:

                    

                        
- A product comprising any combination of a **drug and a device**

                        
- A product comprising a combination of a **biological product and a device**

                        
- A product comprising a combination of a **drug and a biological product**

                        
- A product comprising a combination of a **drug, device, and a biological product**

                    

                    

The product must have two or more regulated article types working together to achieve the product's intended use. The combination may be physical, chemical, or purely functional (cross-labeling).

                    

### Four Types of Combination Products

                    

                        
1. **Single-Entity Combination Product** — Two or more regulated components physically, chemically, or otherwise combined or mixed and produced as a single entity. The components cannot be separated without affecting the product's function.

                        
2. **Co-Packaged Combination Product** — Two or more separate products packaged together in a single container or as a unit, where each component retains its own regulatory identity but is intended to be used together.

                        
3. **Cross-Labeled Combination Product** — Two or more separate products manufactured separately, distributed separately, but labeled for use together. The labeling of one product references the other as required for safe and effective use.

                        
4. **Investigational Combination Product** — Any of the above types when used under an Investigational New Drug (IND) application or Investigational Device Exemption (IDE). Regulatory requirements apply even in the investigational stage.

                    

                    

### Real-World Examples

                    
                        
                            
                                
                                
                                
                                
                                
                            
| Product | Drug Constituent | Device Constituent | Type | Lead Center |
| --- | --- | --- | --- | --- |
                        
                        
                            
                                
                                
                                
                                
                                
                            
| Pre-filled syringe | Drug (liquid) | Syringe + needle | Single-entity | CDER |
                            
                                
                                
                                
                                
                                
                            
| Drug-eluting stent | Drug (antiproliferative) | Metal stent (primary) | Single-entity | CDRH |
                            
                                
                                
                                
                                
                                
                            
| mAb autoinjector pen | Biologic (mAb) | Autoinjector mechanism | Single-entity | CBER or CDER |
                            
                                
                                
                                
                                
                                
                            
| Antibiotic-coated surgical mesh | Antibiotic drug | Mesh (primary) | Single-entity | CDRH |
                            
                                
                                
                                
                                
                                
                            
| Photodynamic therapy kit | Photosensitizer drug | Light-delivery device | Co-packaged | CDER |
                        
                    

                

                

                    

                    

                        

## Why Part 4 Was Created — Part 4

                

Historical context, regulatory gaps, and the creation of OCP

            

        

        

            

                

                    

Regulatory Text & Summary (English)

                    

### The Problem: Three Centers, One Product

                    

Before Part 4, FDA had three separate centers with distinct regulatory standards, review timelines, and post-market requirements:

                    

                        
- **CDER** (Center for Drug Evaluation and Research) — governed drugs under 21 CFR 210/211

                        
- **CDRH** (Center for Devices and Radiological Health) — governed medical devices under 21 CFR 820 and the Quality System Regulation

                        
- **CBER** (Center for Biologics Evaluation and Research) — governed biologics under 21 CFR 600–680

                    

                    

Combination products fell into regulatory gaps where no center had clear jurisdiction, or they faced duplicative review by multiple centers. This created:

                    

                        
- Prolonged and unpredictable review timelines

                        
- Inconsistent CGMP requirements across similar products

                        
- Manufacturer confusion about which submission pathway to use (NDA, BLA, PMA, 510(k))

                        
- Post-market surveillance and adverse event reporting ambiguities

                    

                    

### Legislative Solution

                    

The **Safe Medical Devices Act of 1990** created **§3(g) of the FD&C Act**, which required FDA to:

                    

                        
- Designate a **lead center** (primary regulatory jurisdiction) for each combination product

                        
- Base the designation on the product's **primary mode of action (PMOA)**

                        
- Ensure consistency and predictability in the designation process

                    

                    

**21 CFR Part 4** operationalizes §3(g) by establishing the regulatory procedures for designation, including the formal **Request for Designation (RFD)** process.

                    

### Office of Combination Products (OCP)

                    

The **Medical Device User Fee and Modernization Act (MDUFMA) of 2002** established the **Office of Combination Products (OCP)** within the FDA Commissioner's Office. OCP:

                    

                        
- Manages the RFD process and issues binding jurisdictional determinations

                        
- Resolves inter-center disputes about jurisdiction

                        
- Develops and updates guidance on combination product regulation

                        
- Monitors combination product reviews to ensure timely, consistent decisions

                        
- Reports annually to Congress on combination product activities

                    

                    

                        "The purpose of Part 4 is to achieve timely and effective premarket review of combination products and to ensure consistent and appropriate post-market regulation of these products." — 21 CFR Part 4, Preamble
                    

                

                

                    

                    

                        

#### 

                        

                        

                            

                            

                        

                        

                    

                    

                        

#### 

                        

                            

                            

                            

                            

                            

                        

                    

                    

                        

#### OCP

                        

                        

                            

                            

                            

                        

                        

                    

                    

                        

#### ICA vs. Part 4

                        

                    

                

            

        

    

    
    

        

            

0.3

            

                

## Why Part 4 Matters for CDMOs — Part 4 CDMO

                

CGMP overlap, quality agreements, and the mAb autoinjector scenario

            

        

        

            

                

                    

Regulatory Text & Summary (English)

                    

### Four Critical Questions for CDMO Operations

                    

A CDMO manufacturing a sterile injectable drug for a combination product must answer four questions before beginning manufacturing:

                    

                        
1. **Which FDA center leads regulation?** — Determines which submission type applies (NDA vs. PMA vs. BLA), which division within FDA reviews the product, and which reviewers have authority over manufacturing-related questions.

                        
2. **Which CGMP applies — or does dual CGMP apply?** — Under 21 CFR Part 4 Subpart B (the 2013 CGMP rule), manufacturers of combination products may be subject to both 21 CFR Part 211 (drug CGMP) and 21 CFR Part 820 (Quality System Regulation for devices). The CDMO must know which applies to their specific operations.

                        
3. **How do quality agreements allocate compliance responsibility?** — The sponsor (drug/device brand owner) and CDMO must explicitly allocate who is responsible for CGMP compliance for each constituent part. Ambiguity in quality agreements is a direct FDA 483 observation risk.

                        
4. **When do manufacturing changes require prior approval vs. notification?** — A change to the drug formulation may require a Prior Approval Supplement (PAS), while the same change to device labeling may only require an Annual Report. The CDMO must follow the change control requirements of the lead center.

                    

                    

### CDMO Scenario: mAb Autoinjector Sterile Fill-Finish

                    

A CDMO performs sterile fill-finish for a monoclonal antibody (mAb) in a prefilled autoinjector pen. The product is a single-entity combination product: biologic drug (mAb) + device (autoinjector mechanism + prefilled syringe).

                    
                        
                            
                                
                                
                                
                            
| Question | Analysis | Implication for CDMO |
| --- | --- | --- |
                        
                        
                            
                                
                                
                                
                            
| Lead center? | mAb is the PMOA  CBER or CDER (mAbs transferred to CDER in 2003) | CDER leads; BLA is the likely submission; CMC review under CDER standards |
                            
                                
                                
                                
                            
| Which CGMP? | 21 CFR Part 4 Subpart B: both 21 CFR 211 (drug) and 21 CFR 820 (device) may apply to the combination | CDMO must document how its QMS covers both 211 and 820 requirements for the prefilled syringe/autoinjector components |
                            
                                
                                
                                
                            
| Device CGMP responsibility? | Autoinjector device constituent parts require Design History File (DHF), Device History Record (DHR) under 21 CFR 820 | Quality agreement must specify whether sponsor or CDMO maintains the DHF/DHR; CDMO must confirm its QMS is 820-compatible |
                            
                                
                                
                                
                            
| Change control? | Changes to the prefilled syringe design (e.g., new needle gauge) may require a PAS for the BLA | CDMO change control SOP must route device component changes through sponsor's BLA change management process |
                        
                    

                    

                        

#### Common CDMO Trap

                        

**Assuming only drug CGMP (21 CFR 211) applies** when manufacturing the drug constituent for a combination product. Under 21 CFR Part 4 Subpart B, if the CDMO also assembles or tests device constituent parts, the quality system must also satisfy relevant provisions of 21 CFR 820. This is frequently flagged in FDA inspections of CDMOs filling combination product presentations.

                    

                

                

                    

                    

                        

#### CDMO CGMP

                        

                        

                        

                        

                    

                    

                        

## Relationship to Other Regulations —

                

Cross-reference map: Part 4  Part 3  CGMP regulations; what Part 4 does NOT govern

            

        

        

            

                

                    

Regulatory Text & Summary (English)

                    

### Cross-Reference Map

                    

21 CFR Part 4 does not operate in isolation. It is part of a regulatory framework that must be read in conjunction with several other parts of the CFR:

                    
                        
                            
                                
                                
                                
                            
| Regulation | Title / Purpose | Relationship to Part 4 |
| --- | --- | --- |
                        
                        
                            
                                ****
                                
                                
                            
| 21 CFR Part 3 | Product Jurisdiction — Procedures for designating the lead center | Part 4 references Part 3 for the formal RFD mechanism and jurisdictional order procedures |
                            
                                ****
                                
                                
                            
| 21 CFR Part 211 | Current Good Manufacturing Practice for Finished Pharmaceuticals | Applies to drug constituent parts; under Part 4 Subpart B, may apply to full combination product when drug CGMP is applicable |
                            
                                ****
                                
                                
                            
| 21 CFR Part 820 | Quality System Regulation (Device CGMP) | Applies to device constituent parts; under Part 4 Subpart B, may apply to combination products where device CGMP is applicable |
                            
                                ****
                                
                                
                            
| 21 CFR Parts 600–680 | Biologics Standards and CGMP | Applies to biological product constituent parts; Part 4 determines whether CBER or CDER leads biologics-containing combination products |
                            
                                ****
                                
                                
                            
| 21 CFR Part 4 Subpart B | Current Good Manufacturing Practice Requirements for Combination Products (2013) | Specifies how CGMP requirements from 211, 820, and 600s apply to combination products and how manufacturers may comply with streamlined provisions |
                        
                    

                    

### What Part 4 Does NOT Govern

                    

Part 4 is frequently misunderstood as covering the entire regulatory lifecycle of combination products. It does not:

                    

                        
- **Govern approval pathways** — NDA (21 CFR Part 314), BLA (21 CFR Part 601), PMA (21 CFR Part 814), and 510(k) (21 CFR Part 807) are governed by their respective regulations. Part 4 only determines *which center* manages those pathways.

                        
- **Establish submission formats** — The Common Technical Document (CTD) format and electronic submission requirements are set by the lead center, not Part 4.

                        
- **Define safety standards** — Biocompatibility (ISO 10993), sterility, container-closure integrity, and other technical standards are governed by USP, ISO, and center-specific guidance, not Part 4.

                        
- **Override other CFR requirements** — Part 4 operates alongside existing requirements; it does not supersede 21 CFR 211, 820, or 600.

                    

                    

### 21 CFR Part 4 Subpart B (2013 CGMP Rule)

                    

The most operationally significant addition to Part 4 was the 2013 final rule establishing **Subpart B: Current Good Manufacturing Practice Requirements for Combination Products**. Key provisions:

                    

                        
- Manufacturers must comply with the CGMP requirements applicable to each constituent part

                        
- A manufacturer complying with one set of CGMP requirements (e.g., 21 CFR 820) may demonstrate compliance with certain overlapping requirements from another set (e.g., 21 CFR 211) using its own CGMP system

                        
- The rule provides a streamlined compliance pathway to reduce dual-CGMP burden while maintaining safety and quality

                        
- Applies to all combination products subject to FDA premarket review

                    

                

                

                    

                    

                        

#### Part 4

                        

                        

                            

                                **FD&C Act §3(g)**  

                            

                            



                            

                                **21 CFR Part 3**  

                            

                            



                            

                                **21 CFR Part 4**  

                            

                            



                            

                                

                                    **21 CFR 211**  
                                

                                

                                    **21 CFR 820**  
                                

                                

                                    **21 CFR 600s**  
                                

                            

                        

                    

                    

                        

#### Part 4 —

                        

                        

                            

                            

                            

                            

                        

                    

                    

                        

#### 2013 Subpart B CGMP

                        

                        

                        

                        

                    

                    

                        

#### —

                        

                        

                            

                            

                            

                            

                            

                        

                        

                    

                

            

        

    

    
    

        

            



            

                

## Section Summary —

                

Key takeaways from Section 0

            

        

        

            

                

                    

Key Takeaways (English)

                    

### What You Should Know After This Section

                    

                        

#### 1. Definition and Types

                        

A combination product under FD&C Act §3(g) is any product combining two or more of the following: drug, device, biological product. There are four operational types: single-entity, co-packaged, cross-labeled, and investigational.

                    

                    

                        

#### 2. Why Part 4 Exists

                        

Part 4 was created to resolve the pre-1990 problem of combination products falling between FDA's three separate centers (CDER, CDRH, CBER). The 1990 Safe Medical Devices Act mandated lead center designation based on primary mode of action. OCP (est. 2002) enforces this through the RFD process.

                    

                    

                        

#### 3. CGMP Complexity for Manufacturers

                        

Under Part 4 Subpart B (2013), combination product manufacturers may need to comply with both 21 CFR 211 and 21 CFR 820. The streamlined compliance pathway allows a single QMS to satisfy both if equivalence is documented. CDMOs must never assume only drug CGMP applies.

                    

                    

                        

#### 4. What Part 4 Does NOT Do

                        

Part 4 designates jurisdiction — it does not set approval pathways (NDA/BLA/PMA), technical standards, or override other CFR requirements. It is a jurisdictional and procedural rule, not a manufacturing or submission standard.

                    

                    

                        

#### 5. CDMO Practical Implication

                        

Before accepting any combination product contract, a CDMO must confirm: lead center designation, applicable CGMP regulations, quality agreement allocation of responsibilities, and change control routing for device constituent parts.

                    

                

                

                    

                    

                        

#### 1.

                        

                    

                    

                        

#### 2. Part 4

                        

                    

                    

                        

#### 3. CGMP

                        

                    

                    

                        

#### 4. Part 4

                        

                    

                    

                        

#### 5. CDMO

                        

                        

                            

                            

                            

                            

                        

                        

                    

                

            

            
            

                21 CFR Part 3 (Product Jurisdiction Order procedures) |
                21 CFR Part 4 §4.3 (Subpart A: Designation procedures) |
                21 CFR Part 4 §4.4 (Subpart B: CGMP requirements) |
                21 CFR Part 211 (Drug CGMP) |
                21 CFR Part 820 (Device Quality System Regulation) |
                21 CFR Parts 600–680 (Biologics)
            

        

    

    

21 CFR Part 4 — Regulation of Combination Products | FDA eCFR

    

SterileGMP Knowledge Hub | Educational Use Only — Not Legal Advice

    

Last Updated: 2026-04-14



## Section 1: §4.1–4.3 — Definitions, Types & Applicable Regulations (§§ 4.1–4.3)

# Section 1: §4.1–4.3 — Definitions, Types & Applicable Regulations

    

    

21 CFR Part 4 — Regulation of Combination Products | FDA | §§ 4.1–4.3

    

        

**§4.1 — Scope.**

        

**(a)** This subpart applies to combination products as defined in §3.2(e) of this chapter. It establishes, for purposes of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, which current good manufacturing practice (CGMP) requirements in parts 4, 210, 211, 600 through 680, and 820 of this chapter apply to combination products, and provides for the assignment of combination products to a component of FDA.

        

**(b)** This subpart does not cover biological products that are regulated solely under the Public Health Service Act and that do not have a drug or device constituent part.

        

**(c)** Agreements and decisions made under this part regarding which CGMP requirements apply to a specific combination product are intended to promote the efficient and timely review of applications and the timely compliance of manufacturers with applicable CGMP requirements.

        

            "This subpart applies to combination products as defined in §3.2(e) of this chapter."
              
*— 21 CFR §4.1(a)*
        

        

**Key cross-references:**

        

            
- §3.2(e) — Definition of "combination product" (the operative definition)

            
- Parts 210, 211 — Drug CGMPs (manufacturing and finished product)

            
- Parts 600–680 — Biological product regulations

            
- Part 820 — Device Quality System Regulation / QMSR

            
- 21 CFR Part 3 — Product Jurisdiction (designation authority)

## Section 2: §4.5–4.9 — RFD Process, PMOA Determination & Center Assignment (§§ 4.5–4.9)

# Section 2: §4.5–4.9 — RFD Process, PMOA Determination & Center Assignment

    

    

21 CFR Part 4 — Regulation of Combination Products | FDA | §§ 4.5–4.9 (+ 21 CFR Part 3 §§3.7–3.10)

    

        

**§4.5 — Agreement, Determination, and Designation Procedures.**

        

Under 21 CFR §3.4 and §4.5, a manufacturer or sponsor seeking to determine which FDA center has primary jurisdiction over a combination product has three procedural options:

        

**Option 1 — Informal OCP Consultation (Non-binding)**  

        A sponsor may contact OCP informally to discuss product classification questions. OCP staff will provide informal guidance based on precedent products and existing regulatory determinations. This path is fastest and costs no application time, but the response is not a formal designation and does not bind FDA.

        

**Option 2 — Pre-RFD Meeting**  

        Before filing a formal RFD, a sponsor may request a pre-RFD meeting with OCP to discuss the product's constituent parts, proposed PMOA, and likely center assignment. This meeting clarifies whether a formal RFD is warranted and helps the sponsor prepare a stronger submission. Pre-RFD meetings are especially useful when the PMOA is scientifically ambiguous.

        

**Option 3 — Formal Request for Designation (RFD)**  

        A sponsor files a written RFD with OCP under §3.7. FDA must respond within 60 calendar days. The designation issued is binding on FDA and establishes the lead center for the product's lifecycle. Filing an RFD is strongly recommended before submitting the first marketing application (IND, NDA, BLA, or PMA).

        

**When to file formal RFD vs. proceed directly:**

        

            
- File formal RFD when: PMOA is unclear; no clear precedent product exists; the product spans two or more center jurisdictions; sponsor needs binding confirmation for regulatory strategy

            
- Proceed directly to lead center when: prior OCP informal guidance is consistent; the product is nearly identical to a previously designated combination product; the primary constituent part classification is unambiguous

## Section 3: §4.10–4.11 — CGMP Dual Compliance, Post-Market Obligations & CDMO Responsibilities (§§ 4.10–4.11)

# Section 3: §4.10–4.11 — CGMP Dual Compliance, Post-Market Obligations & CDMO Responsibilities

    

    

21 CFR Part 4 — Regulation of Combination Products | FDA | §§ 4.10–4.11

    

## Regulatory Framework

        

**§ 4.4 Current good manufacturing practice requirements.**  

        21 CFR Part 4 Subpart B establishes CGMP requirements for combination products. The 2013 Final Rule (effective December 22, 2013) clarified how manufacturers demonstrate compliance when a combination product includes both drug and device constituents.

        

### §4.4(a) — Default Dual Compliance Rule

        

The default rule is straightforward: a combination product must comply with the CGMP regulations applicable to *each* constituent part.

        

            
- If the combination product includes a **drug constituent part**  must comply with 21 CFR Parts 210 and 211 (drug CGMP)

            
- If the combination product includes a **device constituent part**  must comply with 21 CFR Part 820 (Quality System Regulation / QSR)

            
- If the combination product includes a **biological product constituent part**  must also comply with 21 CFR Parts 600–680

            
- If a combination product includes all three types  all three sets of CGMP requirements apply

        

        

### §4.4(b) — The Streamlined Approach

        

The streamlined approach is the practical pathway for most manufacturers. Under §4.4(b), a manufacturer may comply with *only one* set of CGMP regulations — either Part 211 or Part 820 as the primary framework — provided the manufacturer demonstrates that the **controls established under the primary CGMP framework satisfy the requirements** of the other applicable CGMP regulation.

        

Key operational requirement: The manufacturer must **document how** each applicable requirement from the non-primary CGMP set is satisfied by the primary system. This documentation is the gap analysis crosswalk — FDA will review it during inspection.

        

### §4.4(b) — What "Streamlined" Does NOT Mean

        

Critically, "streamlined" does not mean the manufacturer can ignore requirements that exist only in one regulation and not the other. If a requirement is unique to one regulation with no functional equivalent in the other, that unique requirement must still be implemented. The streamlined approach only allows avoiding literal duplication of procedures when the same outcome is already achieved through an existing system.

        

            "A person who manufactures or processes a combination product may satisfy the current good manufacturing practice requirements applicable to the combination product by complying with either the drug current good manufacturing practice regulations in parts 210 and 211 of this chapter or the device quality system regulation in part 820 of this chapter, provided the person demonstrates that compliance with that regulation satisfies the requirements of the other applicable regulation(s)."
              
*— 21 CFR §4.4(b), the streamlined compliance option*
        

        

### 2013 Final Rule — FDA's Operational Guidance

        

The 2013 Final Rule clarified several key implementation questions:

        

            
- FDA confirmed that the lead center's CGMP framework should typically serve as the **primary** CGMP system

            
- The crosswalk documentation does not need to be a separate standalone document — it may be embedded in SOPs, quality agreements, or the Quality Manual

            
- FDA's "Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products" (January 2017) provides detailed guidance on implementing the streamlined approach

            
- FDA confirmed that both CDRH and CDER/CBER may conduct inspections of a single site manufacturing combination products

---

### Document: FDA Aseptic Complete (FDA)

# FDA Guidance for Industry: Sterile Drug Products by Aseptic Processing — CGMP (2004)

--- PAGE 1 ---

Guidance for Industry

Sterile Drug Products
Produced by Aseptic Processing —
Current Good Manufacturing Practice

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Regulatory Affairs (ORA)

September 2004
Pharmaceutical CGMPs

--- PAGE 2 ---

Guidance for Industry
 Sterile Drug Products
Produced by Aseptic Processing —
Current Good Manufacturing Practice

Additional copies are available from:
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
(Tel) 301-827-4573
 http://www.fda.gov/cder/guidance/index.htm

or

 Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
 Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
 http://www.fda.gov/cber/guidelines.htm.
(Tel) Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Office of Regulatory affairs (ORA)

September 2004
Pharmaceutical CGMPs

--- PAGE 3 ---

Contains Nonbinding Recommendations
TABLE OF CONTENTS

I.
INTRODUCTION............................................................................................................. 1
II.
BACKGROUND ............................................................................................................... 2
A.
Regulatory Framework .................................................................................................................2
B.
Technical Framework....................................................................................................................2
III.
SCOPE ............................................................................................................................... 3
IV.
BUILDINGS AND FACILITIES .................................................................................... 4
A.
Critical Area – Class 100 (ISO 5) .................................................................................................5
B.  Supporting Clean Areas ................................................................................................................7
C.  Clean Area Separation ..................................................................................................................7
D.
Air Filtration ..................................................................................................................................8
1. Membrane ........................................................................................................................................8
2. High-Efficiency Particulate Air (HEPA) .........................................................................................8
E.
Design............................................................................................................................................10
V.
PERSONNEL TRAINING, QUALIFICATION, & MONITORING........................ 12
A.
Personnel.......................................................................................................................................13
B.
Laboratory Personnel..................................................................................................................15
C.
Monitoring Program....................................................................................................................15
VI. COMPONENTS AND CONTAINER/CLOSURES.......................................................... 15
A.  Components..................................................................................................................................16
B.  Containers/Closures.....................................................................................................................17
1. Preparation....................................................................................................................................17
2.  Inspection of Container Closure System........................................................................................18
VII. ENDOTOXIN CONTROL................................................................................................. 19
VIII. TIME LIMITATIONS...................................................................................................... 20
IX.
VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION.................. 20
A.  Process Simulations .....................................................................................................................20
1.  Study Design .................................................................................................................................21
2. Frequency and Number of Runs ....................................................................................................22
3. Duration of Runs............................................................................................................................22
4. Size of Runs....................................................................................................................................23
5. Line Speed......................................................................................................................................23
6. Environmental Conditions .............................................................................................................24
7.  Media ............................................................................................................................................24
8. Incubation and Examination of Media-Filled Units......................................................................24
9. Interpretation of Test Results.........................................................................................................26
B.  Filtration Efficacy........................................................................................................................27

--- PAGE 4 ---

Contains Nonbinding Recommendations
C.  Sterilization of Equipment, Containers, and Closures .............................................................28
1. Qualification and Validation .........................................................................................................29
2. Equipment Controls and Instrument Calibration ..........................................................................30
X.
LABORATORY CONTROLS ...................................................................................... 31
A.   Environmental Monitoring .........................................................................................................32
1.   General Written Program.............................................................................................................32
2. Establishing Levels and a Trending Program ...............................................................................33
3. Disinfection Efficacy......................................................................................................................34
4.  Monitoring Methods......................................................................................................................34
B.  Microbiological Media and Identification .................................................................................35
C.  Prefiltration Bioburden...............................................................................................................36
D.  Alternate Microbiological Test Methods ...................................................................................36
E.  Particle Monitoring......................................................................................................................36
XI.
STERILITY TESTING.................................................................................................. 37
A.  Microbiological Laboratory Controls........................................................................................38
B.  Sampling and Incubation ............................................................................................................38
C.  Investigation of Sterility Positives ..............................................................................................39
XII.
BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION ........ 42
APPENDIX 1:  ASEPTIC PROCESSING ISOLATORS....................................................... 44
APPENDIX 2:  BLOW-FILL- SEAL TECHNOLOGY.......................................................... 49
APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS.... 52
REFERENCES............................................................................................................................ 54
RELEVANT GUIDANCE DOCUMENTS............................................................................... 55
GLOSSARY................................................................................................................................. 56

--- PAGE 5 ---

Contains Nonbinding Recommendations

Guidance for Industry1
Sterile Drug Products Produced by
Aseptic Processing — Current Good Manufacturing Practice

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I.
INTRODUCTION

This guidance is intended to help manufacturers meet the requirements in the Agency's current
good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when
manufacturing sterile drug and biological products using aseptic processing.  This guidance
replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing
(Aseptic Processing Guideline).  This revision updates and clarifies the 1987 guidance.

For sterile drug products subject to a new or abbreviated drug application (NDA or ANDA) or a
biologic license application (BLA), this guidance document should be read in conjunction with
the guidance on the content of sterile drug applications entitled Guideline for the Submission of
Documentation for Sterilization Process Validation in Applications for Human and Veterinary
Drug Products (Submission Guidance).  The Submission Guidance describes the types of
information and data that should be included in drug applications to demonstrate the efficacy of a
manufacturer's sterilization process. This guidance compliments the Submission Guidance by
describing procedures and practices that will help enable a sterile drug manufacturing facility to
meet CGMP requirements relating, for example, to facility design, equipment suitability, process
validation, and quality control.

FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited.  The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.

1 This guidance was developed by the Office of Compliance in the Center for Drug Evaluation and Research
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) and the Office of Regulatory
Affairs (ORA).

--- PAGE 6 ---

Contains Nonbinding Recommendations

The text boxes included in this guidance include specific sections of parts 210 and 211 of the
Code of Federal Regulations (CFR), which address current good manufacturing practice for
drugs.  The intent of including these quotes in the text boxes is to aid the reader by providing a
portion of an applicable regulation being addressed in the guidance.  The quotes included in the
text boxes are not intended to be exhaustive.  Readers of this document should reference the
complete CFR to ensure that they have complied, in full, with all relevant sections of the
regulations.

II.
BACKGROUND

This section describes briefly both the regulatory and technical reasons why the Agency is
developing this guidance document.

A.
Regulatory Framework

This guidance pertains to current good manufacturing practice (CGMP) regulations (21 CFR
parts 210 and 211) when manufacturing sterile drug and biological products using aseptic
processing.  Although the focus of this guidance is on CGMPs in 21 CFR 210 and 211,
supplementary requirements for biological products are in 21 CFR 600-680.  For biological
products regulated under 21 CFR parts 600 through 680, §§ 210.2(a) and 211.1(b) provide that
where it is impossible to comply with the applicable regulations in both parts 600 through 680
and parts 210 and 211, the regulation specifically applicable to the drug product in question shall
supercede the more general regulations.

B.
Technical Framework

There are basic differences between the production of sterile drug products using aseptic
processing and production using terminal sterilization.

Terminal sterilization usually involves filling and sealing product containers under high-quality
environmental conditions. Products are filled and sealed in this type of environment to minimize
the microbial and particulate content of the in-process product and to help ensure that the
subsequent sterilization process is successful. In most cases, the product, container, and closure
have low bioburden, but they are not sterile. The product in its final container is then subjected to
a sterilization process such as heat or irradiation.

In an aseptic process, the drug product, container, and closure are first subjected to sterilization
methods separately, as appropriate, and then brought together.2  Because there is no process to
sterilize the product in its final container, it is critical that containers be filled and sealed in an
extremely high-quality environment.  Aseptic processing involves more variables than terminal
sterilization. Before aseptic assembly into a final product, the individual parts of the final product

2 Due to their nature, certain products are aseptically processed at an earlier stage in the process, or in their entirety.
Cellular therapy products are an example. All components and excipients for these products are rendered sterile, and
release of the final product is contingent on determination of sterility.  See Appendix III.

--- PAGE 7 ---

Contains Nonbinding Recommendations

are generally subjected to various sterilization processes.  For example, glass containers are
subjected to dry heat; rubber closures are subjected to moist heat; and liquid dosage forms are
subjected to filtration.  Each of these manufacturing processes requires validation and control.
Each process could introduce an error that ultimately could lead to the distribution of a
contaminated product.  Any manual or mechanical manipulation of the sterilized drug,
components, containers, or closures prior to or during aseptic assembly poses the risk of
contamination and thus necessitates careful control.  A terminally sterilized drug product, on the
other hand, undergoes final sterilization in a sealed container, thus limiting the possibility of
error.3

Sterile drug manufacturers should have a keen awareness of the public health implications of
distributing a nonsterile product.  Poor CGMP conditions at a manufacturing facility can
ultimately pose a life-threatening health risk to a patient.

III.
SCOPE

This guidance document discusses selected issues and does not address all aspects of aseptic
processing.  For example, the guidance addresses primarily finished drug product CGMP issues
while only limited information is provided regarding upstream bulk processing steps.  This
guidance updates the 1987 Aseptic Processing Guideline primarily with respect to personnel
qualification, cleanroom design, process design, quality control, environmental monitoring, and
review of production records.  The use of isolators for aseptic processing is also discussed.

Although this guidance document discusses CGMP issues relating to the sterilization of
components, containers, and closures, terminal sterilization of drug products is not addressed.  It
is a well-accepted principle that sterile drugs should be manufactured using aseptic processing
only when terminal sterilization is not feasible.  However, some final packaging may afford
some unique and substantial advantage (e.g., some dual-chamber syringes) that would not be
possible if terminal sterilization were employed.  In such cases, a manufacturer can explore the
option of adding adjunct processing steps to increase the level of sterility assurance.

A list of references that may be of value to the reader is included at the conclusion of this
document.

3 Nearly all drugs recalled due to nonsterility or lack of sterility assurance in the period spanning 1980-2000 were
produced via aseptic processing.

--- PAGE 8 ---

Contains Nonbinding Recommendations

IV.
BUILDINGS AND FACILITIES

21 CFR 211.42(b) states, in part, that “The flow of components, drug product containers, closures, labeling,
in-process materials, and drug products through the building or buildings shall be designed to prevent
contamination.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of
adequate size.  There shall be separate or defined areas or such other control systems for the firm’s operations
as are necessary to prevent contamination or mixups during the course of the following procedures: * * *
(10)  Aseptic processing, which includes as appropriate:  (i)  Floors, walls, and ceilings of smooth, hard
surfaces that are easily cleanable; (ii) Temperature and humidity controls;  (iii)  An air supply filtered
through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or
nonlaminar; (iv) A system for monitoring environmental conditions;   (v) A system for cleaning and
disinfecting the room and equipment to produce aseptic conditions; (vi) A system for maintaining any
equipment used to control the aseptic conditions.”

21 CFR 211.46(b) states that “Equipment for adequate control over air pressure, micro-organisms, dust,
humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or
holding of a drug product.”

21 CFR 211.46(c) states, in part, that “Air filtration systems, including prefilters and particulate matter air
filters, shall be used when appropriate on air supplies to production areas * * *.”

21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug
product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its
intended use and for its cleaning and maintenance.”

21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, in-
process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety,
identity, strength, quality, or purity of the drug product beyond the official or other established
requirements.”

21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at
appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength,
quality, or purity of the drug product beyond the official or other established requirements.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established and followed.  Such procedures
shall include validation of any sterilization process.”

As provided for in the regulations, separate or defined areas of operation in an aseptic processing
facility should be appropriately controlled to attain different degrees of air quality depending on
the nature of the operation.  Design of a given area involves satisfying microbiological and
particle criteria as defined by the equipment, components, and products exposed, as well as the
operational activities conducted in the area.

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Clean area control parameters should be supported by microbiological and particle data obtained
during qualification studies.  Initial cleanroom qualification includes, in part, an assessment of
air quality under as-built, static conditions.  It is important for area qualification and
classification to place most emphasis on data generated under dynamic conditions (i.e., with
personnel present, equipment in place, and operations ongoing).  An adequate aseptic processing
facility monitoring program also will assess conformance with specified clean area
classifications under dynamic conditions on a routine basis.

The following table summarizes clean area air classifications and recommended action levels of
microbiological quality (Ref. 1).

TABLE 1- Air Classificationsa

 Clean Area
Classification
(0.5 um particles/ft3)
ISO
Designationb
> 0.5 µm
particles/m3
Microbiological
Active Air Action
Levelsc (cfu/m3 )
Microbiological Settling
Plates Action Levelsc,d
(diam. 90mm; cfu/4 hours)
3,520
1e
1e
1000
35,200
10,000
352,000
100,000
3,520,000

a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity.
b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries.  An ISO 5 particle
concentration is equal to Class 100 and approximately equals EU Grade A.
c- Values represent recommended levels of environmental quality.  You may find it appropriate to establish alternate microbiological action
levels due to the nature of the operation or method of analysis.
d- The additional use of settling plates is optional.
e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

Two clean areas are of particular importance to sterile drug product quality: the critical area and
the supporting clean areas associated with it.

A.
Critical Area – Class 100 (ISO 5)

A critical area is one in which the sterilized drug product, containers, and closures are exposed to
environmental conditions that must be designed to maintain product sterility (§ 211.42(c)(10)).
Activities conducted in such areas include manipulations (e.g., aseptic connections, sterile
ingredient additions) of sterile materials prior to and during filling and closing operations.

This area is critical because an exposed product is vulnerable to contamination and will not be
subsequently sterilized in its immediate container.  To maintain product sterility, it is essential
that the environment in which aseptic operations (e.g., equipment setup, filling) are conducted be
controlled and maintained at an appropriate quality.  One aspect of environmental quality is the
particle content of the air.  Particles are significant because they can enter a product as an
extraneous contaminant, and can also contaminate it biologically by acting as a vehicle for
microorganisms (Ref. 2).  Appropriately designed air handling systems minimize particle content
of a critical area.

Air in the immediate proximity of exposed sterilized containers/closures and filling/closing
operations would be of appropriate particle quality when it has a per-cubic-meter particle count

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of no more than 3520 in a size range of 0.5 µm and larger when counted at representative
locations normally not more than 1 foot away from the work site, within the airflow, and during
filling/closing operations.  This level of air cleanliness is also known as Class 100 (ISO 5).

We recommend that measurements to confirm air cleanliness in critical areas be taken at sites
where there is most potential risk to the exposed sterilized product, containers, and closures.  The
particle counting probe should be placed in an orientation demonstrated to obtain a meaningful
sample.  Regular monitoring should be performed during each production shift.  We recommend
conducting nonviable particle monitoring with a remote counting system.  These systems are
capable of collecting more comprehensive data and are generally less invasive than portable
particle counters.   See Section X.E. for additional guidance on particle monitoring.

Some operations can generate high levels of product (e.g., powder) particles that, by their nature,
do not pose a risk of product contamination.  It may not, in these cases, be feasible to measure air
quality within the one-foot distance and still differentiate background levels of particles from air
contaminants.  In these instances, air can be sampled in a manner that, to the extent possible,
characterizes the true level of extrinsic particle contamination to which the product is exposed.
Initial qualification of the area under dynamic conditions without the actual filling function
provides some baseline information on the non-product particle generation of the operation.

HEPA-filtered4 air should be supplied in critical areas at a velocity sufficient to sweep particles
away from the filling/closing area and maintain unidirectional airflow during operations.  The
velocity parameters established for each processing line should be justified and appropriate to
maintain unidirectional airflow and air quality under dynamic conditions within the critical area
(Ref. 3).5

Proper design and control prevents turbulence and stagnant air in the critical area.  Once relevant
parameters are established, it is crucial that airflow patterns be evaluated for turbulence or eddy
currents that can act as a channel or reservoir for air contaminants (e.g., from an adjoining lower
classified area).  In situ air pattern analysis should be conducted at the critical area to
demonstrate unidirectional airflow and sweeping action over and away from the product under
dynamic conditions.  The studies should be well documented with written conclusions, and
include evaluation of the impact of aseptic manipulations (e.g., interventions) and equipment
design.  Videotape or other recording mechanisms have been found to be useful aides in
assessing airflow initially as well as facilitating evaluation of subsequent equipment
configuration changes.  It is important to note that even successfully qualified systems can be
compromised by poor operational, maintenance, or personnel practices.

Air monitoring samples of critical areas should normally yield no microbiological contaminants.
We recommend affording appropriate investigative attention to contamination occurrences in this
environment.

4High Efficiency Particulate Air filter

5 A velocity of 0.45 meters/second (90 feet per minute) has generally been established, with a range of plus or minus
20 percent around the setpoint.  Higher velocities may be appropriate in operations generating high levels of
particulates.

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B.
Supporting Clean Areas

Supporting clean areas can have various classifications and functions.  Many support areas
function as zones in which nonsterile components, formulated products, in-process materials,
equipment, and container/closures are prepared, held, or transferred.  These environments are
soundly designed when they minimize the level of particle contaminants in the final product and
control the microbiological content (bioburden) of articles and components that are subsequently
sterilized.

The nature of the activities conducted in a supporting clean area determines its classification.
FDA recommends that the area immediately adjacent to the aseptic processing line meet, at a
minimum, Class 10,000 (ISO 7) standards (see Table 1) under dynamic conditions.
Manufacturers can also classify this area as Class 1,000 (ISO 6) or maintain the entire aseptic
filling room at Class 100 (ISO 5).  An area classified at a Class 100,000 (ISO 8) air cleanliness
level is appropriate for less critical activities (e.g., equipment cleaning).

C.
Clean Area Separation

An essential part of contamination prevention is the adequate separation of areas of operation.
To maintain air quality, it is important to achieve a proper airflow from areas of higher
cleanliness to adjacent less clean areas.  It is vital for rooms of higher air cleanliness to have a
substantial positive pressure differential relative to adjacent rooms of lower air cleanliness.  For
example, a positive pressure differential of at least 10-15 Pascals (Pa)6 should be maintained
between adjacent rooms of differing classification (with doors closed).  When doors are open,
outward airflow should be sufficient to minimize ingress of contamination, and it is critical that
the time a door can remain ajar be strictly controlled (Ref. 4).

In some cases, the aseptic processing room and adjacent cleanrooms have the same
classification.  Maintaining a pressure differential (with doors closed) between the aseptic
processing room and these adjacent rooms can provide beneficial separation.  In any facility
designed with an unclassified room adjacent to the aseptic processing room, a substantial
overpressure (e.g., at least 12.5 Pa) from the aseptic processing room should be maintained at all
times to prevent contamination.  If this pressure differential drops below the minimum limit, it is
important that the environmental quality of the aseptic processing room be restored and
confirmed.

The Agency recommends that pressure differentials between cleanrooms be monitored
continuously throughout each shift and frequently recorded.  All alarms should be documented
and deviations from established limits should be investigated.

Air change rate is another important cleanroom design parameter.  For Class 100,000 (ISO 8)
supporting rooms, airflow sufficient to achieve at least 20 air changes per hour is typically
acceptable.  Significantly higher air change rates are normally needed for Class 10,000 and Class
100 areas.

6 Equal to 0.04-0.06 inches of water gauge.

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A suitable facility monitoring system will rapidly detect atypical changes that can compromise
the facility’s environment.  An effective system facilitates restoration of operating conditions to
established, qualified levels before reaching action levels.  For example, pressure differential
specifications should enable prompt detection (i.e., alarms) of an emerging low pressure problem
to preclude ingress of unclassified air into a classified room.

D.
Air Filtration

1.
Membrane

A compressed gas should be of appropriate purity (e.g., free from oil) and its microbiological and
particle quality after filtration should be equal to or better than that of the air in the environment
into which the gas is introduced.  Compressed gases such as air, nitrogen, and carbon dioxide are
often used in cleanrooms and are frequently employed in purging or overlaying.

Membrane filters can be used to filter a compressed gas to meet an appropriate high-quality
standard.  These filters are often used to produce a sterile compressed gas to conduct operations
involving sterile materials, such as components and equipment.  For example, we recommend
that sterile membrane filters be used for autoclave air lines, lyophilizer vacuum breaks, and tanks
containing sterilized materials.  Sterilized holding tanks and any contained liquids should be held
under positive pressure or appropriately sealed to prevent microbial contamination.  Safeguards
should be in place to prevent a pressure change that can result in contamination due to back flow
of nonsterile air or liquid.

Gas filters (including vent filters) should be dry.  Condensate on a gas filter can cause blockage
during use or allow for the growth of microorganisms.  Use of hydrophobic filters, as well as
application of heat to these filters where appropriate, prevents problematic moisture residues.
We recommend that filters that serve as sterile boundaries or supply sterile gases that can affect
product be integrity tested upon installation and periodically thereafter (e.g., end of use).
Integrity tests are also recommended after activities that may damage the filter.  Integrity test
failures should be investigated, and filters should be replaced at appropriate, defined intervals.

2.
High-Efficiency Particulate Air (HEPA)7

HEPA filter integrity should be maintained to ensure aseptic conditions.  Leak testing should be
performed at installation to detect integrity breaches around the sealing gaskets, through the
frames, or through various points on the filter media.  Thereafter, leak tests should be performed
at suitable time intervals for HEPA filters in the aseptic processing facility.  For example, such
testing should be performed twice a year for the aseptic processing room.  Additional testing may
be appropriate when air quality is found to be unacceptable, facility renovations might be the
cause of disturbances to ceiling or wall structures, or as part of an investigation into a media fill
or drug product sterility failure.  Among the filters that should be leak tested are those installed
in dry heat depyrogenation tunnels and ovens commonly used to depyrogenate glass vials.
Where justified, alternate methods can be used to test HEPA filters in the hot zones of these
tunnels and ovens.

7 The same broad principles can be applied to ULPA filters.

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Any aerosol used for challenging a HEPA filter should meet specifications for critical
physicochemical attributes such as viscosity.  Dioctylphthalate (DOP) and poly-alpha-olefin
(PAO) are examples of appropriate leak testing aerosols.  Some aerosols are problematic because
they pose the risk of microbial contamination of the environment being tested.  Accordingly, the
evaluation of any alternative aerosol involves ensuring it does not promote microbial growth.

There is a major difference between filter leak testing and efficiency testing. An efficiency test is
a general test used to determine the rating of the filter.8  An intact HEPA filter should be capable
of retaining at least 99.97 percent of particulates greater than 0.3 µm in diameter.

The purpose of performing regularly scheduled leak tests, on the other hand, is to detect leaks
from the filter media, filter frame, or seal.  The challenge involves use of a polydispersed aerosol
usually composed of particles with a light-scattering mean droplet diameter in the submicron size
range,9 including a sufficient number of particles at approximately 0.3 µm.  Performing a leak
test without introducing a sufficient upstream challenge of particles of known size upstream of
the filter is ineffective for detecting leaks.  It is important to introduce an aerosol upstream of the
filter in a concentration that is appropriate for the accuracy of the aerosol photometer.  The leak
test should be done in place, and the filter face scanned on the downstream side with an
appropriate photometer probe, at a sampling rate of at least one cubic foot per minute.  The
downstream leakage measured by the probe should then be calculated as a percent of the
upstream challenge.  An appropriate scan should be conducted on the entire filter face and frame,
at a position about one to two inches from the face of the filter.  This comprehensive scanning of
HEPA filters should be fully documented.

A single probe reading equivalent to 0.01 percent of the upstream challenge would be considered
as indicative of a significant leak and calls for replacement of the HEPA filter or, when
appropriate, repair in a limited area.  A subsequent confirmatory retest should be performed in
the area of any repair.

HEPA filter leak testing alone is insufficient to monitor filter performance.  It is important to
conduct periodic monitoring of filter attributes such as uniformity of velocity across the filter
(and relative to adjacent filters).  Variations in velocity can cause turbulence that increases the
possibility of contamination.  Velocities of unidirectional air should be measured 6 inches from
the filter face and at a defined distance proximal to the work surface for HEPA filters in the
critical area.  Velocity monitoring at suitable intervals can provide useful data on the critical area
in which aseptic processing is performed.  The measurements should correlate to the velocity
range established at the time of in situ air pattern analysis studies.  HEPA filters should be
replaced when nonuniformity of air velocity across an area of the filter is detected or airflow
patterns may be adversely affected.

8 The efficiency test uses a monodispersed aerosol of 0.3 micron sized particles and assesses filter media.
Downstream readings represent an average over the entire filter surface.  Efficiency tests are not intended to test for
filter leaks.

9 Although the mean is normally less than one micron, it is greater than 0.3µm.

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Although contractors often provide these services, drug manufacturers are responsible for
ensuring that equipment specifications, test methods, and acceptance criteria are defined, and
that these essential certification activities are conducted satisfactorily.

E.
Design

Note: The design concepts discussed within this section are not intended to be exhaustive.  Other
appropriate technologies that achieve increased sterility assurance are also encouraged.

Aseptic processes are designed to minimize exposure of sterile articles to the potential
contamination hazards of the manufacturing operation.  Limiting the duration of exposure of sterile
product elements, providing the highest possible environmental control, optimizing process flow,
and designing equipment to prevent entrainment of lower quality air into the Class 100 (ISO 5)
clean area are essential to achieving high assurance of sterility (Ref. 4).

Both personnel and material flow should be optimized to prevent unnecessary activities that
could increase the potential for introducing contaminants to exposed product, container-closures,
or the surrounding environment.  The layout of equipment should provide for ergonomics that
optimize comfort and movement of operators.  The number of personnel in an aseptic processing
room should be minimized.  The flow of personnel should be designed to limit the frequency
with which entries and exits are made to and from an aseptic processing room and, most
significant, its critical area.  Regarding the latter, the number of transfers into the critical area of
a traditional cleanroom, or an isolator, should be minimized.  To prevent changes in air currents
that introduce lower quality air, movement adjacent to the critical area should be appropriately
restricted.

Any intervention or stoppage during an aseptic process can increase the risk of contamination.
The design of equipment used in aseptic processing should limit the number and complexity of
aseptic interventions by personnel.  For example, personnel intervention can be reduced by
integrating an on-line weight check device, thus eliminating a repeated manual activity within
the critical area.  Rather than performing an aseptic connection, sterilizing the preassembled
connection using sterilize-in-place (SIP) technology also can eliminate a significant aseptic
manipulation.  Automation of other process steps, including the use of technologies such as
robotics, can further reduce risk to the product.

Products should be transferred under appropriate cleanroom conditions.  For example,
lyophilization processes include transfer of aseptically filled product in partially sealed
containers.  To prevent contamination, a partially closed sterile product should be transferred
only in critical areas.10  Facility design should ensure that the area between a filling line and the
lyophilizer provide for Class 100 (ISO 5) protection. Transport and loading procedures should
afford the same protection.

The sterile drug product and its container-closures should be protected by equipment of suitable
design.  Carefully designed curtains and rigid plastic shields are among the barriers that can be

10 Appropriately designed transfer equipment provides these conditions and can be qualified for this purpose.

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Contains Nonbinding Recommendations

used in appropriate locations to achieve segregation of the aseptic processing line.  Use of an
isolator system further enhances product protection (see Appendix 1).

Due to the interdependence of the various rooms that make up an aseptic processing facility, it is
essential to carefully define and control the dynamic interactions permitted between cleanrooms.
Use of a double-door or integrated sterilizer helps ensure direct product flow, often from a lower
to a higher classified area.  Airlocks and interlocking doors will facilitate better control of air
balance throughout the aseptic processing facility.  Airlocks should be installed between the
aseptic manufacturing area entrance and the adjoining unclassified area.  Other interfaces such as
personnel transitions or material staging areas are appropriate locations for air locks.  It is critical
to adequately control material (e.g., in-process supplies, equipment, utensils) as it transfers from
lesser to higher classified clean areas to prevent the influx of contaminants.  For example, written
procedures should address how materials are to be introduced into the aseptic processing room to
ensure that room conditions remain uncompromised.  In this regard, materials should be
disinfected according to appropriate procedures or, when used in critical areas, rendered sterile
by a suitable method.

If stoppered vials exit an aseptic processing zone or room prior to capping, appropriate
assurances should be in place to safeguard the product, such as local protection until completion
of the crimping step.  Use of devices for on-line detection of improperly seated stoppers can
provide additional assurance.

Cleanrooms are normally designed as functional units with specific purposes.  The materials of
construction of cleanrooms ensure ease of cleaning and sanitizing.  Examples of adequate design
features include seamless and rounded floor to wall junctions as well as readily accessible
corners.  Floors, walls, and ceilings should be constructed of smooth, hard surfaces that can be
easily cleaned.  Ceilings and associated HEPA filter banks should be designed to protect sterile
materials from contamination.  Cleanrooms also should not contain unnecessary equipment,
fixtures, or materials.

Processing equipment and systems should be equipped with sanitary fittings and valves. With
rare exceptions, drains are considered inappropriate for classified areas of the aseptic processing
facility other than Class 100,000 (ISO 8) areas.  It is essential that any drain installed in an
aseptic processing facility be of suitable design.

Equipment should be appropriately designed (§ 211.63) to facilitate ease of sterilization.  It is
also important to ensure ease of installation to facilitate aseptic setup.  The effect of equipment
design on the cleanroom environment should be addressed.  Horizontal surfaces or ledges that
accumulate particles should be avoided.  Equipment should not obstruct airflow and, in critical
areas, its design should not disturb unidirectional airflow.

Deviation or change control systems should address atypical conditions posed by shutdown of air
handling systems or other utilities, and the impact of construction activities on facility control.
Written procedures should address returning a facility to operating conditions following a
shutdown.

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V.
PERSONNEL TRAINING, QUALIFICATION, & MONITORING

21 CFR 211.22(a) states that “There shall be a quality control unit that shall have the responsibility and authority to
approve or reject all components, drug product containers, closures, in-process materials, packaging material,
labeling, and drug products, and the authority to review production records to assure that no errors have occurred or,
if errors have occurred, that they have been fully investigated.  The quality control unit shall be responsible for
approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.”

21 CFR 211.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all
procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.”

21 CFR 211.25(a) states that “Each person engaged in the manufacture, processing, packing, or holding of a drug
product shall have education, training, and experience, or any combination thereof, to enable that person to perform
the assigned functions.  Training shall be in the particular operations that the employee performs and in current
good manufacturing practice (including the current good manufacturing practice regulations in this chapter and
written procedures required by these regulations) as they relate to the employee's functions. Training in current
good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient
frequency to assure that employees remain familiar with CGMP requirements applicable to them.”

21 CFR 211.25(b) states that “Each person responsible for supervising the manufacture, processing, packing, or
holding of a drug product shall have the education, training, and experience, or any combination thereof, to perform
assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength,
quality, and purity that it purports or is represented to possess.”

21 CFR 211.25(c) states that “There shall be an adequate number of qualified personnel to perform and supervise
the manufacture, processing, packing, or holding of each drug product.”

21 CFR 211.28(a) states that “Personnel engaged in the manufacture, processing, packing, or holding of a drug
product shall wear clean clothing appropriate for the duties they perform.  Protective apparel, such as head, face,
hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.”

21 CFR 211.28(b) states that “Personnel shall practice good sanitation and health habits.”

21 CFR 211.28(c) states that “Only personnel authorized by supervisory personnel shall enter those areas of the
buildings and facilities designated as limited-access areas.”

21 CFR 211.28(d) states that “Any person shown at any time (either by medical examination or supervisory
observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug
products shall be excluded from direct contact with components, drug product containers, closures, in-process
materials, and drug products until the condition is corrected or determined by competent medical personnel not to
jeopardize the safety or quality of drug products.  All personnel shall be instructed to report to supervisory
personnel any health conditions that may have an adverse effect on drug products.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate
size.  There shall be separate or defined areas or such other control systems for the firm’s operations as are
necessary to prevent contamination or mixups during the course of the following procedures: * * * (10)  Aseptic
processing, which includes as appropriate: * * * (iv) A system for monitoring environmental conditions * * *.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination
of drug products purporting to be sterile, shall be established and followed.  Such procedures shall include
validation of any sterilization process.”

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Contains Nonbinding Recommendations

A.
Personnel

A well-designed, maintained, and operated aseptic process minimizes personnel intervention.  As
operator activities increase in an aseptic processing operation, the risk to finished product
sterility also increases. To ensure maintenance of product sterility, it is critical for operators
involved in aseptic activities to use aseptic technique at all times.

Appropriate training should be conducted before an individual is permitted to enter the aseptic
manufacturing area.  Fundamental training topics should include aseptic technique, cleanroom
behavior, microbiology, hygiene, gowning, patient safety hazards posed by a nonsterile drug
product, and the specific written procedures covering aseptic manufacturing area operations.
After initial training, personnel should participate regularly in an ongoing training program.
Supervisory personnel should routinely evaluate each operator’s conformance to written
procedures during actual operations.  Similarly, the quality control unit should provide regular
oversight of adherence to established, written procedures and aseptic technique during
manufacturing operations.

Some of the techniques aimed at maintaining sterility of sterile items and surfaces include:

• Contact sterile materials only with sterile instruments

Sterile instruments should always be used in the handling of sterilized materials.
Between uses, sterile instruments should be held under Class 100 (ISO 5) conditions and
maintained in a manner that prevents contamination (e.g., placed in sterilized containers).
Instruments should be replaced as necessary throughout an operation.

After initial gowning, sterile gloves should be regularly sanitized or changed, as
appropriate, to minimize the risk of contamination.  Personnel should not directly contact
sterile products, containers, closures, or critical surfaces with any part of their gown or
gloves.

• Move slowly and deliberately

Rapid movements can create unacceptable turbulence in a critical area.  Such movements
disrupt the unidirectional airflow, presenting a challenge beyond intended cleanroom
design and control parameters.  The principle of slow, careful movement should be
followed throughout the cleanroom.

• Keep the entire body out of the path of unidirectional airflow

Unidirectional airflow design is used to protect sterile equipment surfaces, container-
closures, and product.  Disruption of the path of unidirectional flow air in the critical area
can pose a risk to product sterility.

• Approach a necessary manipulation in a manner that does not compromise sterility of
the product

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To maintain sterility of nearby sterile materials, a proper aseptic manipulation should be
approached from the side and not above the product (in vertical unidirectional flow
operations).  Also, operators should refrain from speaking when in direct proximity to the
critical area.

• Maintain Proper Gown Control

Prior to and throughout aseptic operations, an operator should not engage in any activity
that poses an unreasonable contamination risk to the gown.

Only personnel who are qualified and appropriately gowned should be permitted access to the
aseptic manufacturing area.  The gown should provide a barrier between the body and exposed
sterilized materials and prevent contamination from particles generated by, and microorganisms
shed from, the body.  The Agency recommends gowns that are sterilized and nonshedding, and
cover the skin and hair (face-masks, hoods, beard/moustache covers, protective goggles, and
elastic gloves are examples of common elements of gowns).  Written procedures should detail
the methods used to don each gown component in an aseptic manner.  An adequate barrier
should be created by the overlapping of gown components (e.g., gloves overlapping sleeves).  If
an element of a gown is found to be torn or defective, it should be changed immediately.  Gloves
should be sanitized frequently.

There should be an established program to regularly assess or audit conformance of personnel to
relevant aseptic manufacturing requirements.  An aseptic gowning qualification program should
assess the ability of a cleanroom operator to maintain the quality of the gown after performance
of gowning procedures.  We recommend that this assessment include microbiological surface
sampling of several locations on a gown (e.g., glove fingers, facemask, forearm, chest).
Sampling sites should be justified.  Following an initial assessment of gowning, periodic
requalification will provide for the monitoring of various gowning locations over a suitable
period to ensure consistent acceptability of aseptic gowning techniques.  Annual requalification
is normally sufficient for those automated operations where personnel involvement is minimized
and monitoring data indicate environmental control.  For any aseptic processing operation, if
adverse conditions occur, additional or more frequent requalification could be indicated.

To protect exposed sterilized product, personnel should to maintain gown quality and strictly
adhere to appropriate aseptic techniques.  Written procedures should adequately address
circumstances under which personnel should be retrained, requalified, or reassigned to other
areas.

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B.
Laboratory Personnel

The basic principles of training, aseptic technique, and personnel qualification in aseptic
manufacturing also are applicable to those performing aseptic sampling and microbiological
laboratory analyses.  Processes and systems cannot be considered to be in control and
reproducible if the validity of data produced by the laboratory is in question.

C.
Monitoring Program

Personnel can significantly affect the quality of the environment in which the sterile product is
processed.  A vigilant and responsive personnel monitoring program should be established.
Monitoring should be accomplished by obtaining surface samples of each operator's gloves on a
daily basis, or in association with each lot.  This sampling should be accompanied by an
appropriate sampling frequency for other strategically selected locations of the gown (Ref. 5).
The quality control unit should establish a more comprehensive monitoring program for
operators involved in operations which are especially labor intensive (i.e., those requiring
repeated or complex aseptic manipulations).

Asepsis is fundamental to an aseptic processing operation.  An ongoing goal for manufacturing
personnel in the aseptic processing room is to maintain contamination-free gloves and gowns
throughout operations.  Sanitizing gloves just prior to sampling is inappropriate because it can
prevent recovery of microorganisms that were present during an aseptic manipulation.  When
operators exceed established levels or show an adverse trend, an investigation should be
conducted promptly.  Follow-up actions can include increased sampling, increased observation,
retraining, gowning requalification, and in certain instances, reassignment of the individual to
operations outside of the aseptic manufacturing area.  Microbiological trending systems, and
assessment of the impact of atypical trends, are discussed in more detail under Section X.
Laboratory Controls.

VI. COMPONENTS AND CONTAINER/CLOSURES

21 CFR 210.3(b)(3) states that “Component means any ingredient intended for use in the manufacture of a drug product,
including those that may not appear in such drug product.”

21 CFR 211.80(a) states that “There shall be written procedures describing in sufficient detail the receipt, identification,
storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures;
such written procedures shall be followed.”

21 CFR 211.80(b) states that “Components and drug product containers and closures shall at all times be handled and stored
in a manner to prevent contamination.”

21 CFR 211.84(d) states, in part, that “Samples shall be examined and tested as follows: * * *  (6) Each lot of a component,
drug product container, or closure that is liable to microbiological contamination that is objectionable in view of its
intended use shall be subjected to microbiological tests before use.”

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21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of the
drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.”

21 CFR 211.94(d) states that “Standards or specifications, methods of testing, and, where indicated, methods of cleaning,
sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and
closures.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug
products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of any
sterilization process.”

A.
Components

A drug product produced by aseptic processing can become contaminated through the use of one
or more components that are contaminated with microorganisms or endotoxins.  Examples of
components include active ingredients, Water for Injection (WFI), and other excipients.  It is
important to characterize the microbial content (e.g., bioburden, endotoxin) of each component
that could be contaminated and establish appropriate acceptance limits.

Endotoxin load data are significant because parenteral products are intended to be nonpyrogenic.
There should be written procedures and appropriate specifications for acceptance or rejection of
each lot of components that might contain endotoxins.  Any components failing to meet defined
endotoxin limits should be rejected.

In aseptic processing, each component is individually sterilized or several components are
combined, with the resulting mixture sterilized.11  Knowledge of bioburden is important in
assessing whether a sterilization process is adequate.  Several methods can be suitable for
sterilizing components (see relevant discussion in Section IX).  A widely used method is
filtration of a solution formed by dissolving the component(s) in a solvent such as Water For
sterilization is used where the component is soluble and is likely to be adversely affected by heat.
A variation of this method includes subjecting the filtered solution to aseptic crystallization and
precipitation (or lyophilization) of the component as a sterile powder.  However, this method
involves more handling and manipulation and therefore has a higher potential for contamination
during processing.

Dry heat sterilization is a suitable method for components that are heat stable and insoluble.
However, conducting carefully designed heat penetration and distribution studies is of particular
significance for powder sterilization because of the insulating effects of the powder.

Irradiation can be used to sterilize some components.  Studies should be conducted to
demonstrate that the process is appropriate for the component.

11 See Appendix III for discussion of certain biologic components that are aseptically handled from the start of the
process.

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B.
Containers/Closures

1.
Preparation

Containers and closures should be rendered sterile and, for parenteral drug products,
nonpyrogenic.  The process used will depend primarily on the nature of the container and/or
closure materials.  The validation study for such a process should be adequate to demonstrate its
ability to render materials sterile and non-pyrogenic.  Written procedures should specify the
frequency of revalidation of these processes as well as time limits for holding sterile,
depyrogenated containers and closures.

Pre-sterilization preparation of glass containers usually involves a series of wash and rinse
cycles. These cycles serve an important role in removing foreign matter.  We recommend use of
rinse water of high purity so as not to contaminate containers.  For parenteral products, final
rinse water should meet the specifications of WFI, USP.

The adequacy of the depyrogenation process can be assessed by spiking containers and closures
with known quantities of endotoxin, followed by measuring endotoxin content after
depyrogenation.  The challenge studies can generally be performed by directly applying a
reconstituted endotoxin solution onto the surfaces being tested.  The endotoxin solution should
then be allowed to air dry.  Positive controls should be used to measure the percentage of
endotoxin recovery by the test method.  Validation study data should demonstrate that the
process reduces the endotoxin content by at least 99.9 percent (3 logs) (see Section VII).12

Subjecting glass containers to dry heat generally accomplishes both sterilization and
depyrogenation.  Validation of dry heat sterilization and depyrogenation should include
appropriate heat distribution and penetration studies as well as the use of worst-case process
cycles, container characteristics (e.g., mass), and specific loading configurations to represent
actual production runs.  See Section IX.C.  Plastic containers used for parenteral products also
should be non-pyrogenic.  Where applicable, multiple WFI rinses can be effective in removing
pyrogens from these containers.

Plastic containers can be sterilized with an appropriate gas, irradiation, or other suitable means.
For gases such as Ethylene Oxide (EtO), certain issues should receive attention.  For example,
the parameters and limits of the EtO sterilization cycle (e.g., temperature, pressure, humidity, gas
concentration, exposure time, degassing, aeration, and determination of residuals) should be
specified and monitored closely.  EtO is an effective surface sterilant and is also used to
penetrate certain packages with porous overwrapping.  Biological indicators are of special
importance in demonstrating the effectiveness of EtO and other gas sterilization processes.  We
recommend that these methods be carefully controlled and validated to evaluate whether
consistent penetration of the sterilant can be achieved and to minimize residuals.  Residuals from
EtO processes typically include ethylene oxide as well as its byproducts, and should be within
specified limits.

12 When this level of depyrogenation by dry heat has been successfully validated using endotoxin challenge, a
sterilization validation using a biological indicator challenge would not be indicated.

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Rubber closures (e.g., stoppers and syringe plungers) can be cleaned by multiple cycles of
washing and rinsing prior to final steam or irradiation sterilization.  At minimum, the initial
rinses for the washing process should employ at least Purified Water, USP, of minimal endotoxin
content, followed by final rinse(s) with WFI for parenteral products.  Normally, depyrogenation
can be achieved by multiple rinses of hot WFI.  The time between washing, drying (where
appropriate), and sterilizing should be minimized because residual moisture on the stoppers can
support microbial growth and the generation of endotoxins.  Because rubber is a poor conductor
of heat, extra attention is indicated in the validation of processes that use heat with respect to its
penetration into the rubber stopper load (See Section IX.C).  Validation data from the washing
procedure should demonstrate successful endotoxin removal from rubber materials.

A potential source of contamination is the siliconization of rubber stoppers.  Silicone used in the
preparation of rubber stoppers should meet appropriate quality control criteria and not have an
adverse effect on the safety, quality, or purity of the drug product.

Contract facilities that perform sterilization and/or depyrogenation of containers and closures are
subject to the same CGMP requirements as those established for in-house processing.  The
finished dosage form manufacturer should review and assess the contractor's validation protocol
and final validation report.  In accord with 211.84(d)(3), a manufacturer who establishes the
reliability of the supplier’s test results at appropriate intervals may accept containers or closures
based on visual identification and Certificate of Analysis review.

2.
Inspection of Container Closure System

A container closure system that permits penetration of microorganisms is unsuitable for a sterile
product.  Any damaged or defective units should be detected, and removed, during inspection of
the final sealed product.  Safeguards should be implemented to strictly preclude shipment of
product that may lack container closure integrity and lead to nonsterility.  Equipment suitability
problems or incoming container or closure deficiencies can cause loss of container closure
system integrity.  For example, failure to detect vials fractured by faulty machinery as well as by
mishandling of bulk finished stock has led to drug recalls.  If damage that is not readily detected
leads to loss of container closure integrity, improved procedures should be rapidly implemented
to prevent and detect such defects.

Functional defects in delivery devices (e.g., syringe device defects, delivery volume) can also
result in product quality problems and should be monitored by appropriate in-process testing.

Any defects or results outside the specifications established for in-process and final inspection
are to be investigated in accord with § 211.192.

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VII. ENDOTOXIN CONTROL

21 CFR 211.63 states that “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be
of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning
and maintenance.”

21 CFR 211.65(a) states that “Equipment shall be constructed so that surfaces that contact components, in-process
materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality,
or purity of the drug product beyond the official or other established requirements.”

21 CFR 211.67(a) states that “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals
to prevent malfunctions or contamination that would alter the safety, identify, strength, quality, or purity of the drug
product beyond the official or other established requirements.”

21 CFR 211.94(c) states that “Drug product containers and closures shall be clean and, where indicated by the nature of
the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.”

21 CFR 211.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be
appropriate laboratory testing to determine conformance to such requirements.  The test procedures shall be in writing and
shall be followed.”

Endotoxin contamination of an injectable product can occur as a result of poor CGMP controls.
Certain patient populations (e.g., neonates), those receiving other injections concomitantly, or
those administered a parenteral in atypically large volumes or doses can be at greater risk for
pyrogenic reaction than anticipated by the established limits based on body weight of a normal
healthy adult (Ref. 6, 7).  Such clinical concerns reinforce the importance of exercising
appropriate CGMP controls to prevent generation of endotoxins.  Drug product components,
containers, closures, storage time limitations, and manufacturing equipment are among the areas
to address in establishing endotoxin control.

Adequate cleaning, drying, and storage of equipment will control bioburden and prevent
contribution of endotoxin load.  Equipment should be designed to be easily assembled and
disassembled, cleaned, sanitized, and/or sterilized.  If adequate procedures are not employed,
endotoxins can be contributed by both upstream and downstream processing equipment.

Sterilizing-grade filters and moist heat sterilization have not been shown to be effective in
removing endotoxin.  Endotoxin on equipment surfaces can be inactivated by high-temperature
dry heat, or removed from equipment surfaces by cleaning procedures.  Some clean-in-place
procedures employ initial rinses with appropriate high purity water and/or a cleaning agent (e.g.,
acid, base, surfactant), followed by final rinses with heated WFI.  Equipment should be dried
following cleaning, unless the equipment proceeds immediately to the sterilization step.

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VIII. TIME LIMITATIONS

21 CFR 211.111 states that “When appropriate, time limits for the completion of each phase of production shall be
established to assure the quality of the drug product.  Deviation from established time limits may be acceptable if such
deviation does not compromise the quality of the drug product.  Such deviation shall be justified and documented.”

When appropriate, time limits must be established for each phase of aseptic processing
(§ 211.111).  Time limits should include, for example, the period between the start of bulk
product compounding and its sterilization, filtration processes, product exposure while on the
processing line, and storage of sterilized equipment, containers and closures.  The time limits
established for the various production phases should be supported by data.  Bioburden and
endotoxin load should be assessed when establishing time limits for stages such as the
formulation processing stage.

The total time for product filtration should be limited to an established maximum to prevent
microorganisms from penetrating the filter.  Such a time limit should also prevent a significant
increase in upstream bioburden and endotoxin load.  Because they can provide a substrate for
microbial attachment, maximum use times for those filters used upstream for solution
clarification or particle removal should also be established and justified.

IX.
VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION

21 CFR 211.63, 211.65, and 211.67 address, respectively, “Equipment design, size, and location,” “Equipment construction,”
and “Equipment cleaning and maintenance.”

21 CFR 211.84(c) states, in part, that “Samples shall be collected in accordance with the following procedures: * * * (3)
Sterile equipment and aseptic sampling techniques shall be used when necessary.”

21 CFR 211.100(a) states, in part, that “There shall be written procedures for production and process control designed to
assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.  Such
procedures shall include all requirements in this subpart * * *.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug
products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of any
sterilization process.”

This section primarily discusses routine qualification and validation study recommendations.
Change control procedures are addressed only briefly, but are an important part of the quality
systems established by a firm.  A change in facility, equipment, process, or test method should be
evaluated through the written change control program, triggering an evaluation of the need for
revalidation or requalification.

A.
Process Simulations

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To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling and closing
operations must be adequately validated (§ 211.113).  The goal of even the most effective
sterilization processes can be defeated if the sterilized elements of a product (the drug
formulation, the container, and the closure) are brought together under conditions that
contaminate any of those elements.

An aseptic processing operation should be validated using a microbiological growth medium in
place of the product.  This process simulation, also known as a media fill, normally includes
exposing the microbiological growth medium to product contact surfaces of equipment,
container closure systems, critical environments, and process manipulations to closely simulate
the same exposure that the product itself will undergo.  The sealed containers filled with the
medium are then incubated to detect microbial contamination.  Results are then interpreted to
assess the potential for a unit of drug product to become contaminated during actual operations
(e.g., start-up, sterile ingredient additions, aseptic connections, filling, closing).  Environmental
monitoring data from the process simulation can also provide useful information for the
processing line evaluation.

1.
 Study Design

A media fill program should incorporate the contamination risk factors that occur on a
production line, and accurately assesses the state of process control.  Media fill studies should
closely simulate aseptic manufacturing operations incorporating, as appropriate, worst-case
activities and conditions that provide a challenge to aseptic operations.  FDA recommends that
the media fill program address applicable issues such as:

• Factors associated with the longest permitted run on the processing line that can pose
contamination risk (e.g., operator fatigue)
• Representative number, type, and complexity of normal interventions that occur with
each run, as well as nonroutine interventions and events (e.g., maintenance,
stoppages, equipment adjustments)
• Lyophilization, when applicable
• Aseptic assembly of equipment (e.g., at start-up, during processing)
• Number of personnel and their activities
• Representative number of aseptic additions (e.g., charging containers and closures as
well as sterile ingredients) or transfers
• Shift changes, breaks, and gown changes (when applicable)
• Type of aseptic equipment disconnections/connections
• Aseptic sample collections
• Line speed and configuration
• Weight checks
• Container closure systems (e.g., sizes, type, compatibility with equipment)

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• Specific provisions in written procedures relating to aseptic processing (e.g.,
conditions permitted before line clearance is mandated)

A written batch record, documenting production conditions and simulated activities, should be
prepared for each media fill run.  The same vigilance should be observed in both media fill and
routine production runs.  The firm’s rationale for the conditions and activities simulated during
the media fill should be clearly defined.  Media fills should not be used to justify practices that
pose unnecessary contamination risks.

2.
Frequency and Number of Runs

When a processing line is initially qualified, individual media fills should be repeated enough
times to ensure that results are consistent and meaningful.  This approach is important because a
single run can be inconclusive, while multiple runs with divergent results signal a process that is
not in control.  We recommend that at least three consecutive separate successful runs be
performed during initial line qualification.  Subsequently, routine semi-annual qualification
conducted for each processing line will evaluate the state of control of the aseptic process.
Activities and interventions representative of each shift, and shift changeover, should be
incorporated into the design of the semi-annual qualification program.  For example, the
evaluation of a production shift should address its unique time-related and operational features.13
All personnel who are authorized to enter the aseptic processing room during manufacturing,
including technicians and maintenance personnel, should participate in a media fill at least once
a year.  Participation should be consistent with the nature of each operator’s duties during routine
production.

Each change to a product or line change should be evaluated using a written change control
system.  Any changes or events that have the potential to affect the ability of the aseptic process
to exclude contamination from the sterilized product should be assessed through additional
media fills.  For example, facility and equipment modifications, line configuration changes,
significant changes in personnel, anomalies in environmental testing results, container closure
system changes, extended shutdowns, or end product sterility testing showing contaminated
products may be cause for revalidation of the system.

When data from a media fill indicate the process may not be in control, an investigation should
be conducted to determine the origin of the contamination and the scope of the problem.  Once
corrections are instituted, process simulation run(s) should be performed to confirm that
deficiencies have been corrected and the process has returned to a state of control.   When an
investigation fails to reach well-supported, substantive conclusions as to the cause of the media
fill failure, three consecutive successful runs in tandem with increased scrutiny of the production
process may be warranted.

3.
Duration of Runs

13 One example might be the movement of personnel into and out of the aseptic processing and gowning change
rooms during a shift change.

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The duration of aseptic processing operations is a major consideration in media fill design.
Although the most accurate simulation model would be the full batch size and duration because
it most closely simulates the actual production operations, other appropriate models can be
justified.  The duration of the media fill run should be determined by the time it takes to
incorporate manipulations and interventions, as well as appropriate consideration of the duration
of the actual aseptic processing operation.  Interventions that commonly occur should be
routinely simulated, while those occurring rarely can be simulated periodically.

While conventional manufacturing lines are usually automated, operated at relatively high
speeds, and designed to limit operator intervention, some processes still include considerable
operator involvement.  When aseptic processing employs manual filling or closing, or extensive
manual manipulations, the duration of the process simulation should generally be no less than the
length of the actual manufacturing process to best simulate contamination risks posed by
operators.

For lyophilization operations, FDA recommends that unsealed containers be exposed to partial
evacuation of the chamber in a manner that simulates the process.  Vials should not be frozen,
and precautions should be taken that ensure that the medium remains in an aerobic state to avoid
potentially inhibiting the growth of microorganisms.

4.
Size of Runs

The simulation run sizes should be adequate to mimic commercial production conditions and
accurately assess the potential for commercial batch contamination.  The number of units filled
during the process simulation should be based on contamination risk for a given process and
sufficient to accurately simulate activities that are representative of the manufacturing process.
A generally acceptable starting point for run size is in the range of 5,000 to 10,000 units.  For
operations with production sizes under 5,000, the number of media filled units should at least
equal the maximum batch size made on the processing line (Ref. 8).

When the possibility of contamination is higher based on the process design (e.g., manually
intensive filling lines), a larger number of units, generally at or approaching the full production
batch size, should be used.  In contrast, a process conducted in an isolator (see Appendix 1) can
have a low risk of contamination because of the lack of direct human intervention and can be
simulated with a lower number of units as a proportion of the overall operation.

Media fill size is an especially important consideration because some batches are produced over
multiple shifts or yield an unusually large number of units.  These factors should be carefully
evaluated when designing the simulation to adequately encompass conditions and any potential
risks associated with the larger operation.

5.
Line Speed

The media fill program should adequately address the range of line speeds employed during
production.  Each media fill run should evaluate a single line speed, and the speed chosen should
be justified.  For example, use of high line speed is often most appropriate in the evaluation of
manufacturing processes characterized by frequent interventions or a significant degree of

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manual manipulation.  Use of slow line speed is generally appropriate for evaluating
manufacturing processes with prolonged exposure of the sterile drug product and
containers/closures in the aseptic area.

6.
Environmental Conditions

Media fills should be adequately representative of the conditions under which actual
manufacturing operations are conducted.  An inaccurate assessment (making the process appear
cleaner than it actually is) can result from conducting a media fill under extraordinary air
particulate and microbial quality, or under production controls and precautions taken in
preparation for the media fill.  To the extent standard operating procedures permit stressful
conditions (e.g., maximum number of personnel present and elevated activity level), it is
important that media fills include analogous challenges to support the validity of these studies.
Stressful conditions do not include artificially created environmental extremes, such as
reconfiguration of HVAC systems to operate at worst-case limits.

7.
 Media

In general, a microbiological growth medium, such as soybean casein digest medium, should be
used.  Use of anaerobic growth media (e.g., fluid thioglycollate medium) should be considered in
special circumstances.  The media selected should be demonstrated to promote growth of gram-
positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms).  The
QC laboratory should determine if USP indicator organisms sufficiently represent production-
related isolates.  Environmental monitoring and sterility test isolates can be substituted (as
appropriate) or added to the growth promotion challenge.  Growth promotion units should be
inoculated with a <100 CFU challenge.  If the growth promotion testing fails, the origin of any
contamination found during the simulation should nonetheless be investigated and the media fill
promptly repeated.14

The production process should be accurately simulated using media and conditions that optimize
detection of any microbiological contamination.  Each unit should be filled with an appropriate
quantity and type of microbial growth medium to contact the inner container closure surfaces
(when the unit is inverted or thoroughly swirled) and permit visual detection of microbial
growth.

Some drug manufacturers have expressed concern over the possible contamination of the facility
and equipment with nutrient media during media fill runs.  However, if the medium is handled
properly and is promptly followed by the cleaning, sanitizing, and, where necessary, sterilization
of equipment, subsequently processed products are not likely to be compromised.

8.
Incubation and Examination of Media-Filled Units

Media units should be incubated under conditions adequate to detect microorganisms that might
otherwise be difficult to culture.  Incubation conditions should be established in accord with the
following general guidelines:

14 The cause of the growth promotion failure should also be investigated.

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• Incubation temperature should be suitable for recovery of bioburden and environmental
isolates and should at no time be outside the range of 20-35oC.  Incubation temperature
should be maintained within +2.5oC of the target temperature.

• Incubation time should not be less than 14 days.  If two temperatures are used for the
incubation of the media filled units, the units should be incubated for at least 7 days at
each temperature (starting with the lower temperature).

Each media-filled unit should be examined for contamination by personnel with appropriate
education, training, and experience in inspecting media fill units for microbiological
contamination.  If QC personnel do not perform the inspection, there should be QC unit
oversight throughout any such examination.  All suspect units identified during the examination
should be brought to the immediate attention of the QC microbiologist.  To allow for visual
detection of microbial growth, we recommend substituting clear containers (with otherwise
identical physical properties) for amber or other opaque containers.  If appropriate, other
methods can also be considered to ensure visual detection.

When a firm performs a final product inspection of units immediately following the media fill
run, all integral units should proceed to incubation.  Units found to have defects not related to
integrity (e.g., cosmetic defect) should be incubated; units that lack integrity should be rejected.
Erroneously rejected units should be returned promptly for incubation with the media fill lot.

After incubation is underway, any unit found to be damaged should be included in the data for
the media fill run, because the units can be representative of drug product released to the market.
Any decision to exclude such incubated units (i.e., non-integral) from the final run tally should
be fully justified and the deviation explained in the media fill report.  If a correlation emerges
between difficult to detect damage and microbial contamination, a thorough investigation should
be conducted to determine its cause (see Section VI.B).

Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention
type; quantity of units removed), providing for consistent production practices and assessment of
these practices during media fills.  If written procedures and batch documentation are adequate to
describe an associated clearance, the intervention units removed during media fills do not need to
be incubated.15  Where procedures lack specificity, there would be insufficient justification for
exclusion of units removed during an intervention from incubation.  For example, if a production
procedure requires removal of 10 units after an intervention at the stoppering station infeed,
batch records (i.e., for production and media fills) should clearly document conformance with
this procedure.  In no case should more units be removed during a media fill intervention than
would be cleared during a production run.

The ability of a media fill run to detect potential contamination from a given simulated activity
should not be compromised by a large-scale line clearance.  We recommend incorporating

15 To assess contamination risks during initial aseptic setup (before fill), valuable information can be obtained by
incubating all such units that may be normally removed.  These units are typically incubated separately, and would
not necessarily be included in the acceptance criteria for the media fill.

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appropriate study provisions to avoid and address a large line clearance that results in the
removal of a unit possibly contaminated during an unrelated event or intervention.

Appropriate criteria should be established for yield16 and accountability (reconciliation of filled
units).  Media fill record reconciliation documentation should include a full accounting and
description of units rejected from a batch.

9.
Interpretation of Test Results

The process simulation run should be observed by the QC Unit, and contaminated units should
be reconcilable with the approximate time and the activity being simulated during the media fill.
Video recording of a media fill may serve as a useful aide in identifying personnel practices that
could negatively affect the aseptic process.

Any contaminated unit should be considered objectionable and investigated.  The
microorganisms should be identified to species level.  The investigation should survey the
possible causes of contamination.  In addition, any failure investigation should assess the impact
on commercial drugs produced on the line since the last media fill.

Whenever contamination exists in a media fill run, it should be considered indicative of a
potential sterility assurance problem, regardless of run size.  The number of contaminated units
should not be expected to increase in a directly proportional manner with the number of vials in
the media fill run.  Test results should reliably and reproducibly show that the units produced by
an aseptic processing operation are sterile.  Modern aseptic processing operations in suitably
designed facilities have demonstrated a capability of meeting contamination levels approaching
zero (Ref. 8, 9) and should normally yield no media fill contamination.  Recommended criteria
for assessing state of aseptic line control are as follows:

• When filling fewer than 5000 units, no contaminated units should be detected.
-- One (1) contaminated unit is considered cause for revalidation, following an
investigation.

• When filling from 5,000 to 10,000 units:
-- One (1) contaminated unit should result in an investigation, including consideration of
a repeat media fill.
-- Two (2) contaminated units are considered cause for revalidation, following
investigation.

• When filling more than 10,000 units:
-- One (1) contaminated unit should result in an investigation.
-- Two (2) contaminated units are considered cause for revalidation, following
investigation.

For any run size, intermittent incidents of microbial contamination in media filled runs can be
indicative of a persistent low-level contamination problem that should be investigated.

16Total units incubated/total number of units filled.

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Accordingly, recurring incidents of contaminated units in media fills for an individual line,
regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing
line that should lead to problem identification, correction, and revalidation.

A firm's use of media fill acceptance criteria allowing infrequent contamination does not mean
that a distributed lot of drug product purporting to be sterile may contain a nonsterile unit.  The
purpose of an aseptic process is to prevent any contamination.  A manufacturer is fully liable for
the shipment of any nonsterile unit, an act that is prohibited under the FD&C Act (Section 301(a)
21 U.S.C. 331(a)).  FDA also recognizes that there might be some scientific and technical
limitations on how precisely and accurately process simulations can characterize a system of
controls intended to exclude contamination.

As with any process validation run, it is important to note that invalidation of a media fill run
should be a rare occurrence.  A media fill run should be aborted only under circumstances in
which written procedures require commercial lots to be equally handled.  Supporting
documentation and justification should be provided in such cases.

B.
Filtration Efficacy

Filtration is a common method of sterilizing drug product solutions.  A sterilizing grade filter
should be validated to reproducibly remove viable microorganisms from the process stream,
producing a sterile effluent.17  Currently, such filters usually have a rated pore size of 0.2 µm or
smaller.18  Use of redundant sterilizing filters should be considered in many cases.  Whatever
filter or combination of filters is used, validation should include microbiological challenges to
simulate worst-case production conditions for the material to be filtered and integrity test results
of the filters used for the study.  Product bioburden should be evaluated when selecting a suitable
challenge microorganism to assess which microorganism represents the worst-case challenge to
the filter.  The microorganism Brevundimonas diminuta (ATCC 19146) when properly grown,
harvested and used, is a common challenge microorganism for 0.2 µm rated filters because of its
small size (0.3 µm mean diameter).  The manufacturing process controls should be designed to
minimize the bioburden of the unfiltered product.  Bioburden of unsterilized bulk solutions
should be determined to trend the characteristics of potentially contaminating organisms.

In certain cases, when justified as equivalent or better than use of B. diminuta, it may be
appropriate to conduct bacterial retention studies with a bioburden isolate.  The number of
microorganisms in the challenge is important because a filter can contain a number of pores
larger than the nominal rating, which has the potential to allow passage of microorganisms.  The
probability of such passage is considered to increase as the number of organisms (bioburden) in
the material to be filtered increases.  A challenge concentration of at least 107 organisms per cm2
of effective filtration area should generally be used, resulting in no passage of the challenge
microorganism.  The challenge concentration used for validation is intended to provide a margin
of safety well beyond what would be expected in production.

17 This document does not address virus removal.

18 0.22µ and 0.2µ are considered interchangeable nominal pore size ratings.

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Direct inoculation into the drug formulation is the preferred method because it provides an
assessment of the effect of drug product on the filter matrix and on the challenge organism.
However, directly inoculating B. diminuta into products with inherent bactericidal activity
against this microbe, or into oil-based formulations, can lead to erroneous conclusions.  When
sufficiently justified, the effects of the product formulation on the membrane's integrity can be
assessed using an appropriate alternate method.  For example, a drug product could be filtered in
a manner in which the worst-case combination of process specifications and conditions are
simulated.  This step could be followed by filtration of the challenge organism for a significant
period of time, under the same conditions, using an appropriately modified product (e.g., lacking
an antimicrobial preservative or other antimicrobial component) as the vehicle.  Any divergence
from a simulation using the actual product and conditions of processing should be justified.

Factors that can affect filter performance generally include (1) viscosity and surface tension of
the material to be filtered, (2) pH, (3) compatibility of the material or formulation components
with the filter itself, (4) pressures, (5) flow rates, (6) maximum use time, (7) temperature, (8)
osmolality, (9) and the effects of hydraulic shock.  When designing the validation protocol, it is
important to address the effect of the extremes of processing factors on the filter capability to
produce sterile effluent.  Filter validation should be conducted using the worst-case conditions,
such as maximum filter use time and pressure (Ref. 12).  Filter validation experiments, including
microbial challenges, need not be conducted in the actual manufacturing areas.  However, it is
essential that laboratory experiments simulate actual production conditions.  The specific type of
filter membrane used in commercial production should be evaluated in filter validation studies.
There are advantages to using production filters in these bacterial retention validation studies.
When the more complex filter validation tests go beyond the capabilities of the filter user, tests
are often conducted by outside laboratories or by filter manufacturers.  However, it is the
responsibility of the filter user to review the validation data on the efficacy of the filter in
producing a sterile effluent.  The data should be applicable to the user's products and conditions
of use because filter performance may differ significantly for various conditions and products.

After a filtration process is properly validated for a given product, process, and filter, it is
important to ensure that identical filters (e.g., of identical polymer construction and pore size
rating) are used in production runs.  Sterilizing filters should be routinely discarded after
processing of a single lot.  However, in those instances when repeated use can be justified, the
sterile filter validation should incorporate the maximum number of lots to be processed.
Integrity testing of the filter(s) can be performed prior to processing, and should be routinely
performed post-use.   It is important that integrity testing be conducted after filtration to detect
any filter leaks or perforations that might have occurred during the filtration.  Forward flow and
bubble point tests, when appropriately employed, are two integrity tests that can be used.  A
production filter’s integrity test specification should be consistent with data generated during
bacterial retention validation studies.

C.
Sterilization of Equipment, Containers, and Closures

Equipment surfaces that contact sterilized drug product or its sterilized containers or closures
must be sterile so as not to alter purity of the drug (211.67 and 211.113).  Where reasonable
contamination potential exists, surfaces that are in the vicinity of the sterile product should also
be rendered free of viable organisms.  It is as important in aseptic processing to validate the

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processes used to sterilize such critical equipment as it is to validate processes used to sterilize
the drug product and its container and closure.  Moist heat and dry heat sterilization, the most
widely used, are the primary processes discussed in this document.  However, many of the heat
sterilization principles discussed in this guidance are also applicable to other sterilization
methods.

Sterility of aseptic processing equipment should normally be maintained by sterilization between
each batch.19  Following sterilization, transportation and assembly of equipment, containers, and
closures should be performed with strict adherence to aseptic methods in a manner that protects
and sustains the product's sterile state.

1.
Qualification and Validation

Validation studies should be conducted to demonstrate the efficacy of the sterilization cycle.
Requalification studies should also be performed on a periodic basis.  The specific load
configurations, as well as biological indicator and temperature sensor locations, should be
documented in validation records.  Batch production records should subsequently document
adherence to the validated load patterns.

It is important to remove air from the autoclave chamber as part of a steam sterilization cycle.
The insulating properties of air interfere with the ability of steam to transfer its energy to the
load, achieving lower lethality than associated with saturated steam.  It also should be noted that
the resistance of microorganisms can vary widely depending on the material to be sterilized.  For
this reason, careful consideration should be given during sterilization validation to the nature or
type of material chosen as the carrier of the biological indicator to ensure an appropriately
representative study.

Potentially difficult to reach locations within the sterilizer load or equipment train (for SIP
applications) should be evaluated.  For example, filter installations in piping can cause a
substantial pressure differential across the filter, resulting in a significant temperature drop on the
downstream side.  We recommend placing biological indicators at appropriate downstream
locations of the filter.

Empty chamber studies evaluate numerous locations throughout a sterilizing unit (e.g., steam
autoclave, dry heat oven) or equipment train (e.g., large tanks, immobile piping) to confirm
uniformity of conditions (e.g., temperature, pressure).  These uniformity or mapping studies
should be conducted with calibrated measurement devices.

Heat penetration studies should be performed using the established sterilizer loads.  Validation of
the sterilization process with a loaded chamber demonstrates the effects of loading on thermal
input to the items being sterilized and may identify difficult to heat or penetrate items where
there could be insufficient lethality to attain sterility.  The placement of biological indicators at
numerous positions in the load, including the most difficult to sterilize places, is a direct means
of confirming the efficacy of any sterilization procedure.  In general, the biological indicator
should be placed adjacent to the temperature sensor so as to assess the correlation between
microbial lethality and predicted lethality based on thermal input.  When determining which

19 If appropriate, alternate intervals can be defined, justified, and supported by validation studies.

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articles are difficult to sterilize, special attention should be given to the sterilization of filters,
filling manifolds, and pumps.  Some other examples include certain locations of tightly wrapped
or densely packed supplies, securely fastened load articles, lengthy tubing, the sterile filter
apparatus, hydrophobic filters, and stopper load.

Ultimately, cycle specifications for such sterilization methods should be based on the delivery of
adequate lethality to the slowest to heat locations.  A sterility assurance level of 10-6 or better
should be demonstrated for a sterilization process.  For more information, please also refer to the
FDA guidance entitled Guideline for the Submission of Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products.

The sterilizer validation program should continue to focus on the load areas identified as most
difficult to penetrate or heat.  The suitability of the sterilizer should be established by
qualification, maintenance, change control, and periodic verification of the cycle, including
biological challenges.  Change control procedures should adequately address issues such as a
load configuration change or a modification of a sterilizer.

2.
Equipment Controls and Instrument Calibration

For both validation and routine process control, the reliability of the data generated by
sterilization cycle monitoring devices should be considered to be of the utmost importance.
Devices that measure cycle parameters should be routinely calibrated.  Written procedures
should be established to ensure that these devices are maintained in a calibrated state.  For
example, we recommend that procedures address the following:

• Temperature and pressure monitoring devices for heat sterilization should be
calibrated at suitable intervals.  The sensing devices used for validation studies should
be calibrated before and after validation runs.
• Devices used to monitor dwell time in the sterilizer should be periodically calibrated.
• The microbial count of a biological indicator should be confirmed. Biological
indicators should be stored under appropriate conditions.
• If the reliability of a vendor’s Certificate of Analysis is established through an
appropriate qualification program, the D-value of a biological indicator (e.g., spore
strips, glass ampuls) can be accepted in lieu of confirmatory testing of each lot.
However, a determination of resistance (D-value) should be performed for any
biological indicator inoculated onto a substrate, or used in a way that is other than
described by the vendor.  D-value determinations can be conducted by an
independent laboratory.
• Where applicable, instruments used to determine the purity of steam should be
calibrated.
• For dry heat depyrogenation tunnels, devices (e.g. sensors and transmitters) used to
measure belt speed should be routinely calibrated.  Bacterial endotoxin challenges
should be appropriately prepared and measured by the laboratory.

To ensure robust process control, equipment should be properly designed with attention to
features such as accessibility to sterilant, piping slope, and proper condensate removal (as
applicable).  Equipment control should be ensured through placement of measuring devices at

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those control points that are most likely to rapidly detect unexpected process variability.  Where
manual manipulations of valves are required for sterilizer or SIP operations, these steps should
be documented in manufacturing procedures and batch records.  Sterilizing equipment should be
properly maintained to allow for consistent, satisfactory function.  Routine evaluation of
sterilizer performance-indicating attributes, such as equilibrium (come up) time is important in
assuring that the unit continues to operate as per the validated conditions.

X.
LABORATORY CONTROLS

21 CFR 211.22(b) states that “Adequate laboratory facilities for the testing and approval (or rejection) of components,
drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to
the quality control unit.”

21 CFR 211.22(c) states that “The quality control unit shall have the responsibility for approving or rejecting all
procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.”

21 CFR 211.42(c) states, in part, that “Operations shall be performed within specifically defined areas of adequate
size.  There shall be separate or defined areas or such other control systems for the firm’s operations as are necessary
to prevent contamination or mixups during the course of the following procedures: * * * (10) Aseptic processing,
which includes as appropriate: * * * (iv) A system for monitoring environmental conditions; * * *.”

21 CFR 211.56(b) states that “There shall be written procedures assigning responsibility for sanitation and describing
in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and
facilities; such written procedures shall be followed.”

21 CFR 211.56(c) states, in part, that “There shall be written procedures for use of suitable rodenticides, insecticides,
fungicides, fumigating agents, and cleaning and sanitizing agents.  Such written procedures shall be designed to
prevent the contamination of equipment, components, drug product containers, closures, packaging, labeling
materials, or drug products and shall be followed * * *.”

21 CFR 211.110(a) states, in part, that “To assure batch uniformity and integrity of drug products, written procedures
shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on
appropriate samples of in-process materials of each batch.  Such control procedures shall be established to monitor the
output and to validate the performance of those manufacturing processes that may be responsible for causing
variability in the characteristics of in-process material and the drug product * * *.”

21 CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of
drug products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of
any sterilization process.”

21 CFR 211.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and
appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug
product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of
identity, strength, quality, and purity.  Laboratory controls shall include: (1) Determination of conformance to
appropriate written specifications for the acceptance of each lot within each shipment of components, drug product
containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products.  The
specifications shall include a description of the sampling and testing procedures used.  Samples shall be representative
and adequately identified.  Such procedures shall also require appropriate retesting of any component, drug product
container, or closure that is subject to deterioration.  (2) Determination of conformance to written specifications and a
description of sampling and testing procedures for in-process materials.  Such samples shall be representative and

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properly identified. (3) Determination of conformance to written descriptions of sampling procedures and appropriate
specifications for drug products. Such samples shall be representative and properly identified.  (4) The calibration of
instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written
program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial
action in the event accuracy and/or precision limits are not met.  Instruments, apparatus, gauges, and recording devices
not meeting established specifications shall not be used.”

21 CFR 211.165(e) states that “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by
the firm shall be established and documented.  Such validation and documentation may be accomplished in
accordance with § 211.194(a)(2).”

21 CFR 211.192 states, in part, that “All drug product production and control records, including those for packaging
and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established,
approved written procedures before a batch is released or distributed * * *.”

A.
Environmental Monitoring

1.
 General Written Program

In aseptic processing, one of the most important laboratory controls is the environmental
monitoring program.  This program provides meaningful information on the quality of the
aseptic processing environment (e.g., when a given batch is being manufactured) as well as
environmental trends of ancillary clean areas.  Environmental monitoring should promptly
identify potential routes of contamination, allowing for implementation of corrections before
product contamination occurs (211.42 and 211.113).

Evaluating the quality of air and surfaces in the cleanroom environment should start with a well-
defined written program and scientifically sound methods.  The monitoring program should
cover all production shifts and include air, floors, walls, and equipment surfaces, including the
critical surfaces that come in contact with the product, container, and closures.  Written
procedures should include a list of locations to be sampled.  Sample timing, frequency, and
location should be carefully selected based upon their relationship to the operation performed.
Samples should be taken throughout the classified areas of the aseptic processing facility (e.g.,
aseptic corridors, gowning rooms) using scientifically sound sampling procedures.  Sample sizes
should be sufficient to optimize detection of environmental contaminants at levels that might be
expected in a given clean area.

It is important that locations posing the most microbiological risk to the product be a key part of
the program. It is especially important to monitor the microbiological quality of the critical area
to determine whether or not aseptic conditions are maintained during filling and closing
activities.  Air and surface samples should be taken at the locations where significant activity or
product exposure occurs during production.  Critical surfaces that come in contact with the
sterile product should remain sterile throughout an operation.  When identifying critical sites to
be sampled, consideration should be given to the points of contamination risk in a process,
including factors such as difficulty of setup, length of processing time, and impact of
interventions.  Critical surface sampling should be performed at the conclusion of the aseptic
processing operation to avoid direct contact with sterile surfaces during processing.  Detection of
microbial contamination on a critical site would not necessarily result in batch rejection.  The

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contaminated critical site sample should prompt an investigation of operational information and
data that includes an awareness of the potential for a low incidence of false positives.

Environmental monitoring methods do not always recover microorganisms present in the
sampled area.  In particular, low-level contamination can be particularly difficult to detect.
Because false negatives can occur, consecutive growth results are only one type of adverse trend.
Increased incidence of contamination over a given period is an equal or more significant trend to
be tracked.  In the absence of any adverse trend, a single result above an action level should
trigger an evaluation and a determination about whether remedial measures may be appropriate.
In all room classes, remedial measures should be taken in response to unfavorable trends.

All environmental monitoring locations should be described in SOPs with sufficient detail to
allow for reproducible sampling of a given location surveyed.  Written SOPs should also address
elements such as (1) frequency of sampling, (2) when the samples are taken (i.e., during or at the
conclusion of operations), (3) duration of sampling, (4) sample size (e.g., surface area, air
volume), (5) specific sampling equipment and techniques, (6) alert and action levels, and (7)
appropriate response to deviations from alert or action levels.

2.
Establishing Levels and a Trending Program

Microbiological monitoring levels should be established based on the relationship of the sampled
location to the operation.  The levels should be based on the need to maintain adequate
microbiological control throughout the entire sterile manufacturing facility.  One should also
consider environmental monitoring data from historical databases, media fills, cleanroom
qualification, and sanitization studies, in developing monitoring levels.  Data from similar
operations can also be helpful in setting action and alert levels, especially for a new operation.

Environmental monitoring data will provide information on the quality of the manufacturing
environment.  Each individual sample result should be evaluated for its significance by
comparison to the alert or action levels.  Averaging of results can mask unacceptable localized
conditions.  A result at the alert level urges attention to the approaching action conditions.  A
result at the action level should prompt a more thorough investigation.  Written procedures
should be established, detailing data review frequency and actions to be taken.  The quality
control unit should provide routine oversight of near-term (e.g., daily, weekly, monthly,
quarterly) and long-term trends in environmental and personnel monitoring data.

Trend reports should include data generated by location, shift, room, operator, or other
parameters.  The quality control unit should be responsible for producing specialized data reports
(e.g., a search on a particular isolate over a year period) with the goal of investigating results
beyond established levels and identifying any appropriate follow-up actions.  Significant changes
in microbial flora should be considered in the review of the ongoing environmental monitoring
data.

Written procedures should define the system whereby the most responsible managers are
regularly informed and updated on trends and investigations.

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3.
Disinfection Efficacy

The suitability, efficacy, and limitations of disinfecting agents and procedures should be
assessed.  The effectiveness of these disinfectants and procedures should be measured by their
ability to ensure that potential contaminants are adequately removed from surfaces.

To prevent introduction of contamination, disinfectants should be sterile, appropriately handled
in suitable (e.g., sterile) containers and used for no longer than the predefined period specified by
written procedures.  Routinely used disinfectants should be effective against the normal
microbial vegetative flora recovered from the facility.  Many common disinfectants are
ineffective against spores.  For example, 70 percent isopropyl alcohol is ineffective against
Bacillus spp. spores.  Therefore, a sound disinfectant program also includes a sporicidal agent,
used according to a written schedule and when environmental data suggest the presence of
sporeforming organisms.

Disinfection procedures should be described in sufficient detail (e.g., preparation, work
sequence, contact time) to enable reproducibility.  Once the procedures are established, their
adequacy should be evaluated using a routine environmental monitoring program.  If indicated,
microorganisms associated with adverse trends can be investigated as to their sensitivity to the
disinfectants employed in the cleanroom in which the organisms were isolated.

4.
 Monitoring Methods

Acceptable methods for monitoring the microbiological quality of the environment include:

a.
Surface Monitoring

Environmental monitoring involves sampling various surfaces for microbiological
quality.  For example, product contact surfaces, floors, walls, and equipment should be
tested on a regular basis.  Touch plates, swabs, and contact plates can be used for such
tests.

b.
Active Air Monitoring

Assessing microbial quality of air should involve the use of active devices including but
not limited to impaction, centrifugal, and membrane (or gelatin) samplers.  Each device
has certain advantages and disadvantages, although all allow testing of the number of
organisms per volume of air sampled.  We recommend that such devices be used during
each production shift to evaluate aseptic processing areas at carefully chosen locations.
Manufacturers should be aware of a device's air monitoring capabilities, and the air
sampler should be evaluated for its suitability for use in an aseptic environment based on
collection efficiency, cleanability, ability to be sterilized, and disruption of unidirectional
airflow.20  Because devices vary, the user should assess the overall suitability of a
monitoring device before it is placed into service.  Manufacturers should ensure that such
devices are calibrated and used according to appropriate procedures.

20 For example, the volume of air sampled should be sufficient to yield meaningful measurements of air quality in a
given environment.

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c.
Passive Air Monitoring (Settling Plates)

Another method is the use of passive air samplers, such as settling plates (petri dishes
containing nutrient growth medium exposed to the environment).  Because only
microorganisms that settle onto the agar surface are detected, settling plates can be used
as qualitative, or semi-quantitative, air monitors.  Their value in critical areas will be
enhanced by ensuring that plates are positioned in locations posing the greatest risk of
product contamination.  As part of methods validation, the quality control laboratory
should evaluate what media exposure conditions optimize recovery of low levels of
environmental isolates.  Exposure conditions should preclude desiccation (e.g., caused by
lengthy sampling periods and/or high airflows), which inhibits recovery of
microorganisms.  The data generated by passive air sampling can be useful when
considered in combination with results from other types of air samples.

B.
Microbiological Media and Identification

Characterization of recovered microorganisms provides vital information for the environmental
monitoring program.  Environmental isolates often correlate with the contaminants found in a
media fill or product sterility testing failure, and the overall environmental picture provides
valuable information for an investigation.  Monitoring critical and immediately surrounding
clean areas as well as personnel should include routine identification of microorganisms to the
species (or, where appropriate, genus) level.  In some cases, environmental trending data have
revealed migration of microorganisms into the aseptic processing room from either uncontrolled
or lesser controlled areas.  Establishing an adequate program for differentiating microorganisms
in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental
in detecting such trends.  At minimum, the program should require species (or, where
appropriate, genus) identification of microorganisms in these ancillary environments at frequent
intervals to establish a valid, current database of contaminants present in the facility during
processing (and to demonstrate that cleaning and sanitization procedures continue to be
effective).

Genotypic methods have been shown to be more accurate and precise than traditional
biochemical and phenotypic techniques.  These methods are especially valuable for
investigations into failures (e.g., sterility test; media fill contamination).  However, appropriate
biochemical and phenotypic methods can be used for the routine identification of isolates.

The goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of
monitoring the state of environmental control.  Consistent methods will yield a database that
allows for sound data comparisons and interpretations.  The microbiological culture media used
in environmental monitoring should be validated as capable of detecting fungi (i.e., yeasts and
molds) as well as bacteria and incubated at appropriate conditions of time and temperature.
Total aerobic bacterial count can be obtained by incubating at 30 to 35oC for 48 to 72 hours.
Total combined yeast and mold count can generally be obtained by incubating at 20 to 25oC for 5
to 7 days.

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Incoming lots of environmental monitoring media should be tested for their ability to reliably
recover microorganisms.  Growth promotion testing should be performed on all lots of prepared
media.  Where appropriate, inactivating agents should be used to prevent inhibition of growth by
cleanroom disinfectants or product residuals (e.g., antibiotics).

C.
Prefiltration Bioburden

Manufacturing process controls should be designed to minimize the bioburden in the unfiltered
product.  In addition to increasing the challenge to the sterilizing filter, bioburden can contribute
impurities (e.g., endotoxin) to, and lead to degradation of, the drug product.  A prefiltration
bioburden limit should be established.

D.
Alternate Microbiological Test Methods

Other suitable microbiological test methods (e.g., rapid test methods) can be considered for
environmental monitoring, in-process control testing, and finished product release testing after it
is demonstrated that the methods are equivalent or better than traditional methods (e.g.,USP).

E.
Particle Monitoring

Routine particle monitoring is useful in rapidly detecting significant deviations in air cleanliness
from qualified processing norms (e.g., clean area classification).  A result outside the established
classification level at a given location should be investigated as to its cause.  The extent of
investigation should be consistent with the severity of the excursion and include an evaluation of
trending data.  Appropriate corrective action should be implemented, as necessary, to prevent
future deviations.

See Section IV.A for additional guidance on particle monitoring.

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XI.
STERILITY TESTING

21 CFR 210.3(b)(21) states that “Representative sample means a sample that consists of a number of units that are drawn
based on rational criteria such as random sampling and intended to assure that the sample accurately portrays the material
being sampled.”

21 CFR 211.110(a) states, in part, that “To assure batch uniformity and integrity of drug products, written procedures shall
be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate
samples of in-process materials of each batch.  Such control procedures shall be established to monitor the output and to
validate the performance of those manufacturing processes that may be responsible for causing variability in the
characteristics of in-process material and the drug product.”

21 CFR 211.160(b) states that “Laboratory controls shall include the establishment of scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers,
closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality,
and purity.  Laboratory controls shall include: (1) Determination of conformance to appropriate written specifications for
the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the
manufacture, processing, packing, or holding of drug products.  The specifications shall include a description of the
sampling and testing procedures used.  Samples shall be representative and adequately identified.  Such procedures shall
also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.  (2)
Determination of conformance to written specifications and a description of sampling and testing procedures for in-process
materials.  Such samples shall be representative and properly identified. (3) Determination of conformance to written
descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative
and properly identified.  (4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals
in accordance with an established written program containing specific directions, schedules, limits for accuracy and
precision, and provisions for remedial action in the event accuracy and/or precision limits are not met.  Instruments,
apparatus, gauges, and recording devices not meeting established specifications shall not be used.”

21 CFR 211.165(a) states, in part, that “For each batch of drug product, there shall be appropriate laboratory determination
of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active
ingredient, prior to release * * *.”

21 CFR 211.165(e) states that “The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the
firm shall be established and documented.  Such validation and documentation may be accomplished in accordance with  §
211.194(a)(2).”

21 CFR 211.167(a) states that “For each batch of drug product purporting to be sterile and/or pyrogen-free, there shall be
appropriate laboratory testing to determine conformance to such requirements.  The test procedures shall be in writing and
shall be followed.”

21 CFR 211.180(e) states, in part, that “Written records required by this part shall be maintained so that data therein can be
used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug
product specifications or manufacturing or control procedures * * *.”

21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling,
shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written
procedures before a batch is released or distributed.  Any unexplained discrepancy (including a percentage of theoretical
yield exceeding the maximum or minimum percentages established in master production and control records) or the failure
of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the
batch has already been distributed.  The investigation shall extend to other batches of the same drug product and other drug
products that may have been associated with the specific failure or discrepancy.  A written record of the investigation shall
be made and shall include the conclusions and followup.”

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Certain aspects of sterility testing are of particular importance, including control of the testing
environment, understanding the test limitations, and investigating manufacturing systems
following a positive test.

The testing laboratory environment should employ facilities and controls comparable to those
used for aseptic filling operations.  Poor or deficient sterility test facilities or controls can result
in test failure.  If production facilities and controls are significantly better than those for sterility
testing, the danger exists of mistakenly attributing a positive sterility test result to a faulty
laboratory even when the product tested could have, in fact, been nonsterile.  Therefore, a
manufacturing deficiency may go undetected.  The use of isolators for sterility testing minimizes
the chance of a false positive test result.

A.
Microbiological Laboratory Controls

Sterility testing methods are required to be accurate and reproducible, in accordance with
211.194 and 211.165.  USP <71> “Sterility Tests” is the principal source used for sterility
testing methods, including information on test procedures and media.21

As a part of methods validation, appropriate microbiological challenge testing will demonstrate
reproducibility of the method to reliably recover representative microorganisms.  If growth is
inhibited, modifications (e.g., increased dilution, additional membrane filter washes, addition of
inactivating agents) to the test method should be implemented to optimize recovery.  Ultimately,
methods validation studies should demonstrate that the method does not provide an opportunity
for false negatives.

It is essential that the media used to perform sterility testing be rendered sterile and demonstrated
as growth promoting.  Personnel performing sterility testing should be qualified and trained for
the task.  A written program should be in place to maintain updated training of personnel and
confirm acceptable sterility testing practices.

B.
Sampling and Incubation

Sterility tests are limited in their ability to detect contamination because of the small sample size
typically used.  For example, as described by USP, statistical evaluations indicate that the
sterility test sampling plan "only enables the detection of contamination in a lot in which 10% of
the units are contaminated about nine times out of ten in making the test" (Ref. 13).  To further
illustrate, if a 10,000-unit lot with a 0.1 percent contamination level was sterility tested using 20
units, there is a 98 percent chance that the batch would pass the test.

It is important that the samples represent the entire batch and processing conditions.  Samples
should be taken:

• at the beginning, middle, and end of the aseptic processing operation
• in conjunction with processing interventions or excursions

.

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Because of the limited sensitivity of the test, any positive result is considered a serious CGMP
issue that should be thoroughly investigated.

C.
Investigation of Sterility Positives

Care should be taken in the performance of the sterility test to preclude any activity that allows
for possible sample contamination.  When microbial growth is observed, the lot should be
considered nonsterile and an investigation conducted.  An initial positive test would be invalid
only in an instance in which microbial growth can be unequivocally ascribed to laboratory error.

Only if conclusive and documented evidence clearly shows that the contamination occurred as
part of testing should a new test be performed.  When available evidence is inconclusive, batches
should be rejected as not conforming to sterility requirements.

After considering all relevant factors concerning the manufacture of the product and testing of
the samples, the comprehensive written investigation should include specific conclusions and
identify corrective actions.  The investigation's persuasive evidence of the origin of the
contamination should be based on at least the following:

1. Identification (speciation) of the organism in the sterility test

Sterility test isolates should be identified to the species level.  Microbiological monitoring data
should be reviewed to determine if the organism is also found in laboratory and production
environments, personnel, or product bioburden.  Advanced identification methods (e.g., nucleic-
acid based) are valuable for investigational purposes.  When comparing results from
environmental monitoring and sterility positives, both identifications should be performed using
the same methodology.

2. Record of laboratory tests and deviations

Review of laboratory deviation and investigation findings can help to eliminate or implicate the
laboratory as the source of contamination.  For example, if the organism is seldom found in the
laboratory environment, product contamination is more likely than laboratory error.  If the
organism is found in laboratory and production environments, it can still indicate product
contamination.

The proper handling of deviations is an essential aspect of laboratory control.  When a deviation
occurs during sterility testing, it should be documented, investigated, and remedied.  If any
deviation is considered to have compromised the integrity of the sterility test, the test should be
invalidated immediately without incubation.

A sterility positive result can be viewed as indicative of production or laboratory problems, and
the entire manufacturing process should be comprehensively investigated since such problems
often can extend beyond a single batch.  To more accurately monitor potential contamination
sources, we recommend keeping separate trends by appropriate categories such as product,
container type, filling line, sampling, and testing personnel.  Where the degree of sterility test

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sample manipulation is similar for a terminally sterilized product and an aseptically processed
product, a higher rate of initial sterility failures for the latter should be taken as indicative of
aseptic processing production problems.

Microbial monitoring of the aseptic area of the laboratory and personnel can also reveal trends
that are informative.  Upward trends in the microbial load in the aseptic area of the laboratory
should be promptly investigated as to cause, and corrected.  In some instances, such trends can
appear to be more indicative of laboratory error as a possible source of a sterility test failure.

Where a laboratory has a good track record with respect to errors, this history can lower
suspicion of the lab as a source of contamination since chances are higher that the contamination
arose from production.  However, the converse is not true.  Specifically, where a laboratory has a
poor track record, firms should not assume that the contamination is automatically more
attributable to the laboratory and consequently overlook a genuine production problem.
Accordingly, it is essential that all sterility positives be thoroughly investigated.

3. Monitoring of production area environment

Trend analysis of microorganisms in the critical and immediately adjacent areas is especially
helpful in determining the source of contamination in a sterility failure investigation.
Consideration of environmental microbial data should not be limited to results of monitoring the
production environment for the lot, day, or shift associated with the suspect lot.  For example,
results showing little or no recovery of microorganisms can be misleading, especially when
preceded or followed by a finding of an adverse trend or atypically high microbial counts.  It is
therefore important to look at both short- and long-term environmental trend analyses.

4. Monitoring Personnel

The review of data and associated trends from daily monitoring of personnel can provide
important information indicating a route of contamination.  The adequacy of personnel practices
and training also merit significant review and consideration.

5. Product Presterilization Bioburden

We recommend review of trends in product bioburden and consideration of whether adverse
bioburden trends have occurred.

6. Production record review

Complete batch and production control records should be reviewed to detect any signs of failures
or anomalies that could have a bearing on product sterility.  For example, the investigation
should include elements such as:

• Events that could have impacted on the critical zone
• Batch and trending data that indicate whether utility and/or support systems are
functioning properly.  For instance, records of air quality monitoring for filling lines

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could show a time at which there was improper air balance or an unusually high particle
count.
• Whether construction or maintenance activities could have had an adverse impact

7. Manufacturing history

The manufacturing history of a product or similar products should be reviewed as part of the
investigation.  Past deviations, problems, or changes (e.g., process, components, equipment) are
among the factors that can provide an indication of the origin of the problem.

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XII.
BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION

21 CFR 211.100(a) states that “There shall be written procedures for production and process control designed to assure that
the drug products have the identity, strength, quality, and purity they purport or are represented to possess.  Such procedures
shall include all requirements in this subpart.  These written procedures, including any changes, shall be drafted, reviewed,
and approved by the appropriate organizational units and reviewed and approved by the quality control unit.”

21 CFR 211.100(b) states that “Written production and process control procedures shall be followed in the execution of the
various production and process control functions and shall be documented at the time of performance.  Any deviation from
the written procedures shall be recorded and justified.”

21 CFR 211.186 and 211.188 address, respectively, "Master production and control records" and "Batch production and
control records."

21 CFR 211.192 states that “All drug product production and control records, including those for packaging and labeling,
shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written
procedures before a batch is released or distributed.  Any unexplained discrepancy (including a percentage of theoretical
yield exceeding the maximum or minimum percentages established in master production and control records) or the failure
of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the
batch has already been distributed.  The investigation shall extend to other batches of the same drug product and other drug
products that may have been associated with the specific failure or discrepancy.  A written record of the investigation shall
be made and shall include the conclusions and followup.”

Manufacturers should build process and environmental control activities into their aseptic
processing operation.  It is critical that these activities be maintained and strictly implemented on
a daily basis.  The requirement for review of all batch records and data for conformance with
written procedures, operating parameters, and product specifications prior to arriving at the final
release decision for an aseptically processed product calls for an overall review of process and
system performance for that given cycle of manufacture.  All in-process and laboratory control
results must be included with the batch record documentation in accordance with section
211.188.  Review of environmental and personnel monitoring data, as well as other data relating
to acceptability of output from support systems (e.g., HEPA / HVAC, WFI, steam generator) and
proper functioning of equipment (e.g., batch alarms report; integrity of various filters) are
considered essential elements of the batch release decision.

While interventions and/or stoppages are normally recorded in the batch record, the manner of
documenting these occurrences varies.  In particular, line stoppages and any unplanned
interventions should be sufficiently documented in batch records with the associated time and
duration of the event.  In addition to lengthened dwell time of sterile product elements in the
critical area, an extensive intervention can increase contamination risk.  Sterility failures have
often been attributed to atypical or extensive interventions that have occurred as a response to an
undesirable event during the aseptic process.  Written procedures describing the need for line
clearances in the event of certain interventions, such as machine adjustments and any repairs,
should be established.  Such interventions should be documented with more detail than minor
events.  Interventions that result in substantial activity near exposed product or container closures

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or that last beyond a reasonable exposure time should, where appropriate, result in a local or full
line clearance.

Any disruption in power supply, however momentary, that could affect product quality is a
manufacturing deviation and must be included in batch records (211.100, 211.192).

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## APPENDIX 1: ASEPTIC PROCESSING ISOLATORS

Aseptic processing using isolation systems separates the external cleanroom environment from
the aseptic processing line and minimizes its exposure to personnel.  A well-designed positive
pressure isolator, supported by adequate procedures for its maintenance, monitoring, and control,
offers tangible advantages over traditional aseptic processing, including fewer opportunities for
microbial contamination during processing.  However, users should remain vigilant to potential
sources of operational risk. Manufacturers should also be aware of the need to establish new
procedures addressing issues unique to isolators.

A.
 Maintenance

1.  General

Maintenance of isolator systems differs in some significant respects from the traditional, non-
isolated aseptic processing operations.  Although no isolator forms an absolute seal, very high
integrity can be achieved in a well-designed unit.  However, a leak in certain components of the
system can constitute a significant breach of integrity.  The integrity of gloves, half-suits, and
seams should receive daily attention and be addressed by a comprehensive preventative
maintenance program.  Replacement frequencies should be established in written procedures that
ensure parts will be changed before they breakdown or degrade.  Transfer systems, gaskets, and
seals are among the other parts that should be covered by the maintenance program.

2.  Glove Integrity

A faulty glove or sleeve (gauntlet) assembly represents a route of contamination and a critical
breach of isolator integrity.  A preventative maintenance program should be established.  The
choice of durable glove materials, coupled with a well-justified replacement frequency, are key
aspects of good manufacturing practice to be addressed.  With every use, gloves should be
visually evaluated for any macroscopic physical defect.  Physical integrity tests should also be
performed routinely.  A breach in glove integrity can be of serious consequence.  The monitoring
and maintenance program should identify and eliminate any glove lacking integrity and
minimize the possibility of placing a sterile product at risk.

Due to the potential for microbial migration through microscopic holes in gloves and the lack of
a highly sensitive glove integrity test, we recommend affording attention to the sanitary quality
of the inner surface of the installed glove and to integrating the use of a second pair of thin
gloves.

B.
Design

1.  Airflow

There are two types of aseptic processing isolators: open and closed.  Closed isolators employ
connections with auxiliary equipment for material transfer.  Open isolators have openings to the

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surrounding environment that are carefully engineered to segregate the inner isolator
environment from the surrounding room via overpressure.

Turbulent flow can be acceptable within closed isolators, which are normally compact in size
and do not house processing lines.  Other aseptic processing isolators employ unidirectional
airflow that sweeps over and away from exposed sterile materials, avoiding any turbulence or
stagnant airflow in the area of exposed sterilized materials, product, and container closures.  In
most sound designs, air showers over the critical area once and then is systematically exhausted
from the enclosure.  The air handling system should be capable of maintaining the requisite
environmental conditions within the isolator.

2.  Materials of Construction

As in any aseptic processing design, suitable materials should be chosen based on durability, as
well as ease of cleaning and decontamination.  For example, rigid wall construction
incorporating stainless steel and glass materials is widely used.

3.  Pressure Differential

Isolators that include an open portal should be designed to ensure complete physical separation
from the external environment.  A positive air pressure differential adequate to achieve this
separation should be employed and supported by qualification studies.  Positive air pressure
differentials from the isolator to the surrounding environment have largely ranged from
approximately 17.5 to 50 Pascals.22  The appropriate minimum pressure differential  established
by a firm will depend on the system’s design and, when applicable, its exit port.  Air balance
between the isolator and other direct interfaces (e.g., dry heat tunnel) should also be qualified.

The positive pressure differential should be coupled with an appropriately designed opening to
the external environment to prevent potential ingress of surrounding room air by induction.
Induction can result from local turbulent flow causing air swirls or pressure waves that might
push extraneous particles into the isolator.  Local Class 100 (ISO 5) protection at an opening is
an example of a design provision that can provide a further barrier to the external environment.

4.  Clean Area Classifications

The interior of the isolator should meet Class 100 (ISO 5) standards.  The classification of the
environment surrounding the isolator should be based on the design of its interfaces (e.g.,
transfer ports), as well as the number of transfers into and out of the isolator.  A Class 100,000
(ISO 8) background is commonly used based on consideration of isolator design and
manufacturing situations.  An aseptic processing isolator should not be located in an unclassified
room.

C.
Transfer of Materials/Supplies

22 0.07” to 0.20” water gauge

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The ability to maintain integrity of a decontaminated isolator can be affected impacted by the
design of transfer ports.  Various adaptations, of differing capabilities, allow for the transfer of
supplies into and out of the isolator.

Multiple material transfers are generally made during the processing of a batch.  Frequently,
transfers are performed via direct interface with manufacturing equipment.  Properly maintained
and operated rapid transfer ports (RTPs) are an effective transfer mechanism for aseptic transfer
of materials into and out of isolators.  Some transfer ports might have significant limitations,
including marginal decontaminating capability (e.g., ultraviolet) or a design that has the potential
to compromise isolation by allowing ingress of air from the surrounding room.  In the latter case,
localized HEPA-filtered unidirectional airflow cover in the area of such a port should be
implemented.  Isolators often include a mousehole or other exit port through which product is
discharged, opening the isolator to the outside environment.  Sufficient overpressure should be
supplied and monitored on a continuous basis at this location to ensure that isolation is
maintained.

D.
Decontamination

1.  Surface Exposure

Decontamination procedures should ensure full exposure of all isolator surfaces to the chemical
agent.  The capability of a decontaminant to penetrate obstructed or covered surfaces is limited.
For example, to facilitate contact with the decontaminant, the glove apparatus should be fully
extended with glove fingers separated during the decontamination cycle.  It is also important to
clean the interior of the isolator per appropriate procedures to allow for a robust decontamination
process.

2.  Efficacy

The decontamination method should render the inner surfaces of the isolator free of viable
microorganisms.  Multiple available vaporized agents are suitable for achieving decontamination.
Process development and validation studies should include a thorough determination of cycle capability.
The characteristics of these agents generally preclude the reliable use of statistical methods (e.g.,
fraction negative) to determine process lethality (Ref.  13).  An appropriate, quantified Biological
Indicator (BI) challenge should be placed on various materials23 and in many locations throughout the
isolator, including difficult to reach areas.  Cycles should be developed with an appropriate margin of
extra kill to provide confidence in robustness of the decontamination processes.  Normally, a four- to
six-log reduction can be justified depending on the application.  The specific BI spore titer used and the
selection of BI placement sites should be justified.  For example, demonstration of a four-log reduction
should be sufficient for controlled, very low bioburden materials introduced into a transfer isolator,
including wrapped sterile supplies that are briefly exposed to the surrounding cleanroom environment.

23 If the various isolator materials are thoroughly evaluated during cycle development, a firm might consider placing
more focus on material texture and porosity during validation of the decontamination process.

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The uniform distribution of a defined concentration of decontaminating agent should also be
evaluated as part of these studies (Ref. 14).  Chemical indicators may also be useful as a
qualitative tool to show that the decontaminating agent reached a given location.

3.  Frequency

The design of the interior and content of an isolator should provide for its frequent
decontamination.  When an isolator is used for multiple days between decontamination cycles,
the frequency adopted should be justified.  This frequency, established during validation studies,
should be reevaluated and increased if production data indicate deterioration of the
microbiological quality of the isolator environment.

A breach of isolator integrity should normally lead to a decontamination cycle.  Integrity can be
affected by power failures, valve failure, inadequate overpressure, holes in gloves and seams, or
other leaks.  Breaches of integrity should be investigated.  If it is determined that the
environment may have been compromised, any product potentially impacted by the breach
should be rejected.

E.
Filling Line Sterilization

To ensure sterility of product contact surfaces from the start of each operation, the entire path of
the sterile processing stream should be sterilized.  In addition, aseptic processing equipment or
ancillary supplies to be used within the isolator should be chosen based on their ability to
withstand steam sterilization (or equivalent method).  It is expected that materials that permit
heat sterilization (e.g., SIP) will be rendered sterile by such methods.  Where decontamination
methods are used to render certain product contact surfaces free of viable organisms, a minimum
of a six-log reduction should be demonstrated using a suitable biological indicator.

F.
 Environmental Monitoring

An environmental monitoring program should be established that routinely ensures acceptable
microbiological quality of air, surfaces, and gloves (or half-suits) as well as particle levels,
within the isolator.  Nutrient media should be cleaned off of surfaces following a contact plate
sample.  Air quality should be monitored periodically during each shift.  For example, we
recommend monitoring the exit port for particles to detect any unusual results.  Media used for
environmental monitoring should not be exposed to decontamination cycle residues, as recovery
of microorganisms would be inhibited.

G.
Personnel

Although cleanroom apparel considerations are generally reduced in an isolator operation, the
contamination risk contributed by manual factors can not be overlooked.  Isolation processes
generally include periodic or even frequent use of one or more gloves for aseptic manipulations
and handling of material transfers into and out of the isolator.  One should be aware that
locations on gloves, sleeves, or half suits can be among the more difficult to reach places during
decontamination, and glove integrity defects might not be promptly detected.  Traditional aseptic
processing vigilance remains critical, with an understanding that contaminated isolator gloves

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can lead to product nonsterility.  Accordingly, meticulous aseptic technique standards must be
observed (211.113), including appropriate use of sterile tools for manipulations.

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## APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY

Blow-fill-seal (BFS) technology is an automated process by which containers are formed, filled,
and sealed in a continuous operation.  This manufacturing technology includes economies in
container closure processing and reduced human intervention and is often used for filling and
packaging ophthalmics, respiratory care products, and, less frequently, injectables.  This

## appendix discusses: some of the critical control points of this technology.  Except where

otherwise noted below, the aseptic processing standards discussed elsewhere in this document
should apply to blow-fill-seal technology.

A.
Equipment Design and Air Quality

Most BFS machines operate using the following steps.

• Heat a plastic polymer resin
• Extrude it to form a parison (a tubular form of the hot resin)
• Cut the parison with a high-temperature knife
• Move the parison under the blow-fill needle (mandrel)
• Inflate it to the shape of the mold walls
• Fill the formed container with the liquid product
• Remove the mandrel
• Seal

Throughout this operation, sterile-air is used, for example, to form the parison and inflate it prior
to filling.  In most operations, the three steps with the greatest potential for exposure to particle
contamination and/or surrounding air are those in which (1) the parison is cut, (2) the parison is
moved under the blow-fill mandrel, and (3) the mandrel is removed (just prior to sealing).

BFS machinery and its surrounding barriers should be designed to prevent the potential for
extraneous contamination.  As with any aseptic processing operation, it is critical that product
contact surfaces be sterile.  A validated steam-in-place cycle, or equivalent process, should be
used to sterilize the equipment path through which the product is conveyed.  In addition, any
other surface that represents a potential contamination risk to the sterile product should be sterile.

The classified environment surrounding BFS machinery should generally meet Class 100,000
(ISO 8), or better, standards, depending on the design of the BFS machinery and the surrounding
room.  HEPA-filtered or sterile air provided by membrane filters should be used during the steps
when sterile products or materials are exposed (e.g., parison formation, container molding or
filling steps).  Air in the critical area should meet Class 100 (ISO 5) microbiological standards
during operations.  A well-designed BFS system should also normally achieve Class 100 (ISO 5)
airborne particle levels.  Only personnel who have been qualified and appropriately gowned
should enter the classified environment surrounding the BFS machinery.  Refer to Section V of
this document for guidance on personnel training, qualification, and monitoring.

BFS equipment design typically calls for use of specialized measures to reduce particle levels
that can contaminate the exposed product.  In contrast to nonpharmaceutical applications using

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BFS machinery, control of air quality (i.e., particles) is critical for sterile drug product
manufacture.  Particles generated during the plastic extrusion, cutting, and sealing processes
should be controlled.  Provisions for carefully controlled airflow can protect the product by
forcing generated particles outward while preventing any ingress from the adjacent environment.
Furthermore, equipment designs that separate the filling zone from the surrounding environment
provide additional product protection.  Barriers, pressure vacuums, microenvironments, and
appropriately directed high velocities of sterile air have been found useful in preventing
contamination (Ref. 15).  Smoke studies and multi-location particle data can provide valuable
information when performing qualification studies to assess whether proper particle control
dynamics have been achieved throughout the critical area.

In addition to suitable design, it is important to establish an adequate preventative maintenance
program.  For example, because of its potential to contaminate the sterile drug product, the
integrity of the cooling, heating and other utility systems associated with the BFS machine
should be maintained and routinely monitored.

B.
Validation/Qualification

Advantages of BFS processing are known to include rapid container closure processing and
minimized aseptic interventions.  However, only a properly functioning process can realize these
advantages.  We recommend affording special attention to setup, troubleshooting of equipment,
and related aseptic personnel procedures.  Equipment sterilization, media fills, polymer
extrusion/sterilization, product-plastic compatibility, forming and sealing integrity, and unit
weight variation are among the key issues to address in validation and qualification studies.

Data gathered during such studies should ensure that BFS containers are sterile and, if used for
parenteral drugs, nonpyrogenic.  This can generally be achieved by validating that time
temperature conditions of the extrusion process are effective against endotoxin or spore
challenges in the polymeric material.

The choice of appropriate polymer material for a BFS operation includes assessing if a material
is pharmaceutical grade, safe, pure, and passes appropriate criteria (Ref. 17) for plastics.
Polymer suppliers should be qualified and monitored for raw material quality.

C.
Batch Monitoring and Control

Various in-process control parameters (e.g., container weight variation, fill weight, leakers, air
pressure) provide information to monitor and facilitate ongoing process control.   It is essential to
monitor the microbial air quality.  Samples should be taken according to a comprehensive
sampling plan that provides data representative of the entire filling operation.  Continuous
monitoring of particles can provide valuable data relative to the control of a blow-fill-seal
operation.

Container closure defects can be a major problem in control of a BFS operation.  It is critical that
the operation be designed and set-up to uniformly manufacture integral units.  As a final
measure, the inspection of each unit of a batch should include a reliable, sensitive, final product
examination that is capable of identifying defective units (e.g., leakers).  Significant defects due

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to heat or mechanical problems, such as wall thickness, container or closure interface
deficiencies, poorly formed closures, or other deviations should be investigated in accordance
with §§ 211.100 and 211.192.

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## APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS

The purpose of this appendix is to supplement the guidance provided in this document with
information on products regulated by CBER or CDER that are subject to aseptic processing at
points early in the manufacturing process, or that require aseptic processing through the entire
manufacturing process because it is impossible to sterile filter the final drug product.  The scope
of this appendix includes aseptic processing activities that take place prior to the filling and
sealing of the finished drug product.  Special considerations include those for:

A.
Aseptic processing from early manufacturing steps

Some products undergo aseptic processing at some or all manufacturing steps preceding the final
product closing step. With other products, there is a point in the process after which they can no
longer be rendered sterile by filtration.  In such cases, the product would be handled aseptically
at all steps subsequent to sterile filtration.  In other instances, the final drug product cannot be
sterile-filtered and, therefore, each component in the formulation would be rendered sterile and
mixed aseptically.  For example, products containing aluminum adjuvant are formulated
aseptically because once they are alum adsorbed, they cannot be sterile-filtered.

When a product is processed aseptically from the early stages, the product and all components or
other additions are rendered sterile prior to entering the manufacturing process.  It is critical that
all transfers, transports, and storage stages be carefully controlled at each step of the process to
maintain sterility of the product.  In some cases, bulk drug substances or products should be
tested for sterility.24

Procedures (e.g., aseptic connection) that expose a product or product contact surfaces should be
performed under unidirectional airflow in a Class 100 (ISO 5) environment.  The environment of
the room surrounding the Class 100 (ISO 5) environment should be Class 10,000 (ISO 7) or
better.  Microbiological and airborne particle monitoring should be performed during operations.
Microbial surface monitoring should be performed at the end of operations, but prior to cleaning.
Personnel monitoring should be performed in association with operations.

Process simulation studies covering the steps preceding filling and sealing should be designed to
incorporate all conditions, product manipulations, and interventions that could impact on the
sterility of the product.  The process simulation, from the early process steps, should demonstrate
that process controls are adequate to protect the product during manufacturing. These studies
should incorporate all product manipulations, additions, and procedures involving exposure of
product contact surfaces to the environment.  The studies should include worst-case conditions
such as maximum duration of open operations and maximum number of participating operators.
However, the process simulations do not need to mimic total manufacturing time if the
manipulations that occur during manufacturing are adequately represented.

It is also important that process simulations incorporate storage of sterile bulk drug substances or
product and transport to other manufacturing areas.  For instance, there should be assurance of
bulk vessel integrity for specified holding times.  The transport of sterile bulk tanks or other
containers should be simulated as part of the media fill.  Please refer to Section IX.A for more

24 See 21 CFR 610.12 for general biological product standards for sterility.

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guidance on media simulation studies.  Process simulation studies for the formulation stage
should be performed at least twice per year.

B.
Aseptic processing of cellular therapy products and cell-derived products

Cellular therapy and some cell-derived products (e.g., lysates, semi-purified extracts) represent a
subset of the products that cannot be filter-sterilized and therefore undergo aseptic manipulations
throughout the manufacturing process.  Where possible, closed systems should be used during
manufacturing.  Cellular therapy products often have short processing times at each
manufacturing stage, particularly between the harvest, formulation of the final product, and
product release.  These products are frequently released from the manufacturing facility and
administered to patients before final product sterility testing results are available.  In situations
where results of final sterility testing are not available before the product is administered,
additional controls and testing should be considered.  For example, additional sterility tests can
be performed at intermediate stages of manufacture, such as after the last manipulation of the
product prior to harvest.  Other tests that may indicate microbial contamination, such as
microscopic examination, Gram stain (or other bacterial and fungal stain), and endotoxin testing
should be performed and meet acceptance criteria prior to product release.

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REFERENCES

1. ISO 14644-1: Cleanrooms and Associated Controlled Environments, Classification of Air
Cleanliness.
2. NASA Standard for Cleanroom and Work Stations for Microbially Controlled Environment,
Publication NHB 5340.2 (August l967).
3. Technical Order 00-25-203, Contamination Control of Aerospace Facilities, U.S. Air Force,
December l, l972.
4. Ljungqvist, B., and Reinmuller, B., Cleanroom Design: Minimizing Contamination Through
Proper Design; Interpharm Press, 1997.
5. Lord, A. and J. W. Levchuk, "Personnel Issues in Aseptic Processing," Biopharm, 1989.
6. Morbidity and Mortality Weekly Report, "Clinical Sepsis and Death in a Newborn Nursery
Associated with Contaminated Medications" – Brazil, 1996, Centers for Disease Control and
Prevention, July, 1998; 47(29);610-2.
7. Grandics, Peter, “Pyrogens in Parenteral Pharmaceuticals,” Pharmaceutical Technology,
April 2000.
8. Recommendations of PQRI Aseptic Processing Working Group, Product Quality Research
Institute; March, 2003.
9. Technical Report No. 36, “Current Practices in the Validation of Aseptic Processing,"
Parenteral Drug Association, Inc., 2002.
10. Leahy, T. J. and M. J. Sullivan, “Validation of Bacterial - Retention Capabilities of
Membrane Filters," Pharmaceutical Technology, Nov., l978.
11. Pall, D. B. and E. A. Kirnbauer, et al., "Particulate Retention by Bacteria Retentive
Membrane Filters," Pall Corporation Colloids and Surfaces, l (l980) 235-256, Elsevier
Scientific Publishing Company, Amsterdam.
12. Technical Report No. 26, "Sterilizing Filtration of Liquids," Parenteral Drug Association,
Inc., 1998.

13. Sigwarth, V. and A. Stark, “Effect of Carrier Materials on the Resistance of Spores of
Bacillus stearothermophilus to Gaseous Hydrogen Peroxide,” PDA Journal of
Pharmaceutical Science and Technology, Vol. 57, No. 1, January/February 2003.
14. Isolators used for Aseptic Processing and Sterility Testing, Pharmaceutical Inspection
Convention Cooperation Scheme (PIC/S); June, 2002.
15. Price, J., “Blow-Fill-Seal Technology: Part I, A Design for Particulate Control,”
Pharmaceutical Technology, February, 1998.
16. United States Pharmacopoeia

--- PAGE 59 ---

Contains Nonbinding Recommendations

RELEVANT GUIDANCE DOCUMENTS

Some relevant FDA guidance documents include:

 Guidance for the Submission of Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products
 Guideline for Validation of Limulus Amebocyte Lysate Test as an End Product Endotoxin
Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices
 Guide to Inspections of Lyophilization of Parenterals
 Guide to Inspections of High Purity Water Systems
 Guide To Inspections of Microbiological Pharmaceutical Quality Control Laboratories
 Guide To Inspections of Sterile Drug Substance Manufacturers
 Pyrogens: Still a Danger; (Inspection Technical Guide)
 Bacterial Endotoxins/Pyrogens; (Inspection Technical Guide)

Heat Exchangers to Avoid Contamination;  (Inspection Technical Guide)

Compliance Program Guidance Manual 7356.002 A, Sterile Drug Process Inspections

ICH Q5A, Guidance on Viral Safety Evaluation of Biotechnology Products Derived from
Cell Lines of Human or Animal Origin

See also the draft guidance Container and Closure Integrity Testing in Lieu of Sterility
Testing as a Component of the Stability Protocol for Sterile Products, which was issued in
1998.  Once final, it will represent the Agency's thinking on this topic.

--- PAGE 60 ---

Contains Nonbinding Recommendations

GLOSSARY

Air lock- A small room with interlocked doors, constructed to maintain air pressure control
between adjoining rooms (generally with different air cleanliness standards).  The intent of an
aseptic processing airlock is to preclude ingress of particulate matter and microorganism
contamination from a lesser controlled area.

Alert Level- An established microbial or airborne particle level giving early warning of potential
drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address
the potential problem.  Alert levels are always lower than action levels.

Action Level- An established microbial or airborne particle level that, when exceeded, should
trigger appropriate investigation and corrective action based on the investigation.

Aseptic Manufacturing Area- The classified part of a facility that includes the aseptic processing
room and ancillary cleanrooms.  For purposes of this document, this term is synonymous with
“aseptic processing facility” as used in the segregated segment context.

Aseptic Processing Facility- A building, or segregated segment of it, containing cleanrooms in
which air supply, materials, and equipment are regulated to control microbial and particle
contamination.

Aseptic Processing Room- A room in which one or more aseptic activities or processes is
performed.

Asepsis- A state of control attained by using an aseptic work area and performing activities in a
manner that precludes microbiological contamination of the exposed sterile product.

Bioburden- The total number of microorganisms associated with a specific item prior to
sterilization.

Barrier- A physical partition that affords aseptic processing area (ISO 5) protection by partially
separating it from the surrounding area.

Biological Indicator (BI)- A population of microorganisms inoculated onto a suitable medium
(e.g., solution, container or closure) and placed within appropriate sterilizer load locations to
determine the sterilization cycle efficacy of a physical or chemical process.   The challenge
microorganism is selected based upon its resistance to the given process.  Incoming lot D-value
and microbiological count define the quality of the BI.

Clean Area- An area with defined particle and microbiological cleanliness standards.

Cleanroom- A room designed, maintained, and controlled to prevent particle and microbiological
contamination of drug products.  Such a room is assigned and reproducibly meets an appropriate
air cleanliness classification.

--- PAGE 61 ---

Contains Nonbinding Recommendations

Component- Any ingredient intended for use in the manufacture of a drug product, including
those that may not appear in the final drug product.

Colony Forming Unit (CFU)- A microbiological term that describes the formation of a single
macroscopic colony after the introduction of one or more microorganisms to microbiological
growth media.  One colony forming unit is expressed as 1 CFU.

Critical Area - An area designed to maintain sterility of sterile materials.  Sterilized product,
containers, closures, and equipment may be exposed in critical areas.

Clean Zone- See Clean Area.

Critical surfaces- Surfaces that may come into contact with or directly affect a sterilized product
or its containers or closures. Critical surfaces are rendered sterile prior to the start of the
manufacturing operation, and sterility is maintained throughout processing.

Decontamination- A process that eliminates viable bioburden via use of sporicidal chemical
agents.

Disinfection- Process by which surface bioburden is reduced to a safe level or eliminated.  Some
disinfection agents are effective only against vegetative microbes, while others possess
additional capability to effectively kill bacterial and fungal spores.

Depyrogenation- A process used to destroy or remove pyrogens (e.g., endotoxin).

D value- The time (in minutes) of exposure at a given temperature that causes a one-log or 90
percent reduction in the population of a specific microorganism.

Dynamic- Conditions relating to clean area classification under conditions of normal production.

Endotoxin- A pyrogenic product (e.g., lipopolysaccharide) present in the bacterial cell wall.
Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.

Gowning Qualification- A program that establishes, both initially and on a periodic basis, the
capability of an individual to don the complete sterile gown in an aseptic manner.

HEPA filter- High efficiency particulate air filter with minimum 0.3 µm particle retaining
efficiency of 99.97 percent.

HVAC- Heating, ventilation, and air conditioning.

Intervention- An aseptic manipulation or activity that occurs at the critical area.

Isolator- A decontaminated unit, supplied with Class 100 (ISO 5) or higher air quality, that
provides uncompromised, continuous isolation of its interior from the external environment (e.g.,
surrounding cleanroom air and personnel).  There are two major types of isolators:

--- PAGE 62 ---

Contains Nonbinding Recommendations

Closed isolator systems exclude external contamination from the isolator’s interior by
accomplishing material transfer via aseptic connection to auxiliary equipment, rather than
use of openings to the surrounding environment.  Closed systems remain sealed
throughout operations.

Open isolator systems are designed to allow for the continuous or semi-continuous
ingress and/or egress of materials during operations through one or more openings.
Openings are engineered (e.g., using continuous overpressure) to exclude the entry of
external contamination into the isolator.

Laminar flow- An airflow moving in a single direction and in parallel layers at constant velocity
from the beginning to the end of a straight line vector.

Operator- Any individual participating in the aseptic processing operation, including line set-up,
filler, maintenance, or other personnel associated with aseptic line activities.

Overkill sterilization process- A process that is sufficient to provide at least a 12 log reduction of
microorganisms having a minimum D value of 1 minute.

Pyrogen- A substance that induces a febrile reaction in a patient.

Sterile Product- For purposes of this guidance, sterile product refers to one or more of the
elements exposed to aseptic conditions and ultimately making up the sterile finished drug
product.  These elements include the containers, closures, and components of the finished drug
product.

Sterilizing grade filter- A filter that, when appropriately validated, will remove all
microorganisms from a fluid stream, producing a sterile effluent.

Quality Control Unit- An organizational element with authority and responsibility as defined by
211.22.

Unidirectional flow- An airflow moving in a single direction, in a robust and uniform manner,
and at sufficient speed to reproducibly sweep particles away from the critical processing or
testing area.

Terminal sterilization- The application of a lethal agent to sealed, finished drug products for the
purpose of achieving a predetermined sterility assurance level (SAL) of usually less than 10-6
(i.e., a probability of a nonsterile unit of greater than one in a million).

ULPA filter- Ultra-low penetration air filter with minimum 0.3 µm particle retaining efficiency
of 99.999 percent.

Validation- Establishing documented evidence that provides a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined specifications and
quality attributes.

--- PAGE 63 ---

Contains Nonbinding Recommendations

Worst case- A set of conditions encompassing upper and lower processing limits and
circumstances, including those within standard operating procedures, that pose the greatest
chance of process or product failure (when compared to ideal conditions).  Such conditions do
not necessarily induce product or process failure.

---

### Document: FDA CCIT Complete (FDA)

# FDA Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products (2008)

Guidance for Industry

Container and Closure System Integrity
Testing in Lieu of Sterility Testing as a
Component of the Stability Protocol for
Sterile Products

For questions on the content of the guidance, contact CBER’s Office of Compliance and
Biologics Quality at 301-827-3031; CDER’s Office of Pharmaceutical Science at 301-796-1228;
CDRH’s Office of Device Evaluation at 240-276-3747; or CVM’s Office of New Animal Drug
Evaluation at 301-827-6963.

U. S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
Center for Drug Evaluation and Research
Center for Devices and Radiological Health
Center for Veterinary Medicine
February 2008

Guidance for Industry

Container and Closure System Integrity
Testing in Lieu of Sterility Testing as a
Component of the Stability Protocol for
Sterile Products

Additional copies of this guidance are available from:

Office of Communication, Training and Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
Internet: http://www.fda.gov/cber/guidelines.htm
Phone:  800-835-4709 or 301-827-1800
or
Office of Training and Communication
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
Phone:  301-827-4573
Internet:  http://www.fda.gov/cder/guidance/index.htm
or
Division of Small Manufacturers, International, and Consumer Assistance (DSMICA), HFZ-220
Center for Devices and Radiological Health
Food and Drug Administration
1350 Piccard Drive, Rockville, MD 20850
Phone:  800-638-2041
Internet:  http://www.fda.gov/cdrh/guidance.html
Email:  dsmica@cdrh.fda.gov
Fax: 240-276-3151
or
Communications Staff, HFV-12
Center for Veterinary Medicine (CVM)
Food and Drug Administration
7519 Standish Place
Internet at http://www.fda.gov/cvm/guidance/published.htm

Contains Nonbinding Recommendations

Table of Contents

I.
PURPOSE AND SCOPE................................................................................................1
II.
INTRODUCTION...........................................................................................................2
III.
DEFINITIONS................................................................................................................3
IV.
BACKGROUND .............................................................................................................3
V.
ALTERNATIVES...........................................................................................................4
VI.
IMPLEMENTATION ....................................................................................................5
VII.
APPLICATION SUBMISSION ....................................................................................5

i

Contains Nonbinding Recommendations

GUIDANCE FOR INDUSTRY1

Container and Closure System Integrity Testing in Lieu of Sterility
Testing as a Component of the Stability Protocol for Sterile
Products

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this
topic.  It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public.  You can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations.  If you want to discuss an alternative
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this guidance.

I.
PURPOSE AND SCOPE

This guidance document provides recommendations to you, manufacturers, for using methods
other than sterility testing to confirm container and closure system integrity as a part of the
stability protocol for sterile biological products, human and animal drugs, and medical devices.
This guidance document finalizes the draft guidance of the same title dated January 1998
(January 28, 1998, 63 Federal Register (FR) 4272).

Manufacturers of drugs and biologics purporting to be sterile must test each batch or lot, as the
case may be, to ensure that the product in question conforms to sterility requirements.  21 CFR
211.167(a); 21 CFR 610.12.  Such drugs and biologics are also subject to stability testing
requirements.  21 CFR 211.166.  The stability testing requirements include maintaining a written
testing program designed to assess stability characteristics.  Manufacturers of medical devices
must validate processes, including sterilization for a device purporting to be sterile.  21 CFR
820.75.  Stability testing should be part of the design validation of such devices.  In vitro
diagnostic products for human use are required to be labeled with stability information. 21 CFR
809.10.  For products labeled as sterile, we consider sterility to be a stability characteristic.

The purpose of stability testing is to provide evidence on how the quality of a substance or
product varies with time under the influence of a variety of environmental factors such as
temperature, humidity, and light, which enables you to establish or modify recommended storage
conditions, retest periods, and shelf life or dating period, as the case may be.2  This guidance
document applies only to the replacement of the sterility test with an appropriate container and
closure system integrity test in the stability written testing program (referred to in this guidance

1 This guidance document was prepared by an intercenter working group with representatives from the Center for
Biologics Evaluation and Research, Center for Devices and Radiological Health, Center for Drug Evaluation and
Research, and the Center for Veterinary Medicine.
2  "Dating period" being the term used for biologics, as defined at 21 CFR 600.3(l), and "shelf life" being the term
used for other drugs.

Contains Nonbinding Recommendations

as the "stability protocol"), recommending an alternative to sterility testing for supporting the
continued capability of containers to maintain sterility.  The guidance document does not apply
to sterility testing methods for product sterility testing prior to release, as container and closure
system integrity tests cannot demonstrate a product's initial sterility.

This guidance document provides information that we recommend you consider when you
propose using alternative methods to sterility testing to confirm the integrity of a container and
closure system throughout the product's shelf life or dating period.  The recommendations in this
guidance document apply to both pre- and post-approval stability protocols for sterile biological
products, human and animal drugs, including investigational and bulk drugs.  For medical
devices, the recommendations in this guidance document apply to stability protocols for those
devices labeled as sterile.

If you currently perform sterility testing as a stability-indicating test as part of a stability
protocol, you may continue to do so.   If your product is approved for an alternative to sterility
testing as a component of your stability protocol, this document is not intended to recommend
additional testing requirements.

FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

II.
INTRODUCTION

Products labeled as sterile are expected to be free from viable microbial contamination
throughout the product's entire shelf life or dating period.  For products labeled as sterile, we
consider sterility to be a stability characteristic.  As a result, the stability protocol should include
confirmation of continuing sterility throughout the product's shelf life or dating period.    The
minimum sterility testing generally performed as a component of the stability protocol for sterile
products is at the initial time point (release) and final testing interval (i.e., expiration).
Additional testing is often performed at appropriate intervals within this time period (e.g.,
annually).  However, as discussed below sterility tests for the purpose of demonstrating
continuing sterility have limitations, with respect to the method's reliability, accuracy, and the
conclusions that may be derived from the results.  Because of the limitations of sterility tests
described below, sterility tests are not recommended as a component of a stability program for
confirming the continued sterility throughout a product's shelf life or dating period.  Alternative
methods may be more reliable in confirming the integrity of the container and closure system as
a component of the stability protocol for sterile products.

This guidance document does not suggest specific test methods and acceptance criteria (except
for references to USP methods), nor does it provide comprehensive lists of tests.  You should
determine these details based on good scientific principles for each specific container and closure
system taking into consideration particular product formulations and, where applicable, routes of
administration.

Contains Nonbinding Recommendations

III.
DEFINITIONS

The definitions presented here are for the purposes of this guidance only.

A container and closure system refers to the entirety of packaging components that together
contain and protect the product.

A packaging component means any single part of a container and closure system.  Typical
components are containers (e.g., ampules, vials, bottles), container liners, closures (e.g., screw
caps, stoppers), closure liners, stopper overseals, container inner seals, administration ports (e.g.,
on large-volume parenterals), overwraps, administration accessories, and container labels.

IV.
BACKGROUND

Sterility tests have long been used to verify that products maintain their sterility throughout the
product's entire shelf life or dating period.  However, sterility testing has scientific and practical
limitations, which are well known.  Some of these are:

1. Sterility tests will only detect viable microorganisms present at the time of the test;
2. Viable organisms present at the time of the test can only be detected if they are
capable of growth in the specified culture media;
3. Sterility tests may be subject to potential interference due to adventitious microbial
contamination introduced at the time of testing, resulting in false positive readings;
and
4. Sterility tests are always destructive of the samples tested and do not offer the
opportunity to reexamine the same samples in the event of either positive or negative
findings.

Some Centers of FDA have sought to address these shortcomings and communicated the
information to you in the guidance document:  "Guidance for Industry for the Submission
Documentation for Sterilization Process Validation in Applications for Human and Veterinary
Drug Products" (December 3, 1993, 58 FR 63996).  Section V. A., page 16 of the guidance
states:

The ability of the container-closure system to maintain the integrity of its
microbial barrier, and, hence, the sterility of a drug product throughout its shelf
life, should be demonstrated. […] As previously stated, sterility testing at the
initial time point is not considered sufficient to demonstrate the microbial
integrity of a container-closure system. […].

In the Federal Register of July 10, 1996 (61 FR 36466), we published a notice regarding the final
guideline entitled "Quality of Biotechnological Products: Stability Testing of
Biotechnological/Biological Products", prepared under the auspices of the International
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals

Contains Nonbinding Recommendations

for Human Use (ICH Final Guideline).3  The ICH Final Guideline is intended to provide
guidance to applicants regarding the type of stability studies that should be provided in support
of marketing applications for biotechnological/biological products. 4

V.
ALTERNATIVES

Alternatives to sterility testing as part of the stability protocol, such as replacing the sterility test
with container and closure system integrity testing, might include any properly validated
physical or chemical container and closure system integrity test (e.g., bubble tests,
pressure/vacuum decay, trace gas permeation/leak tests, dye penetration tests, seal force or
electrical conductivity and capacitance tests, etc.), or microbiological container and closure
system integrity tests (e.g., microbial challenge or immersion tests).  Such tests may be more
useful than sterility testing in demonstrating the potential for product contamination over the
product’s shelf life or dating period.  The advantages of using such container and closure system
integrity tests in lieu of sterility tests in the stability protocol for sterile products include:

1. Such alternate methods may detect a breach of the container and/or closure system
prior to product contamination;
2. Some of the alternate methods used to evaluate container and closure integrity can
conserve samples that may be used for other stability tests;
3. Alternative test methods may require less time than sterility test methods which
require at least seven days incubation; and
4. The potential for false positive results may be reduced with some alternative test
methods when compared to sterility tests.

3 For veterinary products, generally, see: VICH GL17, "Stability Testing of New Biotechnological/Biological
Veterinary Medicinal Products," 66 FR 19177, April 13, 2001, and VICH GL3(R), "Stability Testing of New
Veterinary Drug Substances and Medicinal Products (Revision)," 71 FR 19525, April 14, 2006.

4 The ICH Final Guideline is intended to supplement the tripartite ICH guideline entitled, “Stability Testing of New
Drug Substances and Products,” the notice for which is published in the Federal Register of September 22, 1994 (59
FR 48754). This guideline reflects formal scientific principles for stability testing of human drugs, and provides a
general indication of the information to be generated on product stability, but leaves sufficient flexibility to
encompass the variety of different practical approaches required for specific scientific situations and characteristics
of the materials being evaluated.

A revision of the September 22, 1994, ICH guideline with the same title (Q1A (R)) (66 FR 56332, November 7,
2001) was issued to add information to certain sections and to provide clarification to other sections. The most
important changes were as follows:  (1) stress testing of the drug substance was moved from the glossary to the main
text; (2) the text on test procedures was made consistent with ICH guidance  “Q6A Specifications:  Test Procedures
and Acceptance Criteria for New Drug Substances and New Drug Products:  Chemical Substances” (65 FR 83041,
December 29, 2000)), and relevant cross-references to other ICH guidelines were introduced; (3) the text on testing
frequency was amended for accelerated testing conditions; (4) storage conditions are described in more detail, and
testing at low temperature and testing of aqueous liquids in semipermeable containers are specifically addressed; (5)
the postapproval commitment is clearly described; and (6) the guidance was made editorially consistent.  A second
revision of the guideline, “Guidance for Industry Q1A (R2) Stability Testing of New Drug Substances and
Products,” (68 FR 65717, November 21, 2003) was issued to harmonize intermediate storage conditions for zones I
and II with long-term storage conditions for zones III and IV.

Contains Nonbinding Recommendations

Occasionally, applicants have proposed the use of a preservative effectiveness test in lieu of the
appropriate sterility test for products containing antimicrobial preservatives.  However, these
tests only measure the effectiveness of preservatives against a panel of five different test
organisms.  This method cannot confirm product sterility since it does not confirm the presence
or absence of contamination, but rather only demonstrates the microbiological effectiveness of
the preservative system against the five test organisms in question.  For these reasons,
preservative effectiveness tests are not acceptable alternative tests for monitoring container and
closure system integrity or for demonstrating maintenance of sterility.  However, such tests are
appropriate to perform as part of the stability protocol on multi-dose containers at the end of the
product's shelf life or dating period, to verify antimicrobial preservative effectiveness and
preservative content.

VI.
IMPLEMENTATION

When seeking to implement container and closure system integrity testing as an alternative to
sterility testing as a component of the stability protocol for sterile products, we recommend that
you consider the following:

1. A container and closure system integrity test may replace sterility testing in a stability
program at time points other than the product sterility test prior to release;
2. Container and closure system integrity tests do not replace sterility testing methods
for product sterility testing prior to release;
3. Any validated container and closure system integrity test method should be
acceptable provided the method uses analytical detection techniques appropriate to
the method and is compatible with the specific product being tested.  A test method is
adequately validated if it has been proven through scientifically accepted studies to be
capable of detecting a breach in container and closure system integrity; and
4. An appropriate container and closure system integrity test should be conducted
annually and at expiration, or as otherwise required by applicable regulations.

VII.
APPLICATION SUBMISSION

For new marketing applications for sterile products, we recommend that you include container
and closure system integrity tests in your stability protocol.  Pending new marketing applications
may be amended prior to approval.

If you wish to incorporate a validated container and closure system integrity test to demonstrate
the continued capability of containers to maintain sterility for an approved product,5 you must
submit the appropriate application supplement, as follows:

5  As previously mentioned, if you currently perform sterility testing as a stability-indicating test as part of a stability
protocol, you may continue to do so.  Also, if your product is approved for an alternative to sterility testing as a
component of your stability protocol, this document is not intended to impose additional testing requirements.

Contains Nonbinding Recommendations

Human drugs:  Submit methods and data labeled “Special Supplement - Changes Being
Effected” for new and abbreviated new drug applications under § 314.70.

Animal drugs:  Submit methods and data as “Supplement - Changes Being Effected” under §
514.8.

Biological products:  Submit a supplement with proper validation data in support of the
proposed change as a “Supplement - Changes Being Effected” under § 601.12.

Medical devices:  Submit a PMA supplement with proper validation data in support of the
proposed change under § 814.39.

You should include in your application supplement a discussion of what the test method
evaluates and how it is applicable to microbial integrity.  You should select methods that are
appropriate to the product in question, and validate all test methods.  Validation of particular
methods should be specific to the product container and closure system or product type.  Several
alternative container and closure system integrity test methods exist, as described above.  We
encourage you to develop innovative methods of testing the integrity of specific container and
closure systems.

The use of media-filled containers is generally acceptable for initial validation studies.  It may be
acceptable to use media-filled containers instead of product-filled containers for testing during
the product's shelf life or dating period, if the product contains a material, such as a preservative,
which would bias the results of the container and closure system integrity test.  If you propose to
use media-filled containers for some or all of the testing, you should include data in your
application supplement to support this request.

If you manufacture a number of products that use the same type of container and closure system,
you may validate your integrity test method using a bracketing matrix.6  It is not necessary to
perform validation studies on each product.

The number of samples to be tested should be statistically appropriate.  Samples which pass
container and closure system integrity testing may be further utilized in the stability testing for
that specific test period or interval; however, the test should be non-destructive and the sample
unaltered by the container and closure testing method itself.  Samples should not, however, be
tested for container and closure system integrity at one time interval (e.g., 12 months), and then
stored for further stability testing at later time periods (e.g., 24 months).

6 See ICH guidance “Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and
Products” (68 FR 2339, January 16, 2003).

---

### Document: FDA ComboProd CGMP Complete (FDA)

# FDA Guidance: Current Good Manufacturing Practice Requirements for Combination Products (Jan 2017): Current Good Manufacturing Practice Requirements for Combination Products

On February 2, 2024, FDA published the final rule to amend the Quality System (QS) regulation
in 21 CFR part 820 (89 FR 7496, effective February 2, 2026). The revised 21 CFR part 820 is
now titled the Quality Management System Regulation (QMSR). The QMSR harmonizes quality
management system requirements by incorporating by reference the international standard
specific for medical device quality management systems set by the International Organization for
Standardization (ISO), ISO 13485:2016. The FDA has determined that the requirements in ISO
13485 are, when taken in totality, substantially similar to the requirements of the QS regulation,
providing a similar level of assurance in a firm’s quality management system and ability to
consistently manufacture devices that are safe and effective and otherwise in compliance with
the Federal Food, Drug, and Cosmetic Act (FD&C Act).

This guidance document was issued prior to the effective date of the final rule. FDA encourages
manufacturers to review the current QMSR to ensure compliance with the relevant regulatory
requirements.

The QMSR includes conforming edits to 21 CFR part 4 subpart A, Current Good Manufacturing
Practice Requirements for Combination Products, to clarify the device quality management
system requirements for combination products.

Guidance for Industry and
FDA Staff:
Current Good Manufacturing Practice
Requirements for Combination Products

FINAL GUIDANCE

The draft of this document was issued in January 2015.

Additional copies are available from:
Office of Combination Products
 Food and Drug Administration
WO32, Hub/Mail Room #5129
10903 New Hampshire Avenue
Silver Spring, MD 20993
(Tel) 301-796-8930
 (Fax) 301-847-8619
http://www.fda.gov/oc/combination

For questions regarding this document, contact the Office of Combination Products at 301-796-
8930 or combination@fda.gov.

U.S. Department of Health and Human Services
Food and Drug Administration
Office of Combination Products (OCP) in the Office of the Commissioner
Center for Biologics Evaluation and Research (CBER)
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
Office of Regulatory Affairs (ORA)

January 2017

TABLE OF CONTENTS

I.

Introduction ............................................................................................................................ 3

II.  Background ............................................................................................................................ 4

A.  Definition of a combination product ............................................................................................ 4

B.  Quality and Current Good Manufacturing Practices................................................................. 5

C.  Overview of the final rule .............................................................................................................. 5

D.  The role of the lead center and other agency components ......................................................... 9

III.  General Considerations for CGMP Compliance .............................................................. 9

A.  Demonstrating compliance .......................................................................................................... 10

B.

Investigational products .............................................................................................................. 11

C.  Definitions and terminology. ....................................................................................................... 12

D.  What CGMP requirements apply to a product or facility? ..................................................... 15

E.  Control of changes to a combination product ........................................................................... 18

IV.  What do I need to know about the CGMP requirements specified in 21 CFR 4.4(b)? . 19

A.  Provisions from the device QS regulation specified in 21 CFR 4.4(b)(1) ................................ 19

B.  Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2) ............................................ 28

C.  Combination products that include biological products and HCT/Ps .................................... 38

V.  Application of CGMP requirements to specific types of combination products ................ 40

A.  Prefilled syringe ........................................................................................................................... 41

B.  Drug-coated mesh ........................................................................................................................ 46

C.  Drug Eluting Stent (DES) ............................................................................................................ 49

VI.

Contact Us ........................................................................................................................ 53

VII.  Glossary ............................................................................................................................ 54

VIII.

References .................................................................................................................... 56

Contains Nonbinding Recommendations

Guidance for Industry and FDA Staff:
Current Good Manufacturing Practice Requirements for Combination
Products1

This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA
or the public.  You can use an alternative approach if the approach satisfies the requirements of
the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA
office responsible for this guidance as listed on the title page of this guidance.

I.

Introduction

This guidance describes and explains the final rule on current good manufacturing

practice (CGMP) requirements for combination products that FDA issued on January 22, 2013
(final rule).2 (21 Code of Federal Regulations (CFR) part 4).  Prior to issuance of the final rule,
although CGMP regulations were in place to establish requirements for drugs, devices, biological
products, and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), there
were no regulations to clarify and explain the application of these CGMP requirements to
combination products.  The final rule did not establish any new requirements; it was intended to
clarify which CGMP requirements apply when drugs, devices, and biological products are
combined to create combination products, and to set forth a transparent and streamlined
regulatory framework for firms to use when demonstrating compliance with applicable CGMP
requirements.3

Section II of this document provides the definition of “combination product,” an

overview of the final rule, and describes the role of the lead center and other Agency
components4 with respect to combination product CGMP issues.  Section III addresses certain
general considerations for CGMP compliance for combination products.  Section IV presents the
purpose and content of specific CGMP requirements addressed in the final rule.  Finally, Section
V analyzes hypothetical scenarios that illustrate how to comply with certain CGMP requirements

1 This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in
conjunction with the Center for Biologics Evaluation and Research, Center for Drug Evaluation and Research,
Center for Devices and Radiological Health, and the Office of Regulatory Affairs.
2 See the Current Good Manufacturing Practice Requirements for Combination Products, 78 FR 4307 (January 22,
2013).
3 As stated in the preamble to the final rule, combination products were subject to CGMP requirements that apply to
each constituent part of their combination product prior to promulgation of 21 CFR part 4.  Although products
developed prior to promulgation of part 4 are frequently termed “legacy” combination products, FDA deliberately
does not use this terminology in this guidance because it could be inappropriately interpreted to indicate that
products developed prior to promulgation of part 4 are therefore subject to fewer CGMP obligations than products
developed after promulgation of part 4.
4 “Agency component” is defined at 21 CFR 3.2(b) as “the Center for Biologics Evaluation and Research, the Center
for Devices and Radiological Health, the Center for Drug Evaluation and Research, or alternative organizational
component of the agency.”

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for specific types of combination products.  Throughout this guidance, the Agency also refers to
existing guidance and additional resources that address CGMP requirements for drugs, devices,
biological products, and HCT/Ps, to further inform combination product manufacturers on how
to comply with CGMP requirements.

FDA’s guidance documents, including this guidance, do not establish legally enforceable

responsibilities.  Instead, this guidance describes the Agency’s current thinking on a topic that
should be viewed only as recommendations, unless specific regulatory or statutory requirements
are cited.  The use of the word should in Agency guidance means that something is suggested or
recommended, but not required.

II.  Background

A. Definition of a combination product

As set forth in part 3 (21 CFR part 3), a combination product is a product composed of
two or more different types of medical products (i.e., a combination of a drug, device, and/or
biological product with one another).5  The drugs, devices, and biological products included in
combination products are referred to as “constituent parts” of the combination product.

Under 21 CFR 3.2(e), a combination product includes:

•  A product comprised of two or more regulated components, i.e., drug/device,
biologic/device, drug/biologic, or drug/device/biologic, that are physically,
chemically, or otherwise combined or mixed and produced as a single entity (a
“single entity” combination product, such as a prefilled syringe or drug-eluting
stent);

•  Two or more separate products packaged together in a single package or as a unit
and comprised of drug and device products, device and biological products, or
biological and drug products (a “co-packaged” combination product, such as a
surgical or first-aid kit);

•  A drug, device, or biological product packaged separately that according to its
investigational plan or proposed labeling is intended for use only with an
approved, individually specified drug, device, or biological product where both
are required to achieve the intended use, indication, or effect and where upon
approval of the proposed product the labeling of the approved product would need
to be changed (e.g., to reflect a change in intended use, dosage form, strength,

5 Any reference in this guidance to CGMP requirements as applicable to a combination product that includes a drug
constituent part should be understood to refer as well to any combination product that includes a biological product
constituent part that is also subject to regulation under the Federal Food, Drug, and Cosmetic Act (FD&C Act) as a
drug, and any reference to CGMP requirements as applicable to a combination product that includes a device
constituent part should be understood to refer as well to combination products that include a biological product
constituent part that is also subject to regulation as a device under the FD&C Act.

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route of administration, or significant change in dose) (a “cross-labeled”
combination product, as might be the case for a light-emitting device and a light-
activated drug); or

•  Any investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another individually
specified investigational drug, device, or biological product where both are
required to achieve the intended use, indication, or effect (another type of cross-
labeled combination product).

B. Quality and Current Good Manufacturing Practice

One of FDA’s goals is to assure the availability of quality drugs, biologics, devices, and

combination products that consistently meet applicable requirements and specifications.  The
drug CGMP and device QS regulations, as well as the CGMPs for biologics and current good
tissue practices for HCT/Ps, provide a framework of minimum requirements to help assure
product quality.  The core requirements embedded in these regulations  provide for systems that
assure proper design, monitoring, and control of manufacturing processes and facilities.  This
includes establishing a strong quality management system, using appropriate quality raw
materials, establishing robust manufacturing and control procedures based on sound design
principles, and detecting and investigating product quality deviations.  In addition, these
regulations call for ongoing assessment of systems and the implementation of corrective actions
where appropriate.

C. Overview of the final rule

1.  Summary of the Final Rule

The constituent parts of a combination product retain their regulatory status (as a drug or

device, for example) after they are combined.  The final rule clarifies that the CGMP
requirements that apply to each of the constituent parts apply to the combination product they
constitute. This guidance refers to a “CGMP operating system” to mean the operating system
within an establishment that is designed and implemented to address and meet the current good
manufacturing practice requirements applicable to the manufacture of a combination product.

The final rule on CGMP requirements for combination products applies to all
combination products.  The CGMP requirements for constituent parts of cross-labeled
combination products that are entirely manufactured at separate facilities are the same as those
that would apply if these constituent parts were not part of a combination product (e.g., for a
drug/device combination product, only parts 210 and 211 (21 CFR parts 210 and 211) would
apply to the manufacture of the drug constituent part(s) of the cross-labeled combination product,
and only part 820 (21 CFR part 820) would apply to the device constituent part(s)).  With regard
to cross-labeled combination products, part 4 was intended to clarify only that the CGMP
obligations applicable to the drugs, devices, or biological products also apply to these types of
articles when they are constituent parts of cross-labeled combination products.

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Because constituent parts of cross-labeled combination products need only comply with

the requirements otherwise applicable to that type of product (e.g, part 211 for a drug constituent
part or part 820 for a device constituent part), the “streamlined approach” (discussed below) is
generally not relevant or applicable to them.  However, to the extent that the constituent parts of
a cross-labeled combination product are manufactured at the same facility, the manufacturing
process would be akin to when the manufacture of the constituent parts of a co-packaged
combination product occurs at the same facility.  Accordingly, for  cross-labeled combination
products when manufactured at the same facility, the Agency does not intend to object to the use
of a streamlined CGMP operating system for the manufacture of the combination product rather
than distinct systems for the manufacture of each constituent part that is occurring at that facility.
We believe this approach is consistent with the principles of part 4.

For single-entity combination products and co-packaged combination products, part 4

identifies two ways to demonstrate compliance with CGMP requirements.  Under the first
option, manufacturers demonstrate compliance with all CGMP regulations applicable to each of
the constituent parts included in the combination product.6  Under the second option,
manufacturers implement a streamlined approach for combination products that include both a
drug and a device by demonstrating compliance with either the drug CGMPs (21 CFR parts 210
and 211) or the device Quality System (QS) regulation (21 CFR part 820) and also
demonstrating compliance with specified provisions from the other of these two sets of CGMP
requirements.7, 8  In addition, for a combination product that includes a biological product, the
manufacturer must demonstrate compliance with the CGMP requirements specific to biological
products in parts 600 through 680 (21 CFR parts 600 through 680). For a combination product
that includes any HCT/P, the manufacturer must demonstrate compliance with the regulations in
part 1271 (21 CFR part 1271)—including the current good tissue practice (CGTP) requirements
and donor eligibility requirements.9, 10, 11

Specifically, the streamlined approach under 21 CFR 4.4(b) provides that combination

product manufacturers may meet the requirements of both the drug CGMPs and device QS
regulation by designing and implementing a CGMP operating system that demonstrates
compliance with either of the following:

6 See 21 CFR 4.4(a)
7 See 21 CFR 4.4(b).
8 While 21 CFR 211 requirements apply to all combination products because combination products always contain a
drug and/or a biological product, 21 CFR 820 requirements apply only to combination products which include a
device constituent part.
9 See 21 CFR 4.4(a) and (b).
10 As discussed later in section IV.C, an HCT/P may be a “constituent part” of a combination product when the
HCT/P is not regulated solely under section 361 of the PHS Act because it fails to meet one or more of the criteria in
21 CFR 1271.10, and is, therefore, regulated as a drug, device, and/or biological product. See also 21 CFR 1271.20.
11 For the purposes of part 4, FDA uses the term ‘‘CGMP requirements’’ to include all such requirements found in
the standards in parts 600 through 680 that may apply to biological products.  We note that biological products and
combination products that include biological product constituent parts must comply with all applicable requirements
in parts 600 through 680.  Because many of the requirements in parts 600 through 680 are not considered CGMP
requirements, such requirements are not addressed in part 4 and are not a focus of this guidance.

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•  The drug CGMPs and the following provisions from the device QS regulation in
accordance with 21 CFR 4.4(b)(1) (drug CGMP-based streamlined approach):

(i) 21 CFR 820.20
(ii) 21 CFR 820.30
(iii) 21 CFR 820.50
(iv) 21 CFR 820.100
(v) 21 CFR 820.170
(vi) 21 CFR 820.200

Management responsibility
Design controls
Purchasing controls
Corrective and preventive action
Installation
Servicing

OR

•  The device QS regulation and the following provisions from the drug CGMPs in

accordance with 21 CFR 4.4(b)(2) (device QS regulation-based streamlined approach):

(i) 21 CFR 211.84

(ii) 21 CFR 211.103
(iii) 21 CFR 211.132

(iv) 21 CFR 211.137
(v) 21 CFR 211.165
(vi) 21 CFR 211.166
(vii) 21 CFR 211.167
(viii) 21 CFR 211.170

Testing and approval or rejection of components, drug
product containers, and closures
Calculation of yield
Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products
Expiration dating
Testing and release for distribution
Stability testing
Special testing requirements
Reserve samples

A manufacturer may prefer one approach over the other based, for example, on the details

of the manufacturing process used at the facility or in light of other manufacturing activities
undertaken at the facility.  The manufacturer is not required to choose a streamlined approach
based on the CGMP regulations for the constituent part that provides the primary mode of action
(PMOA) of the combination product (see II.D below).  For example, if the drug constituent part
of a drug-device combination product provides the product’s PMOA, the manufacturer of that
combination product may choose to adopt either the device QS regulation-based or drug CGMP-
based streamlined approach, or choose to develop a CGMP operating system that wholly
complies with the specifics of applicable provisions of both the drug CGMPs and the device QS
regulation.

21 CFR 4.4(c) provides that if a facility manufactures only one type of constituent part
(e.g., a drug or device constituent part) of a co-packaged or single-entity combination product,
that facility is subject only to the CGMP regulations applicable to that constituent part (i.e., part
211 for a drug or part 820 for a device, as well as those under parts 600 through 680 for a
biological product and part 1271 for an HCT/P).  21 CFR 4.4(d) provides that when two or more
types of constituent parts to be included in a single-entity or co-packaged combination product
have arrived at the same facility, or the manufacture of these constituent parts is occurring at the
same facility, that facility must comply with all CGMP requirements described in part 4

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applicable to the manufacturing activities at that facility, and a streamlined approach under 21
CFR 4.4(b) may be used to demonstrate compliance with these requirements.

Similarly, if a facility manufactures a drug or device that is not a constituent part of a

combination product and also manufactures a combination product, the CGMP requirements for
the independently marketed drug or device do not change (compliance with parts 210/211 or part
820, respectively).  Accordingly, if a facility manufactures an independently marketed device
that is subject to part 820 and a combination product, it cannot manufacture the device under a
drug CGMP-based streamlined operating system, even if it is used for the combination product,
because this operating system only includes limited, specified provisions from the QS regulation.
However, both the device and the combination product may be manufactured under a device QS
regulation-based streamlined operating system, with the device that is not part of a combination
product then being subject only to part 820.

2.  Documentation of CGMP Approach

Combination product manufacturers should be able to identify all documentation needed

to demonstrate compliance with part 4, and make it readily accessible for an FDA inspection.
The facility’s quality system documentation should identify the CGMP operating system for the
combination product(s) manufactured at that facility, and the manufacturer should share this
information with investigators at the initiation of an inspection.  For combination product
manufacturers implementing a streamlined approach (See Section II.B.1 above), inspection of
the base CGMP operating system (i.e., 21 CFR part 210/211 or 21 CFR part 820) will typically
be consistent with existing compliance programs and policies associated with it.  For specified
provisions from the non-base system, FDA intends to utilize the compliance program and policy
elements specific to these provisions.12

Prior to the promulgation of part 4, manufacturers of combination products already had to

demonstrate compliance with the applicable CGMP requirements for each constituent part of
their combination product.  Manufacturers should ensure that their CGMP procedures and
processes are compliant with the regulatory framework provided in part 4.  If the operating
system requires changes to come into compliance, manufacturers should document the steps they
take to ensure ongoing product safety and effectiveness.  Manufacturers should be prepared to
discuss their approach during inspections.

Combination product manufacturers who are required to address CGMP issues as part of

premarket review should identify in premarket submissions whether they are operating under a
streamlined approach, and if so, whether it is a drug CGMP-based or device QS regulation-based
streamlined approach.13  In premarket submissions, the CGMP approach should be identified for
each relevant facility.  For NDAs, BLAs and ANDAs, the CGMP approach should be described

12 For a listing of existing Compliance Program Guidance Manuals (CPGMs) for drugs, devices, and biologics, see
http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/ucm2005382.htm.
13 Submission of CGMP information is not routinely required prior to clearance of 510(k)’s.  As discussed,
manufacturers of 510(k) combination products should identify their CGMP operating system in the quality system
documentation at their facilities.

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in the Common Technical Document.  For additional details on placement within the CTD, see
eCTD Technical Conformance Guide, Section 3.3.2.14  For PMAs, the CGMP approach should
be documented in the manufacturing section of the PMA (the manufacturing module for a
modular PMA).

D. The role of the lead center and other Agency components

A combination product is assigned to an Agency center that will have primary
jurisdiction (i.e., the lead) for that combination product’s premarket review and regulation.
Under section 503(g)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C.
351(g)), assignment of a combination product to a lead center is based on a determination of
which constituent part provides the PMOA of the combination product.15

If the PMOA of a device-biological product combination product is attributable to the

biological product, for example, the center responsible for premarket review of such a biological
product would have primary jurisdiction for the regulation of the combination product.  The lead
center for premarket review of the combination product also has the lead for ensuring
compliance with CGMP regulatory requirements.  Regardless of the PMOA, Agency
components will coordinate as appropriate to enable efficient, effective CGMP regulatory
oversight, including appropriate CGMP inspections.

The lead center is a manufacturer’s primary point of contact.   Manufacturers may also

contact the Office of Combination Products (OCP) for assistance, as needed, in identifying
appropriate contact points (including those in the lead center), resolving substantive issues, or
otherwise facilitating interactions with the Agency and collaboration among Agency
components, including centers and the Office of Regulatory Affairs (ORA).

III.  General Considerations for CGMP Compliance

This section addresses some general considerations for CGMP compliance for

combination products.  Note that this guidance addresses only CGMP requirements.  Additional
requirements may apply including the need for premarket submissions as a result of changes to
product design, intended use, or manufacture.

14 Available at
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSub
missions/UCM465411.pdf.
15 The “primary mode of action” of a combination product is the single mode of action (drug, device, or biological
product) that provides the most important therapeutic action of the combination product.  The most important
therapeutic action is the mode of action expected to make the greatest contribution to the overall intended
therapeutic effects of the combination product.  See 21 CFR 3.2(k) (which defines “mode of action” and
“therapeutic”) and (m) (which defines primary mode of action).  For more information on product classification,
assignment, and PMOA, see the guidance for industry How to Write a Request for Designation (RFD)(April 2011).

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A. Demonstrating compliance

The final rule identifies two ways for co-packaged and single-entity combination product

manufacturers to demonstrate compliance with applicable CGMP requirements.  The Agency
intends for the term “demonstrate” to apply for part 4 as it would be for purposes of fulfilling the
underlying CGMP regulations listed in 21 CFR 4.3.  Manufacturers must demonstrate
compliance with each applicable CGMP requirement for constituent parts and combination
products.16

If a streamlined approach is used, the manufacturer must demonstrate compliance with all

of the relevant provisions of either the drug CGMPs or device QS regulation, and the provisions
specified in 21 CFR 4.4(b) for the other set(s) of CGMP requirements applicable to the product.
Further guidance on how to demonstrate compliance with the regulations specified in 21 CFR
4.4(b) is provided in section IV of this guidance.  A manufacturer who implements a streamlined
approach is not expected to demonstrate compliance with the specific provisions of the non-base
set of requirements other than those specified in 21 CFR 4.4(b) (e.g., for a drug CGMP-based
streamlined approach, the manufacturer must demonstrate compliance with applicable drug
CGMPs plus the six specified provisions from part 820, as applicable, but the manufacturer does
not need to demonstrate compliance with the other specific provisions in part 820).

As provided in 21 CFR 4.4(e), in the event of a conflict between regulations applicable

under part 4, the regulations most specifically applicable to the constituent part in question
supersede the more general.  The intent of this provision is to address any potential conflicts
between regulations.  This provision does not provide a basis for the Agency to require
manufacturers to demonstrate compliance with provisions not otherwise identified in part 4 as
applicable to them.

Some of the provisions specified in part 4 from the drug CGMPs and device QS
regulation cross-reference other provisions of parts 211 and 820, respectively.  This raises the
question of whether manufacturers must specifically demonstrate compliance with these cross-
referenced provisions.  FDA believes that manufacturers can adequately address the expectations
of these cross-referenced provisions through implementation of either a drug CGMP-based or
device QS regulation-based CGMP streamlined approach.

For example, 21 CFR 211.170 (Reserve samples) references 21 CFR 211.192 (Production

record review).  However, 21 CFR 211.192 is not a specified provision in 21 CFR 4.4(b)(2)
because part 820 encompasses the requirements of that section.  In particular, under the CAPA
requirements in 21 CFR 820.100, a manufacturer operating under a device QS-based streamlined
approach should have the systems in place that would satisfy the requirements of 21 CFR
211.192.  Similarly, 21 CFR 211.103 (Calculation of yield) references 21 CFR 211.68
(Automatic, mechanical, and electronic equipment) in relation to using automated equipment for
yield calculations and maintaining appropriate controls over such equipment.  Corresponding
provisions in 21 CFR 820.70(i), applicable under a QS-regulation based streamlined approach,

16 21 CFR part 4.

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require that automated data processing systems be validated for their intended uses.  To take
another example, the definition of design output in 21 CFR 820.3 makes reference to “device
master record.”  Both part 211 and part 820 have requirements for “master records” (21 CFR
211.186, Master Production and Control Records and 21 CFR 820.181, Device Master Record).
FDA believes the substantive expectations of these master record provisions are aligned and
needed to control product development and manufacture.

This guidance does not focus on how to demonstrate compliance with provisions of the

drug CGMPs and device QS regulation other than those specified in 21 CFR 4.4(b).  Other
provisions of these regulations address a variety of manufacturing considerations regarding, for
example, in-process materials, facility and equipment, record-keeping, labeling, personnel,
inputs, testing, and distribution.

B. Investigational products

Part 4 does not alter the scope of the underlying CGMP regulations for drugs, devices,
biological products, and HCT/Ps.  In particular, part 4 does not alter the applicability of these
CGMP regulations to investigational products.

An investigational drug for use in a phase 1 study is subject to the statutory requirements

set forth in 21 U.S.C. 351(a)(2)(B).  The production of such a drug is generally exempt from
compliance with the regulations in parts 210 and 21117 and, therefore, so is an investigational
combination product that includes a drug constituent part for use in a phase 1 study.  This
exemption does not apply to an investigational combination product or drug constituent part,
however, once it has been made available for use by or for the sponsor in phase 2 or phase 3
studies, nor does the exemption apply to a drug product that has been lawfully marketed.  For
additional information on study phases, see 21 CFR 312.21.

Under 21 CFR 812.1, investigational devices are exempt from part 820 except for design
control requirements under 21 CFR 820.30.  This exemption also applies to the manufacturing of
investigational combination products that include device constituent parts.  Investigational
combination products that include a device constituent part are subject to design controls (except
when the device constituent part is exempt from design controls, see III.C.3 below), but not to
the other provisions of part 820.  Design controls should start as early as possible, once a
company has determined that a product appears to have clinical utility and management has
committed to further development (see also IV.A.2 below).18

The Agency considers these exemptions from requirements under parts 211 and 820

applicable to combination products and constituent parts of combination products whether they

17 See 21 CFR 210.2(c).
18 The preamble to the device QS regulation (61 FR 52602) provides additional detail on when design controls apply
for products early in the design life-cycle:  “The design control requirements are not intended to apply to the
development of concepts and feasibility studies.  However, once it is decided that a design will be developed, a plan
must be established to determine the adequacy of the design requirements and to ensure that the design that will
eventually be released to production meets the approved requirements.” (61 FR 52616, Comment 62)

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are being studied under an investigational device exemption (IDE) or an investigational new
drug application (IND).  Even when these exemptions apply, however, methods, facilities, and
manufacturing controls that are appropriate for the investigational products should be used.
When developing and applying appropriate manufacturing practices, the Agency recommends
that the hazards and associated risks from the manufacturing environment that might adversely
affect an investigational combination product be considered.

For further information on the CGMP requirements for investigational products, see 21

CFR 210.2(c), 21 CFR 820.1, 61 Federal Register (FR) 52,616-52,617, and the Guidance for
Industry on CGMP for Phase 1 Investigational Drugs (July 2008).  Manufacturers who have
questions about IDE or IND requirements for their combination product should contact the lead
center or OCP, if needed, for assistance.

C. Definitions and terminology

Unless 21 CFR part 4 expressly states otherwise, terms used have the same meaning as

when used in the underlying, referenced regulations.  This section addresses the meaning and
significance for combination products of the terms “manufacture” and “manufacturer,”
“constituent part” and “component,” “device,” and drug “container” and “closure.”  It also
addresses the meaning of “convenience kit” as a type of co-packaged combination product.
Other relevant definitions can be found in part 4 and the underlying CGMP regulations (see, e.g.,
21 CFR 210.3, 21 CFR 211.3, 21 CFR 600.3, 21 CFR 606.3, 21 CFR 820.3, and 21 CFR 1271.3)

1.  “Manufacture” and “manufacturer”

The definition of the term “manufacture” in part 4 is intended to include all of the
activities considered within the scope of manufacturing for drugs, devices, biological products,
and HCT/Ps.  Accordingly, the definition of “manufacture” in 21 CFR 4.2 includes, but is not
limited to, designing, fabricating, assembling, filling, processing, testing, labeling, packaging,
repackaging, holding, and storage.  For example, if a company designs a drug-device
combination product, that activity constitutes manufacture of that product, and the facility at
which the design work occurs is a manufacturing facility.  That company is a manufacturer
subject to part 4 for the design activities it performs, even if all other aspects of the combination
product’s manufacture (e.g., fabricating, labeling, or packaging) are performed by another entity.
Similarly, a facility responsible for the holding and storage of a combination product would be
subject to related CGMP requirements such as 21 CFR 211.142 (Warehousing procedures)
and/or 21 CFR 820.150 (Storage), depending upon whether the facility applies a streamlined
approach and if so, which approach it applies.

2.  “Constituent part” versus “component”

The term “constituent part” is used by the Agency as a succinct way to identify a drug,

device, or biological product included in a combination product.  Under the drug CGMPs,
“component” is defined as “any ingredient intended for use in the manufacture of a drug product,

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including those that may not appear in such drug product.”19  Under the device QS regulation,
the term “component” is defined as “any raw material, substance, piece, part, software, firmware,
labeling, or assembly which is intended to be included as part of the finished, packaged, and
labeled device.”20  Components can include sub-assemblies that are further processed to make a
finished device.  In contrast, a finished device is “suitable for use or capable of functioning,
whether or not it is packaged, labeled, or sterilized,”21 as would be the case for a device
constituent part as incorporated into a combination product.22

A facility that manufactures only device components, including device components used
in a combination product, is not made subject to the device QS regulation by part 4.23  Similarly,
a facility that manufactures solely active pharmaceutical ingredients (APIs) is not subject to part
211, though it is subject to statutory CGMP requirements under Section 501 of the FD&C Act
(21 U.S.C. 351).  Part 4 does not make such a drug component manufacturing facility subject to
part 211 if those components are for use in a combination product.  However, a facility that
manufacturers a drug-device combination product formed from components is subject to parts
211 and 820, and must comply with these two sets of regulations as provided in part 4.24

In short, the terms “constituent part” in part 4 and “component” in the CGMP regulations

serve different regulatory purposes.  The use of the term “constituent part” in part 4 refers to
drugs, devices, and biological products included in combination products and does not alter the
meaning of the term “component” or alter whether the regulations listed in 21 CFR 4.3 apply to
component manufacturers.

3.  Drug containers and closures versus delivery devices

The Agency draws a distinction between mere drug containers and closures and
containers and closures that are also devices.  The essential difference is generally whether the
article is designed to deliver the drug it contains or merely to hold it.  If the article merely holds
the drug, it is only subject to drug CGMPs as a container or closure.  An article that holds or
contains a drug, but also delivers it, may also be a device subject to the device QS regulation in
addition to the requirements relating to drug containers and closures.

A container closure system is the sum of packaging components that together contain and

protect the drug product.  This includes primary and secondary packaging components if the
latter are intended to provide additional protection to the drug product.25  Elements of container
closure systems that are device constituent parts include piston syringes, metered dose inhalers
(MDIs), and containers for intravenously-administered (IV) fluids (such as IV bags containing

19 21 CFR 210.3.
20 21 CFR 820.3(c).
21 21 CFR 820.3(l).
22 21 CFR 4.2.
23 See 21 CFR 820.1(a).
24 See 78 FR 4313-4314, Comment 15.
25 See the Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics:
Chemistry, Manufacturing, and Controls Documentation (May 1999).

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saline or anti-coagulants), which both hold and deliver the drugs or biological products they
contain.26  In the case of an IV container, the drug is delivered to the patient via the IV line.

The Agency has exempted some devices from all or certain provisions of the device QS

regulations.  For example, 21 CFR 880.6430 exempts liquid medication dispensers (cups,
droppers, etc.) from all provisions of the device QS regulation with the exception of 820.180 and
820.198.  Such exemptions may extend to device constituent parts of combination products and
to the combination products of which they are a part.  If the exemptions for a device constituent
part of a drug-device combination product cover all of the part 820 provisions included in 21
CFR 4.4(b)(1), then the Agency will consider the combination product manufacturer CGMP
compliant so long as the CGMP operating system is compliant with part 211 (no demonstration
of compliance with part 820 will be necessary).  However, if a device that would ordinarily be
exempt from all or certain provisions in part 820 is incorporated into a container closure system,
for example if a dropper is incorporated into the cap of a bottle of a drug, this may be a new use
of the device such that the exemptions from part 820 may not be applicable.27  In any event,
when incorporated into a container closure system, the device must be addressed as part of the
container closure system for purposes of part 211 (e.g., requirements under 21 CFR 211.84,
211.165, and 211.166, discussed in section IV.B).

Manufacturers should document their evaluation if they believe a container closure

system that has delivery attributes is not a device, or if they believe a device constituent part is
exempt from any or all provisions under the device QS regulation.  Manufacturers who have
questions about whether their container closure system, or an element thereof, is regulated as a
device, or whether exemptions from part 820 apply, are encouraged to discuss the issue with the
lead center or OCP, as needed.

4.  Convenience kits

A kit that includes two or more different types of medical products (e.g., a device and a
drug) is a co-packaged combination product and, therefore, part 4 applies to the manufacture of
the kit.  The CGMP requirements applicable to a kit manufacturer depend on what products are
included in the kit.

If the kit includes only products that are 1) legally marketed independently and 2)

packaged in the kit as they are when independently marketed (including any labeling used for

26 The Agency notes that other Agency guidance addresses syringes and other devices that contain a drug as
“container closures” for the drug, and focuses on considerations related to their use as container closures, while
addressing only in a summary manner other requirements applicable because these container closures are also
regulated as devices.  See, e.g., Guidance for Industry Container Closure Systems for Packaging Human Drugs and
Biologics[1999].  As reflected in this section and elsewhere in this guidance, such devices are subject to container
closure requirements because they hold a drug. However, because they are also devices, they and the combination
product of which they are a part are subject to additional requirements, including under part 820.
27 Although outside the scope of this guidance, we note that changes to the intended use of constituent parts of a
combination product may require premarket review by FDA.

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independent marketing), it is a “convenience kit,”28 and the only manufacturing steps for the
combination product would be the assembly, packaging, labeling, any sterilization, and further
processing of the kit itself.  Accordingly, the kit manufacturer would only have to demonstrate
compliance with CGMP requirements with respect to those manufacturing activities.

Kit manufacturers should carefully analyze what CGMP requirements apply to a kit. 27

If a kit includes any products that are repackaged, relabeled, or otherwise modified from the
independently marketed product, then the kit is not a convenience kit.  Likewise, if the kit
manufacturer includes labeling for the kit that modifies the intended use for a constituent part,
then the kit is not a convenience kit.  In these cases, the manufacturer would have to demonstrate
compliance with CGMP requirements for the constituent parts and the overall product.  Also, if a
device constituent part would be considered exempt from the device QS regulation if marketed
outside the kit, the kit manufacturer may not be able to claim this exemption from part 820 if the
intended use of the device constituent part in the kit is new.

Co-packaged combination product manufacturers, including manufacturers of

convenience kits, should carefully consider the impact of any sterilization process on the items in
the co-package.29  For example, a constituent part may be sensitive to further processing, as may
be the case for surgical sutures.  Similarly, some sterilization methods suitable for devices, such
as irradiation, are not suitable for many drugs.  Also, additional verification to confirm no
degradation in safety and effectiveness after any re-sterilization may be necessary.  For example,
manufacturers should consider whether re-sterilization affects stability, material properties, and
expiration dating/shelf-life of any of the products within the kit.  Additional issues may need to
be considered, including validation of the sterilization process to ensure sterility for each
constituent part within the kit, as appropriate.30

Manufacturers should document their evaluation if they believe a kit qualifies as a

convenience kit or that a device constituent part (and, therefore, a kit) should not be subject to
requirements under part 820.  Kit manufacturers who have questions about whether their kit is a
convenience kit, or about the applicability of part 820 requirements, are encouraged to contact
the lead center or OCP, as needed.

D. What CGMP requirements apply to a product or facility?

While combination product manufacturers must demonstrate compliance with all of the

CGMP regulations applicable to their combination product under 21 CFR 4.3, they may, as
discussed above, demonstrate compliance with the drug CGMPs and device QS regulation
requirements through one of the streamlined approaches under 21 CFR 4.4(b).  Further, not all

28 The term “convenience kit” as used in this guidance embraces solely the definition presented in this section,
initially provided in the preamble to the part 4 regulation (see 78 FR 4310).  The term “convenience kit” is used in
other FDA regulations for different purposes.  See, for example, 21 CFR 801.3.
29 See, e.g., 21 CFR 211.166.
30 See, for example, the Guidance for Industry on Sterilized Convenience Kits for Clinical and Surgical Use (January
2002).

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the provisions of the CGMP regulations listed in 21 CFR 4.3 may be applicable to a specific
combination product or constituent part.

1.  Applicability of CGMP requirements to a product

The preamble to the proposed rule addressed which CGMP requirements apply to which

combination products (see 74 FR at 48426), noting, for example, that only an over-the-counter
(OTC) combination product must comply with the tamper-evident packaging requirements in the
drug CGMPs and only combination products that include a type of device constituent part that is
installed or serviced must comply with installation and servicing requirements in the device QS
regulation.  The preamble to the final rule addressed similar considerations for combination
products that include a biological product constituent part, explaining that many of the
requirements for biological products are applicable only to certain types of biological products.
For example, blood and blood components are subject to the CGMP requirements for such
products under part 606 (21 CFR part 606).  In addition, a vaccine manufactured using a spore-
forming microorganism would be subject to 21 CFR 600.11(e)(3).

Similarly, not all CGMP requirements may apply at a facility that performs only certain

aspects of the manufacture of a combination product.  As 21 CFR 210.2(b) and 820.1(a)(1)
describe, an entity that engages in only some operations subject to the regulations in parts 210,
211, 600 through 680, 820, and 1271, need only comply with the regulations applicable to those
operations.  For example, a facility that manufactures a co-packaged combination product that
includes a finished, already-packaged drug manufactured under the drug CGMPs and received
from another facility need not calculate yield for that drug constituent part.

2.  What is the meaning of “where appropriate” in the CGMP, QS, and CGTP

regulations?

Firms must demonstrate compliance with all regulations applicable to their product and

facility under part 4.  However, the drug CGMPs, device QS regulation, and CGTPs for HCT/Ps
use language such as  “where appropriate” or “as necessary” to acknowledge that certain
measures may not be necessary or applicable under certain circumstances and that manufacturers
must pursue such measures if they are needed.  Such language indicates that firms have the
opportunity to document justifications for determining that such a measure or approach is not
appropriate or necessary for a particular product or the specific manufacturing activity they are
undertaking.31  Such justifications should generally be maintained within the quality system
documentation and may warrant Agency review prior to implementation depending on the
product type and relevant premarket submission obligations.

31 Under both 21 CFR 820.1(a)(3) and 1271.150(e), a requirement that is qualified by “where appropriate,” is
“appropriate” if, for example, non-implementation of the requirement could reasonably be expected to result in the
product not meeting its specified requirements.  In the case of an HCT/P, these may be requirements related to
preventing introduction, transmission, or spread of communicable diseases, or a manufacturer’s inability to carry out
any necessary corrective action. Under both provisions, a requirement is deemed to be appropriate unless the
manufacturer can document justification that it is not.

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For example, 21 CFR 820.30(i) stipulates that each manufacturer establish32 and maintain

procedures for “the identification, documentation, validation or where appropriate verification,
review, and approval of design changes before their implementation” (emphasis added).
Changes to the design, such as changes to properties of the material or dimensional
specifications, may not need to be validated if they can be verified through appropriate
measurement and test methods.  However, changes that could impact user needs, such as changes
to the user interface, may require validation.  Similarly, part 211 requires compliance with
certain duties “as appropriate” (e.g., 21 CFR 211.84(a) addressing the sampling, testing, or
examining of components, containers, and closures prior to release by the quality control unit).
Containers may not need to be tested, for example, if visual examination is sufficient to evaluate
critical attributes.

3.  What CGMP responsibilities apply to specific manufacturers and facilities, and

how should CGMP compliance be coordinated across facilities?

A facility that manufacturers a constituent part of a combination product or a complete

combination product must be compliant with the CGMP requirements applicable to each
manufacturing process that occurs at that specific facility.  In addition, the combination product
owner (the holder of the marketing authorization for the product) retains overall responsibility
for the product, even if the owner is not directly engaged in its manufacture.  As outlined below,
quality agreements and audits can be helpful in assuring compliance with applicable CGMP
requirements.

A facility that manufactures only a finished device intended to be a constituent part of a

combination product (i.e., does not engage in any other manufacturing of the combination
product) must comply only with the device QS regulation.  Similarly, a facility that manufactures
only a drug intended to be a constituent part of a combination product (i.e., does not engage in
any other manufacturing of the combination product), must comply only with the drug CGMPs.
Even if a facility is manufacturing only one type of constituent part for a combination product,
the CGMP operating system should take into account considerations for the combination product
as a whole as appropriate.  Before changes are made to the manufacturing process of a
constituent part, the CGMP operating system should ensure consideration of whether such
changes could affect performance and/or interaction with the other constituent part(s) and, if so,
whether the safety and effectiveness of the combination product could be impacted.  Quality
agreements with constituent part manufacturer(s) are one way to ensure that changes to a
constituent part are transparent to a combination product manufacturer or owner.

Some CGMP requirements concern the product as a whole, such as design controls, and

some concern overarching considerations for the manufacturing process as a whole, such as
CAPA requirements.  Take, for example, a manufacturing facility collecting nonconformance
data that are trended as an input to the CAPA system for a combination product.  If a problem is
detected that requires a product or process design change, the change may require modification
of manufacturing activities at another facility or the expertise to develop and implement the
change may reside at a different facility.  Similarly, a facility that only handles customer calls

32 21 CFR 820.3(k) states that  “Establish means define, document (in writing or electronically), and implement.”

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may provide relevant complaint data to another facility responsible for trending all quality data
and managing the CAPA system.  A CAPA system that is shared between facilities, or facility-
specific CAPA systems with established links between them, may facilitate handling of issues
requiring multi-facility collaboration.  Regardless of the approach, the CAPA system(s) should
allow for adequate flow of information between facilities and manufacturers for the combination
product and appropriate investigation and resolution of identified CAPA issues.

Manufacturing activities that occur at multiple facilities and associated CGMP operating

systems should be coordinated appropriately.  Each manufacturing facility for a combination
product should have documentation specifying its respective responsibilities, and the
manufacturer of the finished combination product should have access to this documentation.  For
example, if the manufacturer of the finished combination product uses a specification developer
to design the finished product, that manufacturer should have the design control records or have
access to them if they are held by the specification developer.  In addition, the manufacturer
should have assurances that the specification developer maintained an adequate design control
system.  To give another example, if product testing occurs at a contract testing facility, the
manufacturer of the finished combination product should have documentation of the testing
conducted and controls applied at the contract facility or have access to the documentation if
held at the contract facility.  Accordingly, manufacturers should address access to such records
among other issues as part of supplier evaluation and oversight.

Measures that might be taken to ensure CGMP compliance at all manufacturing facilities
for the combination product include auditing and other oversight activities.  For example, when
multiple facilities participate in the manufacturing process, the owner may facilitate CGMP
compliance by coordinating interactions among the facilities, including by entering into
comprehensive quality agreements with the various facilities and suppliers .  These quality
agreements may, for instance, specify expectations as to which facility will perform what
activities and develop and maintain what documentation needed to demonstrate compliance with
particular CGMP requirements (based, for example, on which aspects of manufacture each
facility conducts).  These agreements may also detail what measures a facility will take to ensure
compliance with CGMP requirements and any other relevant duties established by the owner for
that facility.  For example, an owner may contract for the manufacture of the final combination
product with a contract manufacturing facility, and detail in the supplier agreements the CGMP
responsibilities and approaches for that facility.

E. Control of changes to a combination product

While not an issue unique to combination products, coordination of changes among
manufacturers participating in the manufacture of a combination product is an important CGMP
issue.  Appropriate consideration should be given to any implications for the safety or
effectiveness of the combination product that might arise from changes to the combination
product or its constituent parts.

Single-entity and co-packaged combination product manufacturers must establish
arrangements with their suppliers, contractors, and consultants to receive notice of changes in the
product or service, where possible, in accordance with 21 CFR 820.50.  This notice should

Contains Nonbinding Recommendations

address changes the supplier makes to its process or product—including to an API, other drug
components, or a container-closure system—that it manufactures, if the change might affect the
downstream manufacturing process or the quality of the combination product itself.  These
combination product manufacturers should also establish procedures for acceptance of
components, containers/closures, and constituent parts to ensure both detection and evaluation of
any changes that are critical to the safety or effectiveness of the combination product prior to
incorporating them into the finished combination product.33

Similarly, if one entity manufactures one constituent part of a cross-labeled combination
product and another entity manufactures the other constituent part, both should have procedures
in place to inform one another of changes that may affect the safety or effectiveness of the
combination product, and to confirm that the specifications for the respective constituent parts
remain appropriate or are updated as needed to ensure that the combination product remains safe
and effective.  For example, a change to the drug constituent part of a cross-labeled combination
product might require a design change to the device constituent part for the combination product
to remain safe and effective.  Accordingly, awareness and assessment of drug changes to
determine whether they require a change to the device constituent part(s) of such a combination
product may be important to compliance with design control requirements for the device under
21 CFR 820.30.  Similarly, a change to a device constituent part of a cross-labeled combination
product may necessitate a change to a drug constituent part, which may require a change in its
chemistry, manufacturing, and controls (CMC).34, 35

IV.  What do I need to know about the CGMP requirements

specified in 21 CFR 4.4(b)?

A. Provisions from the device QS regulation specified in 21 CFR
4.4(b)(1)

This section provides summary descriptions of the provisions from the device QS
regulation with which manufacturers of single-entity and co-packaged combination products that
include a device constituent part must demonstrate compliance when using the drug CGMP-
based streamlined approach established under 21 CFR 4.4(b)(1), including considerations
specific to applying these device QS regulation requirements to combination products.   This
discussion is not meant to provide a comprehensive analysis, but rather to help manufacturers—
particularly drug and biological product manufacturers who may be less familiar with the device
QS regulation—understand the purpose and basic elements of the device QS regulation

33 21 CFR 211.84 details how a manufacturer must sample, test, examine, and accept or reject drug product
components, containers, and closures.
34 For additional information on guidance related to CMC topics, see FDA’s webpage:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064979.htm.
35 While beyond the scope of this guidance, it bears noting that product owners may be obligated to notify the
Agency of changes or seek Agency approval prior to making them, depending upon the nature of the change.  See,
for example, 21 CFR 314.70, 601.12, 807.81(a)(3) and 814.39.  Accordingly, controlling changes to combination
products and the processes and facilities used for their manufacture can be important to ensure compliance with
other regulatory requirements (in addition to CGMP requirements).

Contains Nonbinding Recommendations

provisions specified in 21 CFR 4.4(b)(1). This section also includes references to additional
guidance documents that may be helpful.36  Section V presents hypothetical examples offering
additional guidance on how to address these provisions for a combination product.

1.  Management responsibility (21 CFR 820.20)

Requirements under 21 CFR 820.20 ensure that management with executive
responsibility (i.e., senior employees of a manufacturer who have the authority to establish or
make changes to the quality policy and quality system)37 are actively engaged in oversight of the
quality system, and reflect the expectation that management with executive responsibility
demonstrate an active, ongoing commitment to quality system development and
implementation.38  Statutory CGMP provisions and regulations for drugs establish requirements
related to management responsibility, and the Agency has also issued guidance on this topic.39
However, there are specific requirements in 21 CFR 820.20 that are not explicitly addressed in
drug CGMP requirements, and a manufacturer of a combination product that includes a device
constituent part must ensure that the elements required under 21 CFR 820.20 are satisfied.

A combination product manufacturer must establish and maintain an adequate
organizational structure to ensure that the product is designed and produced in accordance with
CGMP requirements.  This structure must: establish the appropriate responsibility, authority, and
interrelation of all personnel who manage, perform, and assess work affecting quality; provide
adequate resources for management, performance of work, and assessment activities; and include

36 This section does not address 21 CFR 4.4(b)(1)(v) and (vi), which require manufacturers to demonstrate
compliance with installation and servicing requirements under 21 CFR 820.170 and 820.200, respectively.  These
requirements are included in 21 CFR 4.4(b)(1) to ensure manufacturers comply with them when applicable to a
single-entity or co-packaged combination product.  However, the Agency anticipates that installed and serviced
devices will rarely be constituent parts of such combination products.  If they are constituent parts of a combination
product, they are more likely to be separately manufactured and marketed as constituent parts of cross-labeled
combination products.  In such cases, as discussed in Section II.C.1 II.B, each constituent part manufacturer would
be subject to the CGMP requirements associated with the constituent part it manufactures.  Accordingly, the device
constituent part of such a cross-labeled combination product would be subject to installation and servicing
requirements.
37 21 CFR 820.3(n).

 As stated in the preamble to the device QS regulation, “Management with executive responsibility is that level of
management that has the authority to establish and make changes to the company quality policy.  The establishment
of quality objectives, the translation of such objectives into actual methods and procedures, and the implementation
of the quality system may be delegated.  The regulation does not prohibit the delegation.  However, it is the
responsibility of the highest level of management to establish the quality policy and to ensure that it is followed … It
is without question management’s responsibility to undertake appropriate actions to ensure that employees
understand management’s policies and objectives. Understanding is a learning process achieved through training
and reinforcement.  Management reinforces understanding of policies and objectives by demonstrating a
commitment to the quality system visibly and actively on a continuous basis.  Such commitment can be
demonstrated by providing adequate resources and training to support quality system development and
implementation.” (61 FR 52602-52612)
39 See Section 501 of the FD&C Act [21 USC 351], which requires oversight and controls to ensure product quality,
including to manage risks and establish the safety of raw materials, in-process materials, and the finished drug
product (establishing that “current good manufacturing practice” includes management oversight of manufacturing
and controls to ensure quality and lifecycle risk management).  See also 21 CFR 211.22, 211.25, and 211.180; and
the Guidance for Industry Q10 Pharmaceutical Quality System (April 2009).

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an appointed management member who is responsible for ensuring that quality system
requirements are effectively established and maintained, and for reporting on the performance of
the quality system to management with executive responsibility.40  Management with executive
responsibility must establish the policy and objectives for and commitment to quality.41  These
policies and objectives are reflected in the quality plan and quality system procedures.42

The quality plan must define the quality practices, resources, and activities relevant to the
combination product that is being designed and manufactured and must establish how the quality
requirements will be met.43  The plan can either be an independent document, or it can reference
elements of the manufacturer’s quality system.

The quality system procedures (21 CFR 820.20(e)) ensure compliance with each aspect
of the CGMPs applicable to the combination product.44  The number, complexity, and structure
of a combination product manufacturer’s procedures and instructions may vary depending on
factors such as the manufacturer’s organizational structure and the complexity of the
combination product being manufactured.  Drug manufacturers may already have some such
procedures in place as part of the requirements for a quality control unit under 21 CFR 211.22
and can reference these procedures and augment them as needed to meet the requirements of 21
CFR 820.20.

Management with executive responsibility must periodically review the suitability and

effectiveness of the quality system, including to ensure that the quality system satisfies the
established quality policy and objectives.45  These reviews must be conducted at defined
intervals and with sufficient frequency.  Management review procedures should ensure that
management has adequate access to relevant information from facilities contracted to perform
manufacturing activities for the combination product.

2.  Design controls (21 CFR 820.30)

The preamble to the rule discusses design control requirements for combination products

at some length.46  This section discusses the design controls that apply to single-entity or co-
packaged combination products that include a device constituent part that is subject to them.47
Design control activities confirm that there are no negative interactions between constituent
parts, and ensure that their combined use results in a combination product that is safe and
effective and performs as expected.

40 21 CFR 820.20(b).
41 21 CFR 820.20(a).
42 See 21 CFR 820.20(d) and (e).
43 21 CFR 820.20(d).
44 21 CFR 820.20(e)
45 21 CFR 820.20(c).
46 See 78 FR 4314-4315.
47 If a manufacturer claims that the device constituent part or combination product is exempt from 21 CFR 820.30,
the manufacturer should document its evaluation to support this determination.  See sections III.C.3 and C.4 of this
guidance; see also 21 CFR 820.30(a)(1).

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The following is a description of design control requirements and the documentation that

must be maintained for co-packaged and single-entity combination products.48  While
pharmaceutical development focuses on drug considerations, if broadened to take into account
the other constituent parts of combination products and how they interrelate, many
pharmaceutical development practices (for example, Quality by Design principles49) can be
leveraged and built upon when demonstrating compliance with design controls for a combination
product.  The Agency recognizes that the terminology used in 21 CFR 820.30 can differ from
that used for pharmaceutical development.  Manufacturers should be able to communicate to the
Agency how the terminology they use relates to design control principles and requirements.

Design control requirements apply to activities during product development as well as to

postmarket changes to the design or manufacturing process.  Accordingly, the activities
described below may be conducted as part of premarket development and reflected in
documentation submitted as part of the marketing authorization process.  Regardless of when the
activity occurs or where related records may reside, the CGMP operating system should include
or reference appropriate documentation to ensure readily available access to this documentation
for FDA inspection.50

The extent and complexity of the design controls process and associated documentation

will vary based on the product.  For example, consider a drug product that is already legally
marketed independently that will have the same formulation, route of administration and
intended use when marketed as part of a combination product that also incorporates a delivery
device.  Design controls would begin when the delivery device configuration is judged to be
feasible and appropriate to develop.  The drug properties would be inputs for design control
activities that would focus on ensuring that the device appropriately delivers the drug and that
the drug quality is not adversely affected by its contact with the device.  Conversely, for a novel
combination product with novel drug and device constituent parts, design controls ensure
coordinated development of the drug and device resulting in a final combination product that
meets user needs and achieves intended uses.  The extensiveness of design control activities and
related documentation for products should also be commensurate with the phase of product
development.

As part of the design controls, a design and development plan must be established to

describe or reference the design and development activities and define responsibility for
implementation. The plans must identify and describe the interfaces with different groups or
activities that provide, or result in, input to the design and development process.51

48 While outside the scope of 21 CFR 4.4(b)(1), it bears noting that the design control process and design history file
for the device constituent parts of cross-labeled combination products should address the suitability of the device for
use as part of the combination product, including the interactions and interrelationships between it and other
constituent parts of the combination product.
49 See the Guidance for Industry on Q8(R2) Pharmaceutical Development (November 2009),
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf.
50 See 21 CFR 820.30(j), 820.180, and 211.180.
51 21 CFR 820.30(b).

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Design input requirements for the combination product should include considerations

such as performance characteristics, safety and reliability requirements, and expected needs of
product users and patients.52  Design inputs should be considered early in product development
to ensure that development efforts are consistent with the product’s intended use, including the
needs of users, including patients.  Once the design inputs have been established, the design
outputs (e.g., specifications and engineering drawings) must be developed based on those
inputs.53  Once design outputs have been established for all design inputs, design verification and
validation activities must be performed to ensure that the combination product design output
meets design input requirements, including user needs and intended uses.  Design review is also
required to ensure that formal and documented reviews of the design are planned and conducted
at appropriate stages of the product’s design development,54 and all of these activities must be
documented in the design history file.55

Design inputs ensure that design requirements are appropriate to address the intended use

of the product, and design outputs include documentation of the product specifications that can
be evaluated against the design inputs as development progresses.  Similarly, Quality Target
Product Profile (QTPP) in pharmaceutical development involves prospective consideration of the
quality characteristics of a drug product to ensure desired quality taking into account safety and
efficacy of the drug product.  A manufacturer may identify potential Critical Quality Attributes
(CQAs) or properties of a drug product that should be within appropriate limits, ranges, or
distributions to ensure product quality and refine these CQAs as product development continues.
QTPP and CQA principles may be applied for combination products in a manner consistent with
design input and output requirements.  In addition, when developing a combination product, the
QTPP and CQA for the drug constituent part may be helpful in establishing design inputs and
design outputs for the combination product.

Verification means confirmation by examination and provision of objective evidence that

specified requirements have been fulfilled.56  Design verification confirms that the product
developed is consistent with the assumptions made by the design team when developing design
inputs, but does not necessarily confirm that the product is safe and effective for its intended use.
Design verification activities may include, for example, performance tests, safety tests, or visual
inspections.

Design validation means establishing by objective evidence that product specifications

conform to user needs and intended use(s).57  Design validation ensures that the product is
designed correctly to achieve its intended purpose(s), and includes testing of production units or
their equivalents (with appropriate justification58) under actual or simulated use conditions.

52 See 21 CFR 820.30(c).
53 See 21 CFR 820.30(d).
54 See 21 CFR 820.30(e).
55 See 21 CFR 820.30(j).
56 See 21 CFR 820.30(f) and 21 CFR 820.3(aa).
57 See 21 CFR 820.30(g) and 21 CFR 820.3(z)(2).
58 The preamble to the device QS regulation (61 FR 52619) provides additional detail on use of equivalents: “When
equivalent devices are used in the final design validation, the manufacturer must document in detail how the device
was manufactured and how the manufacturing is similar to and possibly different from initial production. Where

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Design validation activities, for example, may include simulated use testing or
clinical/nonclinical evaluation, including human factors59 and software validation.  Some design
verification (e.g., bench and/or pre-clinical testing) and validation (e.g., human factors testing,
when appropriate) will typically be completed prior to the initiation of clinical studies of safety
and efficacy for the combination product, which are also part of design validation.  Clinical
studies conducted to support safety and/or efficacy of the constituent parts of a combination
product may be appropriate to be leveraged as part of the cumulative design validation efforts for
the overall combination product.

In addition, manufacturers must perform risk analysis where appropriate,60 which should

begin early in the design process and continue throughout the lifecycle for the product.  Risk
analysis should enable identification of unacceptable risks so that they can be mitigated.  It
influences other aspects of design control and additional activities including purchasing controls
(see section IV.A.3).  Although existing risk analysis for products used as constituent parts of the
combination products may be relevant, risk analysis should include considerations for the
combination product as a whole to identify risks associated with its design, manufacturing
processes, and intended uses.  Some risks may be identifiable during initial design development
and addressed in design inputs, while others may become apparent later in product development,
during premarket review, or based on postmarket experience (including adverse event reporting)
and used to determine whether any aspect of the design should be modified.  Standards and
guidance addressing conduct of risk management activities such as risk assessment, risk control,
risk reporting, and risk review for devices and drugs are appropriate references to inform these
activities for a combination product.61  Also, risk assessment and management activities
performed for a drug constituent part under pharmaceutical development practices may become
elements of the overall risk analysis for a combination product.

Manufacturers must establish and maintain design transfer procedures to ensure effective
translation of design specifications into production methods and procedures.62  Design transfer is
the bridge between the design of the product and the manufacturing process to make the
commercial product.

there are differences, the manufacturer must justify why design validation results are valid for the production units,
lots, or batches.”  For a combination product, this documentation and justification must account for considerations
arising from inclusion of a drug or biological product, including equivalence of the manufacturing process for the
drug/biologic constituent part or the combination product as a whole.  The rationale for equivalence should be
documented and may require bridging studies, completion of comparability protocols, or other test data to support
that products used for design validation are representative of the combination product that the manufacturer intends
to market.
59 For more information on human factors for combination products, see Draft Guidance for Industry an FDA Staff
Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and
Development (February 2016).  When finalized, this document will represent the Agency’s current thinking on this
topic.
60 21 CFR 820.30(g).
61 For more information on risk analysis and risk management see, e.g.,  ISO 14971 Risk Management – Medical
Devices and FDA Guidance for Industry Q9 Quality Risk Management  (June 2006).
62 21 CFR 820.30(h).

Contains Nonbinding Recommendations

Manufacturers are required to have procedures to ensure that any changes to design

requirements are identified, documented, validated or verified where appropriate, reviewed, and
approved prior to implementation.63  Change controls apply once initial design inputs have been
approved by the manufacturer.64  A change control process is essential to manage design changes
both during the original design process for the combination product and after the design has been
transferred to manufacturing. 65  The records of these changes must be maintained as part of the
design history file (21 CFR 820.30(j)).  They create a history of the evolution of the design,
which can be important when investigating failures or evaluating the appropriateness of
proposed, additional changes to the product.  A manufacturer may choose to use different
processes for premarket (as opposed to postmarket) changes to accommodate the rapid, iterative
design process that is often present during investigational stages, so long as the design change
and transfer process is compliant with 21 CFR 820.30.

The Design History File (DHF) for a combination product captures all design issues
relating to the combined use of the constituent parts.  The DHF may not need to document design
and development planning for established characteristics of the individual constituent parts, for
example the safety and effectiveness of a drug constituent part of a co-packaged combination
product, if that drug constituent part was previously approved for the same indication.  If a
finished device, drug, or biological product is purchased, the combination product manufacturer
is not required to retrospectively “design” that constituent part with respect to such previously
reviewed characteristics.  Rather, the combination product manufacturer should understand the
constituent part’s existing design specifications thoroughly in order to perform design controls
properly for its use in the combination product.66  If a separately developed drug, device, or
biological product constituent part needs to be modified to be used in the combination product,
the manufacturer must assess what design control activities must be performed to ensure safety
and effectiveness of the combination product (e.g., new formulation of a drug or new features of
a device).67

It is appropriate for a DHF for a combination product to leverage and cross-reference
developmental data and data systems.  Manufacturers transitioning from drug development to
combination product development should evaluate existing development documentation and
systems and assess what, if any, changes may be needed to demonstrate compliance with 21 CFR
820.30.  Manufacturers should be able to explain to FDA in premarket submissions and in
inspections how their practices and terminology align with the requirements in 21 CFR 820.30,

63 21 CFR 820.30(i).
64 61 FR 52621, Comment 87.
65 21 CFR 820.30(h).
66 Similarly, if a combination product manufacturer is purchasing device components for inclusion in a combination
product, and the device component supplier is manufacturing a finished device from the same or similar components
and is therefore subject to the device QS regulation, the combination product manufacturer may be able to leverage
elements of that supplier’s design controls in developing the overall design controls for the combination product.
The information leveraged should typically be covered by a formal agreement between the combination product
manufacturer and supplier defining maintenance and sharing of design information.  If the component supplier does
not itself comply with the device QS regulation, the combination product manufacturer’s design control activities for
the device constituent part will likely need to be more extensive.
67 21 CFR 820.30(c).

Contains Nonbinding Recommendations

and be able to identify and readily access for FDA inspection all documentation needed to
demonstrate compliance with design control requirements.

If a manufacturer is evaluating the adequacy of their design controls and documentation

for a currently marketed combination product, it may be helpful to review premarket
submissions, the product risk profile, and postmarket experience for the combination product.
The results of this review can inform decisions on whether additional testing and documentation
is required.  FDA encourages combination product manufacturers to direct specific questions on
the adequacy of their design control measures and documentation to the lead center for their
products, and OCP as needed, for assistance.  For further information on design controls, see the
preamble to the final device QS regulation.68

3.  Purchasing controls (21 CFR 820.50)

Manufacturers of single-entity and co-packaged combination products that include a

device constituent part must control purchased products69 and services as described in 21 CFR
820.50.  They must establish such purchasing controls for products received at their facility for
use in the manufacture of the combination product, for all suppliers of these products, and for
suppliers of services obtained (such as terminal sterilization conducted by an outside entity) (21
CFR 820.50(a)).  Facilities that have previously manufactured only drugs, rather than devices or
combination products, will likely have relevant procedures in place in accordance with part 211,
subpart E.  However, if these procedures do not demonstrate compliance with the specific
requirements of 21 CFR 820.50, they must be augmented to do so.

 Manufacturers must evaluate potential suppliers and define the type and extent of control

to be exercised over them based on the evaluation results.70  Manufacturers may design and
conduct such evaluations based on factors such as the risks associated with the supplied product
or service and complexity of the specifications for it.  Manufacturers must establish and maintain
records of acceptable suppliers for purchased products and services,71 and establish and maintain
data that clearly describe or reference the specified requirements for products and services
received (e.g., contracts with relevant terms).72

One way to facilitate purchasing control is the careful structuring of purchasing
agreements with suppliers.  Where possible, such agreements are used to ensure that the
combination product manufacturer is notified of changes to the products, the manufacturing
process, or the services being provided.73  Such notice of changes facilitates compliance not only
with purchasing control duties, but also, potentially, with other regulatory requirements,
including design control obligations to complete additional design verification testing to address

68 See Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation, 61
FR 52602-52662 (October 7, 1996).
69 Under 21 CFR 820.3(r), the term “product” includes components and manufacturing materials, in addition to in-
process and finished articles.
70 See 21 CFR 820.50(a)(2).
71 See 21 CFR 820.50(a)(3).
72 See 21 CFR 820.50(b).
73 See 21 CFR 820.50(b).

Contains Nonbinding Recommendations

the change (e.g., to ensure that the purity and stability of a drug constituent part is maintained
when the materials change in a device constituent part that is also a container closure).  If it is not
possible to obtain such notice, the combination product manufacturer should implement
additional controls to ensure that changes are identified and appropriate measures are taken.  The
combination product manufacturer should ensure agreements are appropriately structured,
whether through direct agreements with suppliers and contract manufacturers or through
confirmation that such parties have adequate agreements between themselves.  For example, a
combination product manufacturer may choose to maintain a change agreement with a material
supplier who provides material directly to a contract manufacturing facility.

Note that regardless of the nature of purchasing controls, combination product
manufacturers must comply with the testing requirements under 21 CFR 211.84 with respect to
drug components, and product containers and closures (see IV.B.1 below).

4.  Corrective and Preventive Actions (21 CFR 820.100)

Manufacturers of co-packaged or single-entity combination products that have a device
constituent part must establish and maintain procedures for implementing CAPA in accordance
with 21 CFR 820.100.  Relevant requirements in the drug CGMPs include 21 CFR 211.192 and
21 CFR 211.180(e).74  Manufacturers of the combination product must undertake CAPA
measures, when required, for issues arising at their facilities.  All relevant manufacturers should
participate in cross-facility efforts, as appropriate, to determine the root-cause of problems and
the appropriate measures to correct such problems and prevent recurrence.  Manufacturers of
combination products should document these activities.75  The CAPA process for combination
products also should consider implications of corrective and preventive actions for all constituent
parts and for the combination product as a whole.

While combination product manufacturers have flexibility in coordinating CAPA systems
across facilities, they maintain responsibility for ensuring that the 21 CFR 820.100 requirements
are met. Manufacturers should ensure that an appropriately comprehensive review of activities is
undertaken at relevant facilities to determine the cause of existing or potential problems, which
could include manufacturing problems, deviations, or nonconformities for a constituent part or
the combination product as a whole.  The manufacturer should have appropriate mechanisms in
place to ensure that issues are identified, action(s) needed to correct and prevent recurrence are
taken, and necessary changes are implemented.  The manufacturer should take appropriate
measures, which may include CAPAs, with regard to all relevant manufacturing steps at all
relevant facilities to correct problems and to prevent or mitigate them going forward.

74 See also FDA Guidance for Industry,  Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical
Production (October 2006), which discusses appropriate identification, assessment, and investigation of OOS results
for drug products, including results obtained under 21 CFR 211.165 (a provision specified in 21 CFR part 4).
Quality data from OOS investigations and any related corrective actions should be addressed through the
combination product manufacturer’s quality system. Also, FDA guidance for industry, ICH Q10 Pharmaceutical
Quality System (April 2009), includes additional recommendations for preventive actions and, when failures or other
issues occur, corrective actions.
75 For further guidance, see the preamble to the device QS regulation at 61 Fed. Reg. at 52633-52635, Comments
158-166.

Contains Nonbinding Recommendations

B. Provisions from the drug CGMPs specified in 21 CFR 4.4(b)(2)

This section provides a brief description of the provisions from the drug CGMPs with

which single-entity and co-packaged combination product manufacturers must demonstrate
compliance when using the device QS regulation-based streamlined approach established under
21 CFR 4.4(b)(2), including considerations specific to applying these requirements to
combination products.  This discussion is not meant to be a comprehensive analysis, but rather to
help manufacturers—particularly device manufacturers, who may be less familiar with drug
CGMPs—understand the purpose and basic elements of the provisions of the drug CGMPs
specified in 21 CFR 4.4(b)(2), as well as to direct such manufacturers to additional guidance.

The specified provisions of the drug CGMPs include requirements for testing and other

verification procedures for batches or lots, whether of drug components, drug containers and
closures, drug constituent parts, or the whole combination product.  Combination product
manufacturers should establish procedures defining a “batch” or “lot” in all phases of production
and describe all batch and lot numbering systems used for incoming material, in-process
material, and finished products.  These procedures allow manufacturers to connect specific
batches or lots of constituent parts, components, and in-process material to the specific batches
or lots of the combination product for which they are used.  These procedures enable traceability
of sampling and testing, packaging, and labeling activities, and can be important when assessing
and responding to issues including complaints and adverse events.  Master production and
control records should be designed to enable this traceability.  An explanation of batch and lot
definitions, controls, and tracking should be available for review on inspection.

1.  Testing and approval or rejection of drug product components, containers, and

closures (21 CFR 211.84)

Drug product components, containers, and closures must be tested in accordance with 21
CFR 211.84.  A drug component is any ingredient intended for use in the manufacture of a drug
product, including those that may not appear in the drug product.76  A container closure system is
the sum of packaging components that together contain and protect the drug product.  This
includes primary packaging components and also secondary packaging components if the latter
are intended to provide additional protection to the drug product.77  Examples of packaging
components are ampules, vials, screw caps, stoppers, and stopper overseals.  As discussed in
section III.C.3, container closure systems and elements of container closure systems may also be
regulated as devices.

Combination product manufacturers do not need to demonstrate compliance with this

provision for device constituent parts or materials used in the manufacture of a device constituent
part, unless the device constituent part is also the drug container or closure or a part thereof.  For
example, for a CGMP operating system established in accordance with 21 CFR 4.4(b)(2) (device

76 See 21 CFR 210.3(b)(3).
77 See the Guidance for Industry on Container Closure Systems for Packaging Human Drugs and Biologics:
Chemistry, Manufacturing, and Controls Documentation (May 1999).

Contains Nonbinding Recommendations

QS regulation-based streamlined approach), if materials are used solely for manufacture of a
device constituent part that is not part of the drug container or closure (e.g., a co-packaged
device), the manufacturer need only demonstrate compliance with applicable provisions of part
820 to show appropriate control of such materials for that device constituent part (including 21
CFR 820.30, 820.50, 820.80, and 820.86).

21 CFR 211.84 details how to sample, test, examine, and accept or reject drug product
components, containers, and closures.  In lieu of such testing, 21 CFR 211.84 allows for some
reliance on a supplier’s report of analysis, provided that certain identity testing is conducted and
that the reliability of the supplier’s analysis is established by the manufacturer through
appropriate validation of the testing results at appropriate intervals.  These duties augment and
elaborate upon acceptance activity requirements expressly established under 21 CFR 820.80.
Accordingly, if a facility already has 21 CFR 820.80-based acceptance procedures, it would be
appropriate to provide for compliance with 21 CFR 211.84 requirements by augmenting these
existing procedures as needed to incorporate 21 CFR 211.84 compliant measures.

Each lot of drug components, containers, and closures must be withheld from use until it
has been sampled, tested, or examined, as appropriate, and released for use by the quality control
unit.78,  The samples collected for each lot must be representative of the entire lot.79  These
representative samples must be collected and tested or examined in accordance with the
procedures specified in 21 CFR 211.84.  These procedures require, among other things,
appropriate sampling technique to prevent contamination of the sampled component or of other
materials.80  In addition, the number of containers to sample and the amount of material to be
taken from each container must be based on appropriate criteria (e.g., component variability,
confidence levels, degree of precision desired, past quality history of the supplier, and the
quantity needed for analysis).81, 82

2.  Calculation of Yield (21 CFR 211.103)

Actual yields and percentages of theoretical yield for the drug constituent part(s) of a

combination product must be determined as described in 21 CFR 211.103.  Excess or low yields
may suggest problems in the production process, including equipment failure, that may affect
product quality and that may not be discovered, or not be discovered as quickly, using sample-
based release testing alone.  Actual yield discrepancies outside of established and documented
allowable variation from theoretical yield should be investigated.

78 See 21 CFR 211.84(a).
79 See 21 CFR 211.84(b).
80 See 21 CFR 211.84(c).
81 See 21 CFR 211.84(b).
82 Some references that may be useful for sampling by variables and sampling by attributes include “American
Standards for Testing and Materials (ASTM) Standard E2709, Standard Practice for Demonstrating Capability to
Comply with an Acceptance Procedure” and “ASTM Standard E2334, Standard Practice for Setting an Upper
Confidence Bound For a Fraction or Number of Non-conforming Items, or a Rate of Occurrence for Non-
conformities, Using Attribute Data, When there is a Zero Response in the Sample,” respectively.

Contains Nonbinding Recommendations

Yield calculation requirements under 21 CFR 211.103 apply to the drug constituent parts

of combination products.  Data on the number of device constituent parts and components used
and lost during the manufacture of a combination product may be necessary to ensure
appropriate control of the manufacturing process in accordance with 21 CFR 211.100 or 21 CFR
820.70, but yield calculation in accordance with 21 CFR 211.103 is not required for device
constituent parts.  However, problems with the device constituent part during combination
product manufacturing may affect drug yield and result in further investigation.  For example,
prefilled syringes that are rejected due to nonconformity of the syringe needle may result in
corresponding loss of drug from the batch/lot.  Any loss would be captured as part of the yield
calculations for the drug constituent part, and investigation of the cause of that loss should
identify the manufacturing problem that is leading to these device nonconformities.

Yield determinations must be made at the conclusion of each appropriate phase of

manufacturing, processing, packaging, and holding for the drug constituent part(s) and for the
combination product as a whole.83  Accordingly, calculation of yield should be determined at
each phase at which component, in-process material, or product loss may occur, including during
the formulation of the drug prior to incorporation into the combination product, during
incorporation into the combination product (e.g., filling or coating), and, possibly, during the
packaging process.  These calculations must be performed by one person and independently
verified by a second person, unless the yield is calculated by automated equipment in accordance
with section 21 CFR 211.68, in which case it must be independently verified by one person.84

For each appropriate phase of the manufacturing process performed, the formula used

and the data generated for the yield calculation for the phase should be documented.  For
manufacturers operating under a device QS regulation-based system, documentation of yield
calculations may be incorporated into existing part 820 documentation (for example, as part of
the device history record, 21 CFR 820.184).  These records should include actual yields,
percentages of theoretical yields, and the maximum and minimum percentages of theoretical
yield beyond which investigation is required for the drug constituent part, including as it is
processed and combined with the other constituent part(s) of the combination product.

If a third party is manufacturing the drug for the combination product, that manufacturer
is responsible for complying with the calculation of yield requirement at the appropriate phases
of the drug manufacturing process it performs, but the combination product manufacturer is
responsible for ensuring that the supplier satisfies these requirements, as a part of the
combination product manufacturer’s purchasing controls for its product in accordance with 21
CFR 820.50.

3.  Tamper-evident packaging requirements for over-the-counter human drug

products (21 CFR 211.132)

Manufacturers of OTC combination products must comply with the requirements of 21

CFR 211.132.  The required controls include tamper-evident packaging and labeling alerting

83 See 21 CFR 211.103.
84 See 21 CFR 211.103.

Contains Nonbinding Recommendations

customers to these protective features of the product’s packaging.  These controls are important
to help improve the security of OTC combination product packaging and help ensure the safety
and effectiveness of OTC combination products.

For single-entity combination products, tamper-evident packaging requirements apply to
the packaging for the combination product as a whole.  For co-packaged combination products,
these requirements can be met through appropriate packaging of the drug constituent part(s)
within the larger co-package so long as such an approach is otherwise permissible under the
packaging and labeling requirements applicable to that combination product.

Certain combination products may be exempt from OTC tamper-evident packaging

requirements85 (e.g., toothpaste co-packaged with a toothbrush) or from bearing a statement of
tamper-evident features on the package86 (e.g., aerosol saline nasal spray).

An exemption from tamper-evident packaging and labeling requirements for an OTC

combination product may be requested in accordance with 21 CFR 211.132(d).  If the
manufacturer makes changes to packaging and labeling of an approved OTC product to comply
with the requirements of 21 CFR 211.132, it must notify the lead center for the combination
product before distributing it.87

4.  Expiration dating (21 CFR 211.137)

21 CFR 211.137 helps ensure that drug products (drug constituent parts in the case of

combination products) meet applicable standards of identity, strength, quality, and purity at the
time of use, by requiring that the product labeling bear an expiration date.  This date must take
into account any storage conditions stated in the labeling and be based on appropriate stability
testing as described in 21 CFR 211.166 (See section IV.B.6).88  The expiration dating also
should take into account any other applicable shelf-life considerations (e.g., for a product that is
to be provided sterile, the length of time that its packaging material can be ensured to retain its
integrity and, thereby, maintain a sterile barrier).  In some cases, the drug constituent part might
not have an expiration date because current regulations exempt it from this requirement.89
Similarly, some device constituent parts may not have expiration dates.

When expiration dating is required, the constituent parts of combination products may

have individual expiration dates or an expiration date for the entire combination product may be
appropriate.  Generally, when constituent parts of a co-packaged combination product can be
used independently, expiration dating should be addressed separately for each constituent part.
If a single expiration date is listed for a co-packaged combination product, this date should be the
earliest expiration date/shortest shelf-life for any constituent part.  The expiration date for a
combination product may be shorter than the expiration date or shelf life for its constituent

85 See 21 CFR 211.132(b)(1).
86 See 21 CFR 211.132(c)(1).
87 See 21 CFR 211.132(e).
88 See 21 CFR 211.137(b).
89 See 21 CFR 211.137.

Contains Nonbinding Recommendations

part(s) if marketed independently.  Reasons for a shorter expiration period could include
interactions between the constituent parts when combined, the effects of additional
manufacturing steps, or other differences arising from the combination of the constituent parts.

5.  Testing and release for distribution (21 CFR 211.165)

Testing and release for distribution are critical in drug product manufacture and quality
control.  21 CFR 211.165 requires that an appropriate laboratory determination of satisfactory
conformance to final specifications (including the identity and strength of each active ingredient)
is made for each batch of drug product prior to release.  21 CFR 211.165 also requires
appropriate laboratory testing, as necessary, of each batch of a drug product required to be free of
objectionable microorganisms.  In addition, sampling and testing plans must be described by
written procedures.90

Accordingly, manufacturers must test each batch of their combination product to
determine satisfactory conformance to final written specifications for the drug constituent part.91
For single-entity combination products, laboratory testing must be performed on every batch of
the combination product; for co-packaged combination products, laboratory testing must be
performed on every batch of the drug constituent part(s). 92  This testing ensures that all batches
meet appropriate specifications for their approval and release.93  A detailed listing of all the tests
performed and the acceptance criteria used should be maintained and be available for
inspection.94

In some cases, for single-entity combination products, in lieu of using actual units from a

finished combination product batch for testing to determine whether the drug constituent part
meets final specifications, manufacturers may wish to use samples that are not finished
combination products (but that are representative of the finished combination product with
respect to the characteristics and attributes being tested).  The Agency does not intend to object
to such an approach where the manufacturer can establish, including where appropriate through
bridging studies and other quantitative means, that any differences in the manufacturing process
for the samples and the finished combination product do not affect the drug constituent part.
Such approaches should be supported by appropriate justification and data and discussed with
the lead Center, and OCP as needed.

90 See 21 CFR 211.165(c).
91 See 21 CFR 211.165(a).
92 See 21 CFR 211.165(a).
93 See 21 CFR 211.165(a), (b).
94 21 CFR 211.165 addresses testing and release for “drug products”; appropriate controls for intermediate stages
(e.g., in-process materials) in the manufacture of combination products are addressed under separate provisions of
the drug CGMPs and device QS regulation that are not specified in part 4.  If a manufacturer operates under a
streamlined approach under 21 CFR 4.4(b), it should take into consideration the materials and manufacturing steps
for the combination product as a whole in determining how to demonstrate compliance with obligations for in-
process materials, and may find it helpful to refer to the corresponding requirements under the other regulation (that
it did not choose as the base for its CGMP operating system).  For example, if the facility operates under a device
QS regulation-based streamlined approach, in determining how to comply with duties under 21 CFR 820.70, 820.80,
and 820.86 for the combination product as a whole, reference to 21 CFR 211.110 and guidance relating to in-process
materials for drug products may facilitate appropriate consideration of the controls for drug constituent parts.

Contains Nonbinding Recommendations

If one facility is manufacturing a drug product as a constituent part to be supplied to
another facility or manufacturer for inclusion in a co-packaged combination product, appropriate
and adequate laboratory testing should be conducted by the drug product manufacturing facility
prior to release of the drug constituent part(s) for distribution in accordance with 21 CFR
211.165.  For combination products that include a device constituent part, the combination
product manufacturer is responsible for ensuring through purchasing controls in accordance with
21 CFR 820.50 that the drug constituent part conforms to specified requirements, including
laboratory testing requirements.  Appropriate testing or examination (such as visual inspection)
should also be conducted throughout the remaining manufacture of the finished co-packaged
combination product to ensure that the drug constituent part(s) continues to conform to its final
specifications.

6.  Stability testing (21 CFR 211.166)

21 CFR 211.166 requires a testing program designed to assess the stability characteristics

of drug products.  Furthermore, 21 CFR 211.166 sets forth required elements of the testing
program, including elements concerning sample size, storage conditions for samples retained for
testing, and other elements related to testing methodology and frequency.95

Stability testing is performed to determine appropriate storage conditions and expiration
dates (see section IV.B.4).  Among other considerations, this testing must enable evaluation of
any effects on the stability of the drug due to storage in its marketed container closure system,
which may be a device constituent part (or component of a device constituent part).96  For a
single-entity combination product, testing must be performed on the drug constituent part as
incorporated into the finished combination product.97

The Agency does not intend to object to the use of bracketing and matrix approaches for

stability studies where the approach has been adequately justified and, where applicable,
reviewed by FDA.98  The Agency also does not intend to object to leveraging stability data for an
already marketed combination product during new product development, with adequate
justification and, where applicable, review by FDA.  In particular, for purposes of establishing an
expiration date for a new combination product, such leveraging may be acceptable if the new
product represents a modification to the existing marketed combination product that would not
impact the stability of the drug constituent part (for example, a change to the catheter length for a

95 For further information on stability testing considerations, see, for example, the Guidance for Industry on
Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003).
96 See 21 CFR 211.166(a)(4).
97 See 21 CFR 4.3, 4.4, and 211.166.  In addition, while stability testing requirements under 21 CFR 211.166 do not
apply to device constituent parts of a co-packaged combination product, under design control requirements, testing
must be performed to demonstrate that device functionality (i.e., mechanical performance of the device constituent
part) is maintained until the specified expiration date for the combination product. See 21 CFR 820.30.
98 For further information on bracketing and matrixing considerations, see, for example, the Guidance for Industry
on Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January
2003).

Contains Nonbinding Recommendations

drug-coated balloon, where the balloon component remains unchanged) and is not otherwise
material to the expiration date.99

If a new product has minor differences that present a low risk of affecting the stability of

the drug (for example, a different size of a drug-coated balloon that is bracketed within the
balloon size matrix previously used to establish the expiration date, and without other changes
relevant to stability, for example, in the coating application process),100 the Agency does not
intend to object, in appropriate cases, to: i) the use of previously generated stability data for the
existing product (or family of products) to support reduced stability data requirements for the
new product (for example, generation of only short-term accelerated data) or ii) to incorporating
the product into the ongoing stability program for the existing marketed product(s), provided that
stability data trends and stability history for the existing product or product family are
sufficiently robust for this purpose.  Applicants should contact the lead center for their product,
or OCP as needed, regarding such approaches.101

The need for new stability studies should be evaluated when there are changes to any

constituent part of a combination product.  For example, changes to the manufacturing process,
including changes based on the size or shape of the device constituent part that holds the drug or
that is coated with the drug, or changes in material of construction of such a device constituent
part, may impact drug stability.

Manufacturers are responsible for establishing and managing the stability program.  If a

combination product manufacturer purchases a drug product from another manufacturer for
inclusion in its co-packaged combination product, the combination product manufacturer is
responsible for ensuring the stability of the drug product as marketed in the co-packaged product
through appropriate mechanisms, such as by implementing purchasing controls to ensure the
adequacy of the drug product manufacturer's stability testing or by conducting additional
stability testing (see 21 CFR 820.50).  Documentation of such oversight should be included in
the CGMP records.

If a drug constituent part of a co-packaged combination product has an expiration date,

the combination product manufacturer may be able to rely on that labeled expiration date in lieu
of conducting new stability studies, if it can be documented that any additional manufacturing
operations conducted on the co-packaged product would not be expected to impact the
constituent part, including its container-closure system.

99 Note that shelf life testing to evaluate the impact of the modification to the device constituent part may still be
appropriate.
100 This might also be the case for a family of products that vary in shape from one another, provided, again, that
these variations pose a low risk.
101 Note that shelf life testing to evaluate the impact of a modification on the device constituent part may still be
appropriate.

Contains Nonbinding Recommendations

7.  Special testing requirements (21 CFR 211.167)

21 CFR 211.167 establishes requirements for batch testing applicable to drug products

having particular characteristics.  Specifically, 21 CFR 211.167(a) requires appropriate
laboratory testing of drug products purporting to be sterile and/or pyrogen-free to determine
conformance with such requirements; 21 CFR 211.167(b) requires appropriate testing of
ophthalmic ointments to determine conformance to specifications regarding the presence of
foreign particles and harsh or abrasive substances; and 21 CFR 211.167(c) requires appropriate
laboratory testing of controlled-release dosage forms to determine conformance to the
specifications for the rate of release of each active ingredient.

A special testing requirement specified in 21 CFR 211.167 applies to a combination

product only if the combination product or a drug constituent part of it falls into one or more of
the three categories described above.  Special testing may be required for the drug constituent
part, or the combination product as a whole, depending on the product.

With respect to 21 CFR 211.167(a), batch testing requirements would apply both to the

drug constituent part and to the finished combination product for a single-entity combination
product (such as a prefilled syringe) to ensure the combination product is sterile and pyrogen-
free when distributed.  In contrast, if a vial of a vaccine were co-packaged with an empty
syringe, the requirements in 21 CFR 211.167(a) would apply only to the vial of vaccine.102  A
similar analysis would apply for compliance with 21 CFR 211.167(b) for a single-entity versus a
co-packaged combination product that includes an ophthalmic ointment.

For purposes of conducting pyrogen and endotoxin testing, it may be permissible in some

circumstances to define a “batch” based on the finished drug product rather than the finished
combination product.  For example, it may be acceptable to define a batch as a subcomponent of
the combination product that incorporates the drug constituent part.  However, the viability of
such an approach would depend on many factors including:  appropriate upstream controls to
reduce/limit pyrogens and endotoxins; the chemical or materials-mediated pyrogenicity of the
constituent parts, and the risks of pyrogen and endotoxin introduction to the combination product
by manufacturing operations that occur after the step at which the batch is defined.  For instance,
for some products, it may be possible to test material for endotoxin during an in-process
manufacturing step and there may be no need to test for endotoxins in the single entity
combination product.

21 CFR 211.167(c) would apply both to a controlled-release drug constituent part of a co-
packaged combination product and also to a controlled release single-entity combination product,
to confirm rate of release of the active ingredient. For example, a transdermal drug patch or drug-

102 The requirements related to sterility and non-pyrogenicity of the empty syringe would be addressed through
compliance with other provisions (for example, process controls requirements under 21 CFR 211 or 21 CFR 820,
design controls requirements under 21 CFR 820.30, and purchasing controls requirements under 21 CFR 820.50).
For additional information on pyrogen and endotoxin testing, see the Guidance for Industry on Pyrogen and
Endotoxins Testing: Questions and Answers (June 2012)).

Contains Nonbinding Recommendations

eluting disc or stent would be subject to 21 CFR 211.167(c).

As with drugs and devices, parametric release may be acceptable for some combination

products when supported by appropriate data.  Such approaches should be discussed with the
lead Center, or OCP as needed, prior to implementation and included in premarket
submissions.103

8.  Reserve samples (21 CFR 211.170)

Reserve samples are needed to help ensure the safety and effectiveness of combination

products in distribution, as they are for drugs and biological products.  They are used, for
example, to address certain product complaints, evaluate stability concerns, and assess the causes
of adverse events.  The reserve sampling requirements of 21 CFR 211.170 must be met for the
drug constituent parts of combination products.

Under 21 CFR 211.170, reserve samples must be kept that are representative of both:

•
•

each lot of the active ingredient (21 CFR 211.170(a)), and
each lot or batch of the drug product (21 CFR 211.170(b)).

All reserve samples must consist of at least twice the quantity necessary to perform all
required tests, except those for sterility and pyrogenicity.104  Furthermore, reserve samples of
drug products must be retained and stored under conditions consistent with product labeling and
stored in the same immediate container-closure system in which the drug product is marketed or
in one that has essentially the same characteristics.105

Accordingly, single-entity and co-packaged combination product manufacturers alike

must keep reserve samples of each lot of the active ingredient, if any, that they receive, in
whatever form it arrives at their facility (e.g., as bulk active pharmaceutical ingredient or
incorporated into an in-process material).

For co-packaged combination products, the requirement to keep reserve samples of drug

products can be met by maintaining samples of the drug constituent part in its immediate
container-closure system, without the need to retain any samples of the device or portions of
it.106  For single-entity combination products, the drug product reserve samples should be of the
drug constituent part in or upon the device constituent part or components thereof that come into
contact with the drug product as packaged for distribution.

103 See, for example, Guidance for Industry Submission of Documentation in Applications for Parametric Release of
Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes (February 2010) .
104 21 CFR 211.170. Stability is not required to be assessed on every drug batch. See 21 CFR 211.166(b).   Drug
product reserve samples must be visually examined at least once a year while in storage as an ongoing check on the
quality of the material in distribution, unless a visual examination would affect the integrity of the reserve sample.
21 CFR 211.170(b).
105 21 CFR 211.170(b).
106 See 21 CFR 211.170(b).

Contains Nonbinding Recommendations

Manufacturers must examine drug product samples for deterioration, investigate evidence

of deterioration, and record and maintain the results of such examination.107  Drug product
reserve samples generally must be maintained for 1 year after the expiration date for the drug
product; different time periods apply to certain radioactive and OTC products.108  Active
ingredient samples generally must be kept for 1 year after the expiration date for the last lot of
the combination product containing the active ingredient.109  Accordingly, manufacturers should
retain samples from each lot of bulk drug substance for 1 year after the expiration date of the last
lot of the combination product that uses that lot of the active ingredient.

Combination product manufacturers may choose to have their reserve samples of the

API, drug/biologic constituent part, or finished combination product at a location other than the
combination product manufacturing facility.  In these cases, the combination product
manufacturer should have appropriate controls in place to ensure that requirements under 21
CFR 211.170 continue to be met.  Such controls could include agreements with the facilities
holding the reserve samples to ensure appropriate storage conditions, access to the samples by
the combination product manufacturer, ability to analyze the reserve samples, if needed, and
maintenance of adequate numbers of samples for each lot.

For combination products, it is generally sufficient to maintain the appropriate number of

reserve samples from each lot of the active ingredient and from each lot or batch of the drug
constituent part in the immediate container/closure in which it is marketed.  For single-entity
combination products, the device constituent part may be the drug’s container/closure or a part of
it, or the container/closure may be distinct from the device constituent part.  For a drug-eluting
stent or disc, or a prefilled syringe, for example, reserve samples should generally be kept of the
entire combination product.  In contrast, if, for example, the combination product consists of an
injector system (device constituent part) into which the user inserts a prefilled cartridge
containing the drug, reserve samples of the prefilled cartridge alone would generally suffice to
comply with the drug product sample retention requirements.  An injector may need to be
available, however, to enable testing of reserve samples.

Manufacturers that want to retain and store reserve samples that are representative of, but

not identical to, a finished drug constituent part or combination product, as appropriate, should
include adequate justification and data to support that:

•  Any differences in the manufacturing process for the reserve sample and the
finished combination product do not affect the drug constituent part (see
discussion in IV.B.5 above);

•  The immediate container/closure has essentially the same characteristics as the

immediate container/closure for the drug as packaged in the combination product
for distribution (if the actual immediate container closure is not being used), and

•  The proposed representative samples are suitable for all required testing of the

drug constituent part for which those reserve samples are being kept.

107 See 21 CFR 211.170(b).
108 See 21 CFR 211.170(b).
109 See 21 CFR 211.170(a).

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It may be possible to keep properly defined and validated surrogates for some testing

while retaining complete samples of the combination product for other tests as an alternative to
retaining complete samples for all testing.  Bracketing and matrixing approaches also may be
acceptable, as may use of samples from representative lots of a larger batch (for example,
representative samples of each size from within a broadly defined batch that includes multiple
sizes from the same family of coated combination products).110

Manufacturers considering use of novel approaches to comply with reserve sampling

requirements are advised to discuss them with the lead center for their combination product, or
OCP, as needed.

C. Combination products that include biological products and HCT/Ps

In addition to complying with drug CGMP and device QS regulation requirements as
applicable in accordance with part 4, a manufacturer of a combination product that contains a
biological product or an HCT/P must comply with the requirements that would apply to the
biological product or HCT/P if it were not part of a combination product.

1.  Complying with CGMP requirements for biological products

It is important to remember that a biological product regulated under section 351 of the
PHS Act is also, by definition, a drug or a device.  Accordingly, in addition to the requirements
in parts 600 through 680, a biological product is always either subject to the drug CGMPs or
subject to the device QS regulation, regardless of whether the biological product is a constituent
part of a combination product.  The CGMP requirements for biological products in parts 600
through 680 augment the drug CGMPs and device QS regulation to ensure adequate
consideration of issues for biological products.  The CGMP requirements for biological products
in parts 600 through 680 address the particular challenges biological products pose, including
challenges arising from their relative complexity.  For biological products, consistency of
manufacturing procedures can, in fact, be a primary means by which to ensure the safety, purity,
and potency of the product.

The CGMP requirements for biological products in parts 600 through 680 must be
satisfied if a combination product includes a biological product constituent part.  However, many
requirements in parts 600 through 680 are applicable only to certain types of biological products.
For example, while part 600 facially addresses biological products in general, only products
manufactured using a spore-forming microorganism would be subject to 21 CFR 600.11(e)(3)
(work with spore-forming microorganisms).  Similarly, only blood and blood components are
subject to the CGMP requirements for such products under part 606.  In addition, the CGMP
requirements for biological products applicable to a given product can vary based on
considerations specific to the particular biological product.

110 FDA notes that approaches that depend upon retaining samples against more broadly defined batches may
increase the number of distributed products implicated when corrective actions are necessary to address postmarket
issues.

Contains Nonbinding Recommendations

In short, the specific requirements in parts 600 through 680 that must be met to comply

with 21 CFR 4.3 and 4.4(c) for a particular combination product that includes a biological
product constituent part will depend on the type of biological product it includes.  The Agency
welcomes the opportunity to discuss these requirements with manufacturers to ensure sound,
effective CGMP operating systems.  If manufacturers have questions regarding these
requirements, they may contact the lead center for the combination product or OCP, as needed,
for assistance.

2.  Complying with CGMPs for HCT/Ps

An HCT/P that is not regulated solely under section 361 of the PHS Act and Part 1271 is

also regulated as a drug, device, or biological product. 111  The drug CGMPs, device QS
regulation, and the requirements in parts 600 through 680 may apply to an HCT/P depending on
whether the product is regulated as a drug, device, or biological product.112  CGMPs and the
CGTPs for HCT/Ps supplement one another and do not supersede each other unless the
regulation specifically provides otherwise.  In the event that a regulation in part 1271 is in
conflict with a requirement in parts 210, 211, 600 through 680, or 820, the regulations more
specifically applicable to the product in question will supersede the more general.113

The CGTPs, including donor eligibility requirements for the manufacture of HCT/Ps

under part 1271, are designed to prevent the introduction, transmission, and spread of
communicable diseases, and thereby are essential to protecting the public health.  Accordingly,
the current CGTPs apply to combination products that include an HCT/P.  However,
requirements under some sections of part 1271 overlap with the requirements under the drug
CGMPs and the device QS regulation.  These overlaps are addressed in part 1271 and in the
Guidance for Industry on Current Good Tissue Practice (CGTP) and Additional Requirements
for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
(CGTP Guidance).

111 The HCT/P regulations at part 1271 distinguish between HCT/Ps regulated solely under section 361 of the PHS
Act (42 U.S.C. 264) and part 1271 and those that are also regulated as drugs, devices, and/or biological products.
Section 1271.10 provides that an HCT/P is regulated solely under section 361 of the PHS Act if it meets all of the
following criteria:  (1) it is minimally manipulated; (2) it is in intended for homologous use only, as reflected by the
labeling, advertising, or other indications of the manufacturer's objective intent; (3) manufacturer of the HCT/P does
not involve the combination of the cells or tissues with another article (other than water, crystalloids, or a sterilizing,
preserving, or storage agent) provided that the addition of water, crystalloids, or the sterilizing, preserving, or
storage agent does not raise new clinical safety concerns with respect to the HCT/P; and (4) Either: (i) The HCT/P
does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary
function; or (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its
primary function, and is for autologous use, is for allogeneic use in a first-degree or second-degree blood relative; or
is for reproductive use.  Refer to 21 CFR 3.2(e), 1271.10, 1271.15, and 1271.20, to determine whether an HCT/P is
regulated as a drug, device, or biological product constituent part of a combination product.
112 See 78 FR 4317.
113 See 21 CFR 1271.150(d).  Also see the Guidance for Industry on Current Good Tissue Practice (CGTP) and
Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products
(HCT/Ps) (December 2011).

Contains Nonbinding Recommendations

21 CFR 1271.150(d) explains that for HCT/Ps regulated as biological products, drugs or
devices, the procedures contained in subpart D and in subpart C of part 1271 and the procedures
contained in parts 210, 211, and 820, supplement one another.  As a consequence, compliance
with certain provisions of part 211 or 820 may also constitute partial or complete compliance
with certain provisions of part 1271.  However, for certain issues, the CGTP requirements would
require additional manufacturing practices.  The adjustments that might need to be made to an
existing CGMP operating system to be fully compliant with the part 1271 CGTP requirements
for a combination product that includes an HCT/P may differ if the system being augmented is a
drug manufacturing system under 21 CFR 211, a device manufacturing system under part 820, or
a combination product manufacturing system that demonstrates compliance with 21 CFR 211
and 21 CFR part 820 in accordance with 21 CFR 4.4(a)(1), 4.4(b)(1), or 4.4(b)(2).

For further information, see the CGTP Guidance.  FDA understands the complexity of

manufacturing considerations and duties for combination products that contain an HCT/P.
Accordingly, the Agency encourage manufacturers to contact the lead center for their product or
OCP, as needed, with questions about how to comply with CGMP requirements for their
particular product.

V.  Application of CGMP requirements to specific types of

combination products

The hypothetical scenarios addressed in this section focus on three types of combination
products.  While each of these types of combination products is subject both to the drug CGMPs
and to the device QS regulation, each example is used to focus on particular CGMP
considerations relating to CGMP provisions specified in 21 CFR 4.4(b).  Specifically:

•  Section A, a prefilled syringe example, focuses on how to comply with the device QS
regulation provisions specified in 21 CFR 4.4(b)(1) if a manufacturer adopts a drug
CGMP-based streamlined approach for its CGMP operating system.

•  Section B, a drug-coated mesh example, focuses on considerations for complying with
certain device QS regulations after a drug constituent part is combined with a device.

•  Section C, a drug-eluting stent (DES) example, focuses on how to comply with the drug
CGMP provisions specified in 21 CFR 4.4(b)(2) if a manufacturer adopts a device QS
regulation-based streamlined approach for its CGMP operating system.

This discussion is intended to highlight only certain issues that a combination product

might raise relating to the CGMP provisions specified in 21 CFR 4.4(b), and considerations for
addressing these issues.  The discussion may be helpful to inform understanding of the CGMP
provisions that are addressed here not only in regard to the types of combination products in the
scenarios, but for other types of combination products as well.  However, this discussion is not
intended to reflect a complete analysis of the CGMP issues that need to be addressed for the
types of products discussed in the scenarios or other types of combination products.  In addition,
specific products may raise distinct issues that are not taken into account in the hypothetical
scenarios presented below.  If manufacturers have specific questions relating to their particular

Contains Nonbinding Recommendations

products, the Agency recommends that they contact the lead center for the product or OCP, as
needed, for assistance.

A. Prefilled syringe

1.  Scenario Description

A drug manufacturer (Manufacturer A) plans to sell a drug in a prefilled syringe
presentation.114  Manufacturer A already has marketing approval for the drug product and
intends to apply for marketing approval for the prefilled syringe presentation.  No changes to the
drug formulation will be made.  Manufacturer A will buy off-the-shelf syringe components from
a supplier (Manufacturer B) who also manufactures finished syringes using the same
components.  Manufacturer A will assemble the syringe components, prefill the syringe at a
facility it operates, and then package, label, and distribute the prefilled syringe from this facility.

Manufacturer A’s facility has an existing drug CGMP operating system.  As the prefilled

syringe is a single-entity combination product under 21 CFR 3.2(e)(1), Manufacturer A must
demonstrate compliance with both the drug CGMPs and device QS regulation.115  To do so,
Manufacturer A opts to establish a CGMP operating system using the drug CGMP-based
streamlined approach in accordance with 21 CFR 4.4(b)(1).  While Manufacturer A must ensure
that its operating system fully complies with the drug CGMPs for this product, taking into
account all of the issues raised by inclusion of the device constituent part, this example focuses
on considerations for demonstrating compliance with the provisions from the device QS
regulation specified in 21 CFR 4.4(b)(1).

2.  Compliance with device QS regulation requirements

Having chosen to use the drug CGMP-based streamlined approach under 21 CFR
4.4(b)(1), in addition to demonstrating compliance with the drug CGMPs, Manufacturer A must
comply with the provisions of the device Quality System (QS) regulation specified in 21 CFR
4.4(b)(1).  For each such provision, this discussion offers exemplary considerations and activities
for the combination product manufacturer seeking to meet the device QS regulation
requirements.

a)  21 CFR 820.20, Management Responsibility

While section 501 of the FD&C Act (21 U.S.C. 351) and 21 CFR 211.22, 211.25, and
211.180 establish requirements relevant to management responsibility, Manufacturer A must
ensure that its CGMP operating system demonstrates compliance with the specific requirements
in 21 CFR 820.20 (discussed in greater detail in section IV.A.1). 116

114 The design control considerations for a prefilled syringe with a biological product are largely similar to those
covered in the example, although some additional issues may be more common such as the interaction of the
biological product with the syringe materials and the effect of product viscosity on delivery.
115 See 21 CFR part 4.
116 See 21 CFR 4.4(b)(1).

Contains Nonbinding Recommendations

Manufacturer A should, for example, review its existing CGMP operating system to

assess whether changes are needed to comply with this provision.  As part of this review,
management with executive responsibility for Manufacturer A should review the facility’s
quality policy and develop and implement appropriate oversight procedures, if such procedures
are not already in place, to ensure that both the policy and oversight are adequate.  The oversight
procedures should include clear delineation of the personnel to whom management with
executive responsibility is delegating responsibility for implementing the quality policy
(including translation into methods and procedures) and the CGMP operating system for this
product at the facility.

b)  21 CFR 820.30, Design Controls

Manufacturer A is responsible for establishing and maintaining procedures for design

control activities for the combination product.  In this scenario, Manufacturer A is the owner and
is manufacturing the prefilled syringe.  Accordingly, Manufacturer A is responsible for the
design control activities for the syringe as part of the combination product, as well as having
overall responsibility for the combination product.  However, Manufacturer A is buying the
syringe components from Manufacturer B, another manufacturer, which uses the same
components to manufacture finished syringes.  As a result, Manufacturer A may be able to
leverage syringe-specific design control documentation from the design controls Manufacturer B
uses for its finished syringes.117  Because no changes are to be made to the drug other than being
put into the syringe, the drug comes into the design control process as an input to the design of
the syringe to ensure that the syringe’s design reflects adequate consideration of the drug’s
characteristics, as indicated below.

An appropriate first step for Manufacturer A would be to review Manufacturer B’s design

control data to determine what new questions are raised by the use of the syringe with the drug,
and to assess what additional design control activities may be needed as a consequence.  It may
be the case, for example, that Manufacturer A can demonstrate that the only new design
questions that are raised concern the performance of the syringe as a container/closure to store
the drug and the extent to which the contact between the syringe and the drug may affect its
performance as a delivery system.  Regardless, Manufacturer A must ensure that all design
considerations for the combination product are addressed in accordance with 21 CFR 820.30.

117 If the supplier of the device components did not have design control information, Manufacturer A would likely
need to undertake more extensive design control activities for the syringe.  For example, Manufacturer A would
need to perform device-specific verification testing to confirm that the syringe meets necessary specifications for
plunger force or other parameters if the syringe component supplier has not conducted such testing suitable to enable
leveraging.

Contains Nonbinding Recommendations

i.

Design inputs and outputs

The table below includes illustrative examples of design inputs and user needs and

related design outputs for this prefilled syringe.

Design Input/User Needs
Required minimum/maximum dose delivery
for drug
Drug viscosity and desired/required delivery
rate
Expected use condition (e.g., expected user
experience/education level)
Maximum and minimum allowable
temperature for prefilled syringe
No degradation of drug or syringe over the
expected shelf-life as a result of contact with
one another
Expected shipping method and appropriate
storage conditions

Drug delivery method (e.g., needle or
needleless delivery)

Design Output
Drawing/specification for syringe dimensions,
markings, etc.
Drawing/specification for needle bore, glide
force, etc.
Content and reading level for the prefilled
syringe’s labeling
Packaging/labeling specifications for the
prefilled syringe
Specifications for drug-contacting syringe
materials

Design drawings/specifications for primary
and secondary packaging, labeling for
acceptable storage conditions
Drawing/specification for needle and/or other
associated syringe components

ii.

Design verification and validation

Once Manufacturer A has established design outputs for all design inputs, it must
perform design verification and validation activities to ensure that the combination product meets
design input requirements, including user needs and intended uses.118  Examples of appropriate
testing of the prefilled syringe include:  bench testing of the delivery of the drug from the syringe
to ensure repeatable and accurate drug delivery; shock and vibration testing of the packaged
prefilled syringe to ensure no damage or loss of integrity in shipping; validation that expected
users can adequately follow the instructions for use; other human factors studies;
biocompatibility testing; 119 drug and syringe compatibility studies; leachables and extractables
testing; and verification that the prefilled syringe works with all expected delivery methods (i.e.,
needle, needleless).  These activities would be documented in the DHF pursuant to 21 CFR
820.30(j) and would be subject to design change and review requirements pursuant to 21 CFR
820.30(e) and (i).

118 See 21 CFR 820.30(f) and (g).
119 For additional information on biocompatibility, see Guidance for Industry and FDA Staff:  Use of International
Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk
management process" (June 2016).
 See also, USP Chapter <87> Biological Reactivity, In Vitro and USP <88> Biological Reactivity Tests, In Vivo.

Contains Nonbinding Recommendations

iii.

Risk Analysis

Manufacturer A should identify risks associated with the prefilled syringe design, its

manufacturing processes, and intended uses, and also reduce or mitigate any unacceptable
risk(s).120  The table below lists some potential risks associated with prefilled syringes and
potential mitigations for these risks.

Risk
Syringe filled with incorrect drug dose
Loss of sterility

Drug contamination from materials of
syringe construction

Syringe failure during use

Mitigation
In-process acceptance testing, process validation
Container-closure integrity testing, packaging
validation/testing
Purchasing controls (including receiving
acceptance activities for components received from
syringe component manufacturer), in-process and
finished product testing to ensure no introduction of
contaminants during manufacture and over the
product shelf-life
Design verification testing on syringe, purchasing
controls over syringe component manufacturer(s)

iv.

Design changes

Manufacturer A must also have procedures in place to ensure that any changes to design
requirements are identified, documented, validated and/or verified, reviewed, and approved prior
to implementation.121  Activities should include review of the original risk analysis, review and
approval of the revised design inputs and outputs, and review and approval of the design change.
For example, before changing a material used in the syringe that comes into contact with the
drug, Manufacturer A should conduct verification activities to ensure that no degradation of
performance characteristics will occur before the expiration date for the combination product as
a result of the change of materials.122  Likewise, any change to the formulation of the drug
should include design control activities such as verification to confirm that the new formulation
does not degrade performance of the syringe.  All of this information would need to become a
part of the DHF.123

v.

Design history file

The DHF may include references or point to information residing elsewhere so long as

the reference or pointer is precise enough to allow the necessary information to be readily

120 See 21 CFR 820.30(g).
121 See 21 CFR 820.30(i).
122 Changes to materials that contact the drug may raise drug CGMP considerations, for example, under stability
testing and expiration dating requirements (21 CFR 211.137 and 21 CFR 211.167).  When possible, manufacturers
may leverage data collected in meeting these 21 CFR 211 requirements when determining what verification
activities are required under 21 CFR 820.30.
123 See 21 CFR 820.30(j).

Contains Nonbinding Recommendations

accessed as needed, including for inspections.  For example, elements of the syringe component
manufacturer’s design documentation may be relied upon to support the combination product
DHF.  Such information on the syringe may reside at Manufacturer B’s (syringe component
manufacturer) facility, so long as the necessary documentation can be accessed in a reasonable
time during inspection of Manufacturer A.  Manufacturer A should ensure access to such
documentation through supplier agreements with Manufacturer B under its purchasing controls
(21 CFR 820.50).  Documentation of development of the drug product that preceded the design
effort to incorporate the drug product into a prefilled syringe may be referenced in the DHF and
become an input to the combination product design effort (though such drug-only development is
not itself subject to design controls).

c)  21 CFR 820.50, Purchasing Controls

Manufacturer A is required to control its purchasing activities, including for the syringe

components, in accordance with 21 CFR 820.50.124  For example, if the syringe barrel and
plunger material is critical to ensuring that there is no adverse reaction with the drug,
Manufacturer A should structure purchasing agreements with Manufacturer B to ensure that
Manufacturer A is notified of any changes to this material prior to implementation of the change.
Similarly, if Manufacturer A uses an outside facility for terminal sterilization of the prefilled
syringe, Manufacturer A must also have appropriate controls over that sterilization service
provider.125

d)  21 CFR 820.100, Corrective and Preventive Actions

Manufacturer A is required to establish and maintain CAPA procedures for the
combination product.  Following are two examples of issues that might arise and exemplary
steps for addressing them:

Example 1:  Manufacturer A has implemented in-process manufacturing verification

procedures to confirm that the syringe is being filled with the correct amount of the drug, and the
data from this verification are analyzed for potential nonconformities.  Manufacturer A notes an
increase in nonconformities relating to the volume of drug being put in the syringe and in turn
opens a CAPA to investigate the problem.  Upon investigation of the cause of the improper fill
volume, Manufacturer A determines that maintenance procedures on the filling equipment are
the cause of the incorrect fill volume.  Manufacturer A updates the maintenance procedures and
performs verification/validation testing to confirm that the changes correct the problem and do
not cause new ones.

Example 2:  Manufacturer A begins receiving an increased number of customer
complaints related to holes or other damage to the syringe’s sterile package and opens a CAPA
to investigate the issue.  The CAPA reveals that Manufacturer B has made changes to a syringe
component such that there are sharp edges that can damage the sterile pouch during shipping.

124 In addition, because the device constituent part (syringe) is also a container/closure for the drug, Manufacturer A
must perform acceptance testing of the syringe components in accordance with 21 CFR 211.84.
125 See 21 CFR 820.50.

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Manufacturer A works with Manufacturer B to eliminate the sharp edge or finds a new supplier.
Manufacturer A also augments purchasing specifications and acceptance test steps to perform
visual inspection of the syringe components.  Manufacturer A repeats related design verification
testing to ensure that the new syringe meets all design requirements and does not result in pouch
damage during shipping.

e)  21 CFR 820.170, Installation and 820.200, Servicing

Installation and servicing requirements would not apply to the prefilled syringe because

the product does not require installation or servicing activities.

B. Drug-coated mesh

1.  Scenario Description

Manufacturer A plans to sell a synthetic surgical mesh coated with a drug.  Manufacturer

A has a marketing authorization to sell the uncoated mesh.  Manufacturer A wants to coat the
mesh with a drug to treat infection at the site of the product’s implantation.  Manufacturer B has
an approval to market a drug for local administration to treat infection at the site of implantation
of this class of device, but not in a formulation suitable for coating onto the mesh.  Manufacturer
A has established a business relationship with Manufacturer B to use the drug and develop the
data needed to support Manufacturer A’s marketing authorization for the coated mesh.
Manufacturer B will manufacture the drug formulation for spraying onto the mesh, and
Manufacturer A will manufacture the finished drug-coated mesh combination product.

2.  Compliance with QS regulation requirements

The coated mesh product is a single-entity combination product under 21 CFR 3.2(e)(1).
Therefore, Manufacturer A is subject both to the drug CGMPs and the device QS regulation for
this combination product.  Accordingly, Manufacturer A must ensure that its CGMP operating
system complies with both the device QS regulation and drug CGMPs, in accordance with one of
the approaches permitted under 21 CFR 4.4.  Because Manufacturer A is already marketing the
uncoated mesh, it has an existing device QS regulation-based operating system, and chooses to
operate under a device QS regulation-based streamlined approach for the combination product.
This discussion focuses on design control and purchasing control considerations arising from
inclusion of the drug constituent part in the combination product.

a)  21 CFR 820.30, Design Controls

A focus of the design control process for the drug constituent part of the combination

product is to ensure that the drug-coated mesh will be safe and effective for treating infection at
the site of implantation.  Accordingly, if the necessary dose of the drug for effective treatment  of
infection, for example, is already known, it would be an input (if the precise dose is not yet
known, then an input would be that the product elute a safe and effective dose); design outputs

Contains Nonbinding Recommendations

and validation and verification would need to be established to ensure that the required dose is
provided when the drug elutes from the mesh.126  In addition, risk analysis must be conducted to
identify any risks associated with the design, manufacturing, and use of the mesh.127  Mitigation
measures should then be identified and performed to address any identified risks.  Design
reviews should cover these and other related design considerations for the product, and personnel
with expertise in both the drug- and device-specific issues (as well as an individual independent
from the design stage being reviewed) should be included in these reviews.  The transfer of the
product design into production specifications should address all important aspects of the drug
constituent part for use in the combination product.128

i.

Design inputs and outputs

The table below includes illustrative examples of design inputs, including user needs, and

corresponding design outputs relating to the inclusion of the drug constituent part.

Design Input/User Needs
Required delivery dose and delivery rate for
the drug

Expected use condition (e.g., anatomical
location of use, surgical technique)

Maximum allowable temperature during
transportation, handling, and storage for the
combination product
No unacceptable degradation of the drug
over the expected shelf-life

No degradation of the surgical mesh over
the expected shelf-life

Design Output
Drug formulation and concentration, coating
thickness, uniformity of coating, manufacturing
process requirements, allowable storage
conditions
Labeling (instructions for use), material/drug
composition to ensure no damage to mesh or
coating during surgical placement
Packaging/labeling specifications for the
combination product

Specifications for the drug formulation drug-
contacting materials and packaging, shelf-life
labeling
Specifications for mesh material, drug
formulation and packaging, shelf-life labeling

ii.

Design verification and validation

Several examples of design verification and validation activities are described below:

-  One intended use is that the drug-coated mesh will treat infections.  Manufacturer A
must develop adequate clinical data (design validation) to ensure that the drug, when
combined with the mesh, is effective in treating infection and does not raise safety
concerns.129  Design outputs from this study would include the drug concentration in
the coating formulation (to be specified in purchasing controls over Manufacturer B)

126 See 21 CFR 820.30(d), (f), and (g).
127 See 21 CFR 820.30(g).
128 See 21 CFR 820.30(h).
129 See 21 CFR 820.30(g).

Contains Nonbinding Recommendations

and the coating thickness (specified in process controls over the application of the
coating by Manufacturer A).

−  A user need is that a physician be able to use the mesh product as labeled without
damaging the drug coating or the mesh material.  Manufacturer A would have to
verify that the mechanical properties of the coated mesh are such that the product can
withstand the stresses anticipated during the surgical procedure and still perform as
intended.130  The results would be used to define and develop design outputs for the
combination product, including in-process acceptance testing criteria during
manufacturing, appropriate product specifications for the drug coated mesh, and
instructions for use.

−  Another input to the design process is that the product have a shelf-life consistent
with the stability of the drug formulation and the mesh.  Manufacturer A would
perform design verification testing such as bench testing after aging to confirm that
the critical performance properties of the mesh material are not degraded during
storage or as a result of contact with the drug coating, as well as stability studies131 to
ensure that the properties of the drug are not degraded over the expected shelf life.
The design outputs arising from this process would include the labeled expiration date
and storage conditions for the combination product and packaging design
specifications.

iii.

Risk analysis and mitigation

The table below lists some potential risks associated with a surgical mesh coated with a

drug, and potential mitigations for these risks.

Risk
Drug concentration in coating not
sufficient to treat infection (e.g., due to
insufficient drug coating per surface area
of the mesh or non-uniformity of
coating),  inappropriate delivery rate
Mesh erodes or drug degrades during use
or storage

Mitigation
Clinical testing of the combination product, in-
process acceptance testing, manufacturing process
validation

Design verification testing (bench), clinical
testing, labeling (instructions for use, expiration
dating), purchasing controls over drug supplier,
specifications and other process controls

iv.

Design history file

All of the design control activities required by 21 CFR 820.30 (summarized in IV.A.2

above) must be addressed in the DHF for the drug-coated mesh.  The information developed as a

130 See 21 CFR 820.30(f).
131 See the Guidance for Industry on Q1A(R2) Stability Testing of New Drug Substances and Products (November
2003).

Contains Nonbinding Recommendations

result of design control activities will be assessed as part of premarket review of this
combination product (e.g., the suitability of the drug formulation and the compatibility of the
mesh with the drug).  Accordingly, much of the information included in the DHF would be
submitted as part of the premarket review process.  Manufacturer A may opt to incorporate such
information into the DHF by cross-reference to such premarket documentation.  Whatever
approach Manufacturer A selects must ensure that all required design history information is
readily available to FDA for review.

The DHF for the surgical mesh must include design input, output, verification and
validation data, and the results of design reviews for the combination product.  In developing the
design controls related to the drug constituent part, Manufacturer A may rely on the safety,
efficacy, quality and in situ dose data for the drug as independently marketed.  These existing
data that supported approval of the drug would be available as a reference for the combination
product DHF to enable development of design inputs for the drug constituent part and the
combination product as a whole, and thus facilitate its development process.

b)  21 CFR 820.50, Purchasing Controls

Manufacturer A already has established procedures for controlling purchasing/supplier
activities pursuant to 21 CFR 820.50.  Under this provision, Manufacturer A must ensure that
appropriate purchasing controls for Manufacturer B are established and maintained.  In
particular, based on risk associated with the drug and supplier, Manufacturer A must evaluate
Manufacturer B as a potential supplier of the drug and establish the type and extent of control to
be exercised over Manufacturer B as a selected supplier.132

Purchasing controls (and acceptance activities under 21 CFR 211.84) with respect to the

drug constituent part should focus on ensuring that Manufacturer B can supply the drug that
meets the specifications that Manufacturer A has established during the design control process.
Manufacturer A should establish purchasing agreements with Manufacturer B to ensure that
Manufacturer A is notified of any changes that may affect the performance of the combination
product prior to Manufacturer B’s implementation of the changes.  The notifications should
address issues including changes in the drug specification, its components, composition of drug
coating materials, or the drug manufacturing process or facility.  Such proposed changes may
require that Manufacturer A complete additional design verification and/or validation.  For
example, verification testing may be necessary to confirm that the purity and stability of the drug
is maintained, pursuant to the requirements of 21 CFR 820.30(i).

C. Drug Eluting Stent (DES)

1.  Scenario Description

In this scenario, Manufacturer A is the owner for a drug-eluting stent (DES) composed of

a stent coated with a drug.  Manufacturer B manufactures the active pharmaceutical ingredient

132 See 21 CFR 820.50(a)(2).

Contains Nonbinding Recommendations

(API or bulk drug substance), Manufacturer C manufactures a polymer with which the bulk drug
substance will be combined for coating onto the stent, and Manufacturer D manufactures the
materials used for the product’s primary packaging.  Manufacturer A purchases the bulk drug
substance from Manufacturer B and the polymer from Manufacturer C, then formulates the drug
coating solution and uses it to coat the stent in its own facility.  At the same facility,
Manufacturer A packages the DES using the primary packaging materials it purchases from
Manufacturer D.

2.  Compliance with drug CGMP requirements

The DES is a single-entity combination product as defined in 21 CFR 3.2(e)(1) and,

therefore, is subject to both the drug CGMPs and device QS regulation.  As a device
manufacturer, Manufacturer A already has a CGMP operating system designed to comply with
the device QS regulation and has elected to establish a device QS regulation-based streamlined
approach for the DES in accordance with 21 CFR 4.4(b)(2).  While Manufacturer A must ensure
that this operating system complies with the device QS regulation, taking into account all of the
issues raised by inclusion of the drug constituent part, this example focuses on considerations for
complying with the drug CGMP provisions specified in 21 CFR 4.4(b)(2).

a)  21 CFR 211.84, Testing and approval or rejection of drug components, product

containers, and closures

Manufacturer A has controls in place to evaluate suppliers, contractors, and consultants
based on their ability to meet quality and other specified requirements and to control incoming
materials in accordance with 21 CFR 820.50 and 21 CFR 820.80.  Under 21 CFR 4.4(b)(2),
Manufacturer A must augment its existing CGMP operating system as needed to satisfy the
requirements of 21 CFR 211.84 for the DES.

Manufacturer A’s purchasing controls for the DES must include evaluation of

Manufacturer B as the supplier of the bulk drug substance,  Manufacturer C as the supplier of the
polymer for the coating, and Manufacturer D as the supplier of the primary packaging materials,
in conformance with 21 CFR 820.50(a)(1).  In addition, under its CGMP operating system for
the facility, Manufacturer A has controls to identify the acceptance status of manufactured
products.  Manufacturer A’s responsibilities under 21 CFR 211.84 relate to these various
obligations and controls arising from the device QS regulation.

 In accordance with 21 CFR 211.84, the bulk drug substance, polymer, and primary

packaging materials supplied by manufacturers B, C, and D must be sampled, tested, or
examined, as appropriate, by Manufacturer A to determine whether they should be approved or
rejected for use.  The primary packaging materials should be visually inspected to ensure that the
correct, specified materials are received from Manufacturer D.  Each lot of bulk drug substance
and polymer must be tested to verify conformity with written specifications for purity, quality,
and strength.133  Due to the nature and intended use of sterile drug eluting stents, testing must
include microbiological testing of the bulk drug substance and polymer.

133 See 21 CFR 211.84(d)(2).

Contains Nonbinding Recommendations

Under certain circumstances, Manufacturer A may rely on a report of analysis from a

supplier in lieu of conducting some of its own testing.  If, for example, Manufacturer B performs
conformity testing for the bulk drug substance (testing to ensure that the material meets
appropriate purity, strength, and quality specifications) just prior to the shipment of material to
Manufacturer A, then a report of analysis may be accepted by Manufacturer A in lieu of testing
for these characteristics by Manufacturer A, if the following conditions are met.134

Manufacturer A is still responsible for the performance of at least one specific identity

test upon receipt of each lot of the bulk drug substance, even when a report of analysis
accompanies the lot.135  Reliance on reports of analyses is also contingent on Manufacturer A
establishing the reliability of the supplier’s analyses through appropriate validation of the test
results at appropriate intervals.136  The supplier can be evaluated through initial purchasing
controls and subsequently at suitable intervals.  A similar analysis would apply if Manufacturer
C were to conduct conformity testing for the polymer it supplies to Manufacturer A.  Incoming
examination or testing by Manufacturer A and receipt of any reports of analysis must occur prior
to use of the material in the manufacture of the DES.

b)  21 CFR 211.103, Calculation of yield

Calculation of yield should be conducted during all appropriate steps in the
manufacturing process prior to and after application of the coating to the stent, including the
formulation of the coating.137  Manufacturer A is responsible for the calculation of yield at
appropriate phases of manufacture at its facility, including application of the coating to the DES,
and the packaging of the DES.  The formula used and the data generated for the calculation
should be maintained in Manufacturer A’s batch production and control record.

c)  21 CFR 211.132, Tamper-evident packaging requirements for over-the-counter

(OTC) human drug products

This regulatory requirement is not applicable to drug-eluting stents, as they are not OTC

products.

d)  21 CFR 211.137, Expiration dating

As the manufacturer of the combination product, Manufacturer A is responsible for

establishing the expiration date on the labeling of the finished combination product.  The
expiration date must be established based on the data from the stability studies for the finished
packaged DES and should also take into account other shelf-life considerations as required under

134 See 21 CFR 211.84(d)(2).
135 21 CFR 211.84(d)(2).
136 See 21 CFR 211.84(d)(2).
137 Drug-coated stents that are rejected due only to defects in the device constituent part (stent) will result in
corresponding loss of drug constituent part from the batch/lot.  This loss should be captured as part of the yield
calculations for the drug constituent part and investigation of the cause of that loss should identify the manufacturing
problem that is leading to these device constituent part nonconformities.

Contains Nonbinding Recommendations

design control.  These considerations include the functionality of the stent and polymer and the
integrity of the coating and the packaging.138

e)  21 CFR 211.165, Testing and release for distribution

Manufacturer A must test each batch of the finished combination product to determine

conformance with the final written specifications for the product.139  A detailed listing of all the
tests performed on the DES and the acceptance criteria should be incorporated into the
documentation for the manufacturing, production, and laboratory systems.  A description of each
analytical test should be prepared and documented in standard operating procedures.  A general
list of tests for drug-eluting stents is provided below:

Identification

Impurities and Degradation Products

•  Appearance
•
•  Assay
•
•  Content Uniformity
•  Drug Release Rate (immediate and/or extended release rates)
•  Package Integrity and Sterility Assurance
•  Endotoxins
•  Particulate Matter
•  Additional Testing, when applicable (including testing for polymer molecular weight,

residual monomers, catalysts, and other additives)

f)  21 CFR 211.166, Stability testing

Stability testing for the final DES product should address the following considerations:

appearance, assay/drug content, impurities/degradation products, rate of drug release, particulate
matter, sterility, and package integrity.  Methods used for batch release under 21 CFR 211.165
may also be suitable for stability testing.  Analytical procedures for stability testing should be
fully validated as suitable to demonstrate stability.140

g)  21 CFR 211.167, Special testing requirements

Manufacturer A must conduct or contract to conduct testing of the DES in accordance

with 21 CFR 211.167(a) because this class of product is purported to be sterile and non-
pyrogenic.  In addition, testing in accordance with 21 CFR 211.167(c) must be conducted
because the DES constitutes a controlled-release dosage form.

138 See 21 CFR 211.137(a) and (b).
139 See 21 CFR 211.165(a).
140 If Manufacturer A decides to develop a family of drug-eluting stents over time, differing from one another in the
size of the stent, the Agency does not intend to object to the manufacturer’s leveraging previously generated stability
data for the existing versions to establish expiration dating for later versions, or newer products being incorporated
into the ongoing stability program for the existing marketed drug-eluting stents, so long as the manufacturer can
provide adequate justification and such approaches have been reviewed by FDA, where applicable.

Contains Nonbinding Recommendations

h)  21 CFR 211.170, Reserve samples

Manufacturer A must maintain reserve samples representative of each lot of the active
ingredient used in the combination product and of each lot or batch of the finished, packaged
DES.141  Reserve samples must consist of at least twice the quantity necessary to perform all
tests required for the active ingredient and the finished DES, excluding sterility and pyrogen
testing.142  The reserve samples must be kept for the time periods required by 21 CFR 211.170.
The samples of the active ingredient must be kept for 1 year past the expiration date of the last
lot of finished drug-eluting stents to use that lot of the active ingredient.143 The samples for each
lot or batch of the finished DES must be kept for 1 year after the expiration date for the
combination product.144  If Manufacturer A maintains reserve samples in a third-party storage
facility, Manufacturer A should ensure, via purchasing controls (21 CFR 820.50), that the facility
can meet applicable CGMP requirements.145

VI.  Contact Us

If you have questions regarding compliance with CGMP requirements for combination
products after reviewing this guidance and the materials cited in this document, we encourage
you to contact us.  We recommend you contact the lead center for your product in the first
instance.  However, you may also contact OCP for assistance.  Below are contact points for each
center and OCP.  You may follow existing processes for your lead center when requesting
feedback on combination product issues (e.g., meeting requests to CBER/CDER,146 pre-
submissions to CDRH147).

1.  CBER

Mail:

Phone:
Email:

Office of Communication, Outreach and Development (OCOD)
10903 New Hampshire Avenue
Building 71, Room 3128
Silver Spring, MD  20993
1-800-835-4709 or 240-402-8010
ocod@fda.hhs.gov

141 See 21 CFR 211.170(a) and (b).
142 See 21 CFR 211.170(a) and (b).
143 See 21 CFR 211.170(a)(1).
144 See 21 CFR 211.170(b)(1).
145 Additional information on drug-eluting stents is provided in the draft Guidance for Industry on Coronary Drug-
Eluting Stents–Nonclinical and Clinical Studies –(March 2008). When finalized, this guidance will represent FDA’s
current thinking on this topic.
146 See Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants (May 2009).
147 See Guidance for Industry and FDA Staff: Requests for Feedback on Medical Device Submissions:
The Pre-Submission Program and Meetings with Food and Drug Administration Staff  (February 2014).

2.  CDER

Mail:

Phone:
Email:

3.  CDRH

Mail:

Contains Nonbinding Recommendations

Division of Drug Information (DDI)
Hillandale Building
10001 New Hampshire Avenue
Silver Spring, MD  20993
1-855-543-3784 or 301-796-3400
druginfo@fda.hhs.gov

Division of Industry and Consumer Education (DICE)
10903 New Hampshire Avenue
Building 66, Room 4621
Silver Spring, MD  20993

Phone:    1-800-638-2041 or 301-796-7100
Email:    DICE@fda.hhs.gov

4.  OCP

Mail:

  Office of Combination Products
Food and Drug Administration
10903 New Hampshire Avenue
Building 32, Hub/Mail Room #5129
Silver Spring, MD  20993
301-796-8930
301-847-8619
combination@fda.gov

Phone:
Fax:
Email:

VII.  Glossary

Note: this glossary is for use exclusively with this guidance document.  Definitions that have
been taken from federal regulations include the relevant citation.

Constituent part:  A drug, device, or biological product that is part of a combination product.
(21 CFR 4.2)

Co-packaged combination product:  Two or more separate products packaged together in a
single package or as a unit and comprised of drug and device products, device and biological
products, or biological and drug products.  (21 CFR 3.2(e)(2))

Cross-labeled combination product:  (i) A drug, device, or biological product packaged
separately that according to its investigational plan or proposed labeling is intended for use only
with an approved individually specified drug, device, or biological product where both are
required to achieve the intended use, indication, or effect and where upon approval of the
proposed product the labeling of the approved product would need to be changed, e.g., to reflect

Contains Nonbinding Recommendations

a change in intended use, dosage form, strength, route of administration, or significant change in
dose; or (ii) any investigational drug, device, or biological product packaged separately that
according to its proposed labeling is for use only with another individually specified
investigational drug, device, or biological product where both are required to achieve the
intended use, indication, or effect. (21 CFR 3.2(e)(3) and 21 CFR 3.2(e)(4))

Device QS regulation-based streamlined approach:  A CGMP operating system that is
intended to demonstrate compliance with all of the provisions of the device QS regulation and
the following provisions from the drug CGMPs in accordance with 21 CFR 4.4(b)(2):

(i) 21 CFR 211.84

(ii) 21 CFR 211.103
(iii) 21 CFR 211.132

(iv) 21 CFR 211.137
(v) 21 CFR 211.165
(vi) 21 CFR 211.166
(vii) 21 CFR 211.167
(viii) 21 CFR 211.170

Testing and approval or rejection of components, drug
product containers, and closures
Calculation of yield
Tamper-evident packaging requirements for over-the-
counter (OTC) human drug products
Expiration dating
Testing and release for distribution
Stability testing
Special testing requirements
Reserve samples

Drug CGMPs:  The current good manufacturing practice regulations set forth in 21 CFR 210
and 21 CFR part 211. (21 CFR 4.2)

Drug CGMP-based streamlined approach:  A CGMP operating system that is intended to
demonstrate compliance with all of the provisions from the drug CGMPs and the following
provisions from the device QS regulation in accordance with 21 CFR 4.4(b)(1):

(i) 21 CFR 820.20
(ii) 21 CFR 820.30
(iii) 21 CFR 820.50
(iv) 21 CFR 820.100
(v) 21 CFR 820.170
(vi) 21 CFR 820.200

Management responsibility
Design controls
Purchasing controls
Corrective and preventive action
Installation
Servicing

Lead center:  The FDA center (CBER, CDER, or CDRH) that has primary jurisdiction for
premarket review and regulation of a combination product.

Manufacture:  Includes, but is not limited to, designing, fabricating, assembling, filling,
processing, testing, labeling, packaging, repackaging, holding, and storage. (21 CFR 4.2)

CGMP operating system:  The operating system within an establishment that is designed and
implemented to address and meet the current good manufacturing practice requirements for a
combination product. (21 CFR 4.2)

Contains Nonbinding Recommendations

Owner:  For purposes of this guidance, the entity that holds the marketing authorization for a
combination product (regardless of whether that entity is directly engaged in the manufacture of
the product).

Device QS regulation:  The quality system regulation in 21 CFR part 820. (21 CFR 4.2)

Single-entity combination product:  A product comprised of two or more regulated
components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are
physically, chemically, or otherwise combined or mixed and produced as a single entity. (21
CFR 3.2(e)(1))

Streamlined approach:  Either of the two approaches permitted under 21 CFR part 4, which
allows combination product manufacturers to demonstrate compliance with both the drug
CGMPs and device QS regulation by designing and implementing a CGMP operating system
that demonstrates compliance with part 211 or part 820 in its entirety plus specified provisions of
the other set of regulations.

VIII. References

Device

1.  Applying Human Factors and Usability Engineering to Medical Devices

(http://www.fda.gov/downloads/MedicalDevices/.../UCM259760.pdf) (February 2016)

2.  Design Control Guidance for Medical Device Manufacturers, Guidance for Industry

(March 1997)
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm070642.pdf)

3.  Glass Syringes for Delivering Drug and Biological Products: Technical Information to
Supplement International Organization for Standardization (ISO) Standard 11040-4 -
Draft Guidance for Industry and FDA Staff (April 2013)
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM346181.pdf)

4.  Quality System Information for Certain Premarket Application Reviews, Guidance for

Industry and FDA Staff (Feb. 3, 2003)
(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm070899.pdf)

5.  Requests for Feedback on Medical Device Submissions: The Pre-Submission Program

and Meetings with Food and Drug Administration Staff, Guidance for Industry (February
2014)
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidanced
ocuments/ucm311176.pdf)

6.  Sterilized Convenience Kits for Clinical and Surgical Use, Guidance for Industry (Jan.

2002)

Contains Nonbinding Recommendations

(http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
eDocuments/ucm071029.pdf)

7.  Use of International Standard ISO- 1 10993, "Biological Evaluation of 2 Medical Devices

Part 1: Evaluation 3 and Testing", DRAFT Guidance for Industry
(http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidanced
ocuments/ucm348890.pdf)

Drugs

8.  CGMP for Phase 1 Investigational Drugs, Guidance for Industry (July 2008)

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070273.pdf)

9.  Container Closure Systems for Packaging Human Drugs and Biologics:  Chemistry,
Manufacturing, and Controls Documentation, Guidance for Industry, (May 1999)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070551.pdf)

10. Contract Manufacturing Arrangement for Drugs: Quality Agreements, Guidance for

Industry (November 2016)
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm353925.pdf)

11. Formal Meetings Between the FDA and Sponsor or Applicants, Guidance for Industry

(March 2015)
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm437431.pdf)

12. Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production,

Guidance for Industry (Oct. 2006)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070287.pdf)

13. Process Validation:  General Principles and Practices, Guidance for Industry (Jan. 2011)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070336.pdf)

14. Q1A(R2) Stability Testing of New Drug Substances and Products, Guidance for Industry

(Nov. 2003)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073369.pdf)

15. Q1B Photostability Testing of Drug Substances and Products, Guidance for Industry

(November 1996)

Contains Nonbinding Recommendations

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073373.pdf)

16. Q1C Stability Testing for New Dosage Forms, Guidance for Industry (November 1996)
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073374.pdf)

17. Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances

and Products, Guidance for Industry (January 2003)
(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073379.pdf)

18. Q1E Evaluation of Stability Data, Guidance for Industry (June 2004)

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm073380.pdf)

19. Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,

Guidance for Industry (Aug 2001)
(http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/uc
m200364.htm)

20. Q8(R2) Pharmaceutical Development, Guidance for Industry (November 2009)

(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf)

21. Q9 Quality Risk Management, Guidance for Industry (June 2006)

(http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073511.pdf)

22. Q10 Pharmaceutical Quality System, Guidance for Industry (April 2009)

(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM073517.pdf)

23. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing

Practice, Guidance for Industry (Sept. 2004)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM070342.pdf)

24. Submission of Documentation in Applications for Parametric Release of Human and
Veterinary Drug Products Terminally Sterilized by Moist Heat Process, Guidance for
Industry (February 2010)
(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm437431.pdf)

Biological Products

25. Cooperative Manufacturing Arrangements for Licensed Biologics, Guidance for Industry

(Nov. 2008)
(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator

Contains Nonbinding Recommendations

yInformation/Guidances/General/UCM069908.pdf)

HCT/Ps

26. Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), Guidance for
Industry (Dec 2011)
(http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator
yInformation/Guidances/Tissue/UCM285223.pdf)

Combination Products

27. Coronary Drug-Eluting Stents – Nonclinical and Clinical Studies, Draft Guidance for

Industry (March 2008)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM228704.pdf)

28. How to Write a Request for Designation (RFD), Guidance for Industry (April 2011)

(http://www.fda.gov/RegulatoryInformation/Guidances/ucm126053.htm)

29. Human Factors Studies and Related Clinical Study Considerations in Combination

Product Design and Development, Draft Guidance for Industry and FDA Staff  (February
2016) (http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-
afdagen/documents/document/ucm484345.pdf)

30. Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs

and Biological Products, Guidance for Industry and FDA Staff (June 2013)
(http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147095.pdf)

General

31. Pyrogen and Endotoxins Testing:  Questions and Answers, Guidance for Industry (June

2012)
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM310098.pdf)

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### Document: FDA ComboProd HF Complete (FDA)

# FDA Draft Guidance: Human Factors Studies in Combination Product Design and Development (Feb 2016): Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development

Human Factors Studies and Related
Clinical Study Considerations in
Combination Product Design and
Development

Draft Guidance for Industry and
FDA Staff

This guidance document is for comment purposes only.

Submit one set of either electronic or written comments on this draft guidance by the date
provided in the Federal Register notice announcing the availability of the draft guidance.
Submit electronic comments to http://www.regulations.gov.  Submit written comments to the
Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.  You should identify all comments with the docket
number listed in the notice of availability that publishes in the Federal Register.

Additional copies of this guidance are available from the Office of Combination Products
website at http://www.fda.gov/CombinationProducts/default.htm.

For questions on the content of this guidance, contact the Office of Combination Products at
combination@fda.gov or patricia.love@fda.hhs.gov.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Devices and Radiological Health,
Center for Drug Evaluation Research,
Center for Biologics Evaluation and Research, and
Office of Combination Products in the Office of the Commissioner

February 2016

Contains Nonbinding Recommendations

Table of Contents

I.

II.

INTRODUCTION............................................................................................................. 2

BACKGROUND ............................................................................................................... 3

III.  HUMAN FACTORS ......................................................................................................... 5

A.
B.
1.
2.
3.
C.
D.
E.
1.
2.

Glossary and Concepts ......................................................................................... 5
Evaluation of Use-Related Risk ........................................................................... 6
Critical Tasks ........................................................................................................ 7
Intended Users and Use Environment ................................................................ 8
Training ................................................................................................................. 8
Human Factors-Formative Studies ..................................................................... 9
Human Factors Knowledge Task Studies ......................................................... 12
Human Factors Validation Studies ................................................................... 10
Human Factors-Simulated Use Validation Studies ......................................... 10
Human Factors-Actual Use Validation Studies ............................................... 10

IV.  PROCESS CONSIDERATIONS ................................................................................... 12

A.

B.
C.

Considerations on Whether to Submit Combination Product Human Factors
Study Data ........................................................................................................... 12
Considerations for Design Changes After HF-Validation .............................. 14
Human Factors Information to Submit in a Combination Product
Investigational Application ................................................................................ 14
D.  Marketing Application Review of HF Studies and Certain Labeling ............ 15

V.  RELATIONSHIP OF HUMAN FACTORS AND MAJOR CLINICAL STUDIES

OF THE COMBINATION PRODUCT ........................................................................ 16

VI.  HOW TO OBTAIN ADDITIONAL INFORMATION ............................................... 17

APPENDIX A:  USER TASK FAILURE EXAMPLES ........................................................ 18

i

Contains Nonbinding Recommendations

Human Factors Studies and Related Clinical Study Considerations
in Combination Product Design and Development1

Draft Guidance for Industry and FDA Staff

This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person
and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations.  To discuss an alternative approach,
contact the FDA staff responsible for this guidance as listed on the title page.

I.  INTRODUCTION AND SCOPE

This document provides guidance to industry and FDA Staff on the underlying principles of
human factors (HF) studies during the development of combination products as defined under 21
CFR Part 3.  This guidance describes Agency recommendations regarding HF information in a
combination product investigational or marketing application and clarifies the different types of
HF studies; the recommended timing and sequencing of HF studies; and how HF studies are part
of the process to maximize the likelihood that the combination product user interface is safe and
effective for use by the intended users, uses, and environments.  In addition, the guidance
describes how HF studies relate to other clinical studies.  The guidance also provides process
considerations for HF information in investigational or marketing applications to promote
development and timely review of safe and effective combination products.

This guidance focuses on HF issues related to combination products that are comprised of a drug
or biological product and a device (also referred to in this guidance as medical device) for review
in an investigational or marketing application submitted to the Center for Biologics Evaluation
and Research (CBER), the Center for Devices and Radiological Health (CDRH), or the Center
for Drug Evaluation and Research (CDER).  The application types include an investigational
device exemption application (IDE), an investigational new drug application (IND), biologics
license application (BLA), new drug application (NDA), or premarket approval application
(PMA).  However, the principles and recommendations may be applicable to combination
products reviewed under other types of applications (e.g., premarket notification (510(k)) or
abbreviated new drug application (ANDA)) as appropriate.2

1 This guidance has been prepared by the Office of Combination Products in the Office of Special Medical Programs
in the Office of the Commissioner in association with the Center for Biologics Evaluation and Research, the Center
for Drug Evaluation and Research, and the Center for Devices and Radiologic Health.
2 The applicability of HF studies for certain combination product design changes under the 510(k) or ANDA
program are beyond the scope of this document.  Applicants who are considering whether the combination product
design change would change the center assignment should contact the Office of Combination Products
(combination@fda.gov) for questions on the center assignment.  For information on the application types within a
center, contact the respective center jurisdiction officers at CDERproductjurisdiction@fda.hhs.gov ,
CDRHproductjurisction@fda.hhs.gov, or cberombusmana@fda.hhs.gov.  Applicants preparing to submit a
combination product for review under an ANDA that may include HF studies should contact the CDER Office of

Contains Nonbinding Recommendations

Related information is available in the Agency Guidance Applying Human Factors and Usability
Engineering to Optimize Medical Device Design3 and the Agency Draft Guidance Safety
Considerations for Product Design to Minimize Medication Errors.4  Additionally, this guidance
supplements other existing guidance documents developed by CBER, CDRH, CDER, and the
Office of Combination Products (OCP) that describe other aspects of product development.  (See
Section VI for a list of some additional guidance documents.)

FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

II.  BACKGROUND

Combination products, as described in 21 CFR Part 3, are comprised of any combination of a
drug and a device; a device and a biological product; a biological product and a drug; or a drug, a
device, and a biological product.5  The constituent parts of a combination product retain their
regulatory status (as a drug, device, or biological product) after they are combined.  Accordingly,
a combination product remains subject to the regulatory requirements associated with its
constituent parts.

receives requests to clarify how HF concepts apply to the development of a combination product
when one of the constituent parts is a device.  Inquiries include:

•  What types of HF studies might need to be conducted for the combination product?
•  When is the appropriate time to perform HF Validation studies?
•  What is the role of HF studies as compared to other types of clinical studies?
•  Are additional HF studies necessary when the design of the combination product

changes?

Other general inquiries relate to regulatory considerations for combination products such as
when a HF study is subject to review and approval by an institutional review board (IRB),6 and
how HF studies are considered in User Fee determinations.7

Generic Drugs at GenericDrugs@fda.hhs.gov regarding controlled correspondence subject to the Generic Drug User
Fee Act (GDUFA) performance goals to discuss considerations related to HF studies.
3 Guidance for Industry and FDA Staff, Applying Human Factors and Usability Engineering to Optimize Medical
Device Design, accessible at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM259760.
pdf.
4 Draft Guidance Safety Considerations for Product Design to Minimize Medication Errors, accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM331810.pdf.
FDA’s draft guidance documents represent FDA’s proposed approach on the topics.
5 For purposes of this document the term “drug” also refers to biological products unless otherwise indicated.
6 Clinical studies regulated under 21 CFR Part 312 (IND requirements) or Part 812 (IDE requirements) and clinical
studies intended to support an investigational or marketing application are subject to applicable requirements under
21 CFR Parts 50 and 56.  See 21 CFR 50.1(a), 50.20, 56.101(a), and 56.103.  As used in this document, clinical

Contains Nonbinding Recommendations

For medical devices, the use of human factors and usability engineering (e.g., applying the
knowledge of human behavior, abilities, and limitations to the design of a medical device) plays
a key role in maximizing the likelihood that the device will be safe and effective for use by the
intended users, for the intended uses, and for the intended use environments.  Under the medical
device design control requirements described in 21 CFR 820.30, design validation must include a
risk analysis where appropriate.  As part of the risk analysis, device manufacturers should
identify and analyze potential use-related hazards, including lessons learned from reported errors
with similar products, and as appropriate, incorporate and validate design features that mitigate
or eliminate these hazards.  This assessment informs the device design development to eliminate
or minimize use errors that could cause harm or compromise medical treatment.

For a drug product, goals for reducing use-related hazards are reflected in the process and data
that support selection of the drug formulation, assurance of product quality,8 drug risk
management activities,9 and in pharmaceutical quality system principles.10  Drug development
should take into account the user interface and factors that can reduce the risk for medication
errors; i.e., features to enhance patient safety.  Such features include product appearance,
identification markings (such as imprint codes on solid oral dosage forms), container closure,
packaging configurations, labeling (including labels on containers and cartons), and
nomenclature.11  The Prescription Drug User Fee Act IV (PDUFA IV)12 provides that one of the
development goals is to ensure drug safety by prospectively designing a drug that minimizes the
risk for errors made by intended end users.13

study has the same meaning as investigation or clinical investigation as defined in Parts 50, 56, 312, and 812, as
applicable.
7 For information on user fee assessment under the Prescription Drug User Fee Act (PDUFA) for applications
containing clinical studies, see FDA Guidance Submitting Separate Marketing Applications and Clinical Data for
Purposes of Assessing User Fees accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079320.pdf.
As described in that document the term “clinical data, for purposes of assessing user fees, encompasses a broad
range of studies that are purported to be adequate and well-controlled investigations submitted in support of
approval.  This includes [1] study reports or literature of what are explicitly or implicitly represented by the
applicant to be adequate and well-controlled trials for safety or effectiveness; or [2] reports of comparative activity
(other than bioequivalence and bioavailability studies), immunogenicity, or efficacy, where those reports are
necessary to support a claim of comparable clinical effect.  As applicable, FDA will determine whether a HF study
would meet these criteria.
8 See Guidance for Industry Q8(R2) Pharmaceutical Development accessible at
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073507.pdf
9See Guidance for Industry Q9 Quality Risk Management accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073511.pdf   .
10 See Guidance for industry Q10 Pharmaceutical Quality System accessible at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073517.pdf.
11 As defined in FD&C Act section 201(m), “labeling” means “all labels and other written, printed, or graphic
matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.”  As defined in
FD&C Act section 201(k), “label” means “a display of written, printed, or graphic matter upon the immediate
container of any article.”
12 See information under Item-IX accessible at
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm.
13 Measures for designing such a drug could address, among other things, concerns regarding:  look-alike and sound-
alike proprietary names; unclear label abbreviations, acronyms, and dose designations; and other label and
packaging design that may lead to user error.

Contains Nonbinding Recommendations

For a combination product that includes drug and device constituent parts, both the device design
control requirements and drug development expectations apply to the entire combination
product.14  Therefore, when evaluating a combination product, the design of the product user
interface should be assessed in HF studies if needed to ensure that use-related hazards associated
with the product are eliminated or mitigated to reduce patient adverse events and medication
errors attributable to use-related errors.  This document focuses on human factors considerations
for combination products to promote consistency in their design, development and review.

III.  HUMAN FACTORS

A.

Glossary and Concepts

For purposes of this document, the following definitions and concepts apply to HF studies, the
final finished combination product, and the major clinical study.  For additional information on
these terms see the sections that follow the glossary.  For related definitions see Agency
guidance Applying Human Factors and Usability Engineering to Optimize Medical Device
Design.3

1.  Human Factors Study (or HF Study): A study conducted with representative users to
assess the adequacy of the combination product user interface design to eliminate or
mitigate potential use-related hazards.  Typically, HF studies are part of an iterative
design process that is driven by the complexity of the combination product and the nature
of the safety considerations.  The HF study evaluates: (i) the ability of the user to perform
critical tasks, and (ii) the ability of the user to understand the information in the
packaging and labeling, such as product labels or instructions for use, that inform the
user’s actions and that are critical to the safe and effective use of the combination product
(e.g., product preparation, administration, maintenance and disposal, or what actions to
take if an adverse reaction occurs).  Both types of evaluations may be part of the HF
Formative and HF Validation studies described below.

a.  HF Formative Study: A study conducted on a combination product prototype user
interface at one or more stages during the iterative product development process to
assess user interaction with the product and identify potential use errors.  HF
Formative studies are iterative and inform the need for user interface changes (e.g.,
product design or labeling changes) and inform the content of the HF Validation
study.  For additional information on HF Formative studies see Section III.C.

HF Validation Study:  A study conducted to demonstrate that the final finished
combination product user interface can be used by intended users without serious use
errors or problems, for the product’s intended uses and under the expected use
conditions.  The study should demonstrate that use-related hazards for the final
finished combination product (see glossary item A.2 below) have been eliminated or
that the mitigation for residual risks is acceptable; i.e., the benefit of product use

14 For combination products that include a device constituent part, design controls must be applied to the
combination product.  See 21 CFR 4.4; 78 FR 4307 (Jan. 27, 2013).  Current Good Manufacturing Practice
Requirements for Combination Products is accessible at https://www.federalregister.gov/articles/2013/01/22/2013-
01068/current-good-manufacturing-practice-requirements-for-combination-products.

Contains Nonbinding Recommendations

outweigh the residual risk of the product.  The study participants are representative of
the intended users and the study conditions are representative of expected use
conditions.

2.  Final Finished Combination Product: The final finished combination product is the
product intended for market and submitted in the marketing application.  This term
applies to the combined final device, drug, and/or biological product configuration
including all product user interfaces (e.g., proposed packaging, labels and labeling,
including training programs).

3.  Major Clinical Study (or Major Clinical Trial): As opposed to a HF study, a major
clinical study is a larger scale clinical study that occurs during a later phase of
combination product development.  Major clinical studies provide the primary support for
the safety and effectiveness of a product for a proposed indication (e.g., adequate and
well-controlled studies15).16  In addition to adequate and well-controlled studies, other
types of later phase larger scale clinical studies may also be considered major clinical
studies; e.g., a long-term extension study.  .

B.

Evaluation of Use-Related Risk

Consistent with a risk-based design and development paradigm, the foundation for HF study
designs, testing and evaluation should be a use-related risk analysis of a combination product.  A
use-related risk analysis is a crucial step to help identify use-related hazards associated with the
combination product, as well as to characterize high-risk hazards so they can be mitigated or
eliminated through improved product interface design.  The use-related risk analysis will help
identify critical tasks that should be evaluated in a HF study, inform the priority of testing the
tasks in a HF study, and determine if there are specific use scenarios to include in testing.  A
variety of methods can be used to develop and analyze use-related hazards.  Two methods
frequently used are Failure Mode and Effects Analysis (FMEA) and Fault Tree Analysis
(FTA).17

The use-related risk analysis should take into account: all the intended uses, users, and use
environments; therapeutic or diagnostic procedures associated with the use of the combination
product; similar products used within the environments; and any associated medical factors that
may affect the safe use of the combination product.  In addition, if previous models of the same
or similar combination products exist, the risk analysis should incorporate information on known
use-related problems with those products.  This information can be obtained from the applicant’s
own experience as well as from public sources such as literature, adverse event reports, and
product safety communications.

15 See CFR 314.126.
16 The term Major Clinical Study is consistent with other terms such as “phase-3 clinical study,” “key clinical
study,” and “pivotal studies or trials.”
17 For more information on FMEA, FTA and other risk analysis methods, see Guidance for Industry and FDA Staff,
Applying Human Factors and Usability Engineering to Optimize Medical Device Design, accessible at
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationsandGuidance/Guidancedocuments/UCM259760.
pdf.

Contains Nonbinding Recommendations

1.

Critical Tasks

The use-related risk analysis should identify critical tasks.18  Critical tasks are user tasks that, if
performed incorrectly or not performed at all, would or could cause harm to the patient or user,
where harm is defined to include compromised medical care.  Thus, categorizing a task as
critical is dependent on the unique considerations for each combination product.  The Agency
expects the risk analysis for the combination product to include an identification of all the critical
tasks required for using the combination product, the consequences for failing to perform each
critical task correctly, and the strategies that have been applied in the design of the user interface
to eliminate or reduce risks to acceptable levels.  Such an assessment should include
considerations of the indication, the users, the environment and other conditions that might
influence the importance of a particular task. Some examples of critical tasks to illustrate this
concept include:

•  The patient being able to successfully self-administer a drug at the prescribed dose

identified in the labeling.  Failure to successfully perform this task could harm the patient
due to mis-dosing, under-dosing, overdosing, or inability to deliver a dose.

•  The user being able to safely dispose of a used syringe.  Failure to successfully perform

this task could result in needle sticks.

•  The patient being able to appropriately navigate the user interface for a patient-controlled
analgesia (PCA) delivery system.  Failure to successfully perform this task could result in
missed doses, inappropriate repeat doses, or overdoses.

•  The user being able to understand instructions for inserting a capsule into an inhaler to

release the drug, and being able to insert the capsule.  Failure to successfully perform this
task could result in the patient swallowing the capsule instead of inhaling the contents,
lack of treatment effect, or medication related adverse events.

•  The user being able to distinguish a product from others of similar appearance.  Failure to

successfully perform this task could result in delivery of the wrong drug.

•  The user being able to complete a series of several critical tasks required to prepare and
administer a reconstituted drug from a combination product kit containing a prefilled
diluent syringe, drug vial, empty syringe, needle, transfer device and infusion pump.
These tasks could include preparing the drug under sterile conditions, connecting the
system, and introducing the reconstituted drug solution into an infusion pump.  Failure to
successfully complete any of these tasks could result in medication errors and/or use-
related infection.

## Appendix A: identifies task failures that may occur with general categories of combination

products such as injectors and inhalers.  The information can be used to guide the applicant when
conducting a risk analysis, which is recommended for any combination product being developed.
Additionally, these task failure examples may apply to other types of combination products, and
can be used as a reference to help identify and evaluate hazards for other combination products.

18 For additional information on critical tasks, see Sections 7.3 and 7.4 of Applying Human Factors and Usability
Engineering to Optimize Medical Device Design at
http://www.fda.gov/RegulatoryInformation/Guidances/ucm259748.htm.

Contains Nonbinding Recommendations

2.

Intended Users and Use Environments

Prior to performing a risk analysis, it is important to identify all intended users and use
environments for the combination product.  Intended users may be categorized into distinct user
groups by their different characteristics (e.g., use responsibilities, tasks performed, age ranges,
skills, or experience levels).  For combination products, distinct user groups generally are health
care professionals (HCPs) and lay users (non-health care professionals).  Within these two
groups there are likely further subgroups based on different tasks, roles, abilities and education.
Subgroups of the HCP user population can include those with significantly different roles (e.g.,
nurses, pharmacists, physicians, emergency medical technicians, home health care providers).
Also, within the HCP user population there may be individuals that have experience with the use
of similar products and individuals that do not (e.g., injector-experienced vs nave) or that do or
do not have experience with similar appearing products with different instructions for use or
different hazards.  In addition, both the professional role and experience of HCPs can influence
interactions with a product.  These various differences may justify treating HCPs as distinct user
groups that should be evaluated in the HF study as such.

Lay users (non-health care professionals) are those who use the product for self-administration
(the patient) or those who administer the product to others as a caregiver (e.g., a family member,
sports coach).  Within this population, experience of individual users with similar products or
products under development may vary widely.  For example, when considering a drug-
autoinjector combination product, some lay users may be nave to the use of any autoinjector or
may be nave to the use of certain types of autoinjectors; e.g., those for single dose disposable
versus single patient reusable products.  Also, lay users may have experience with a different
product that might influence their interaction.  As a result of these differences, there may be
distinct subgroups that should be considered in the use-related risk analysis.  As applicable, the
HF study should incorporate separate subgroups of lay users.

Environments of use can have diverse characteristics that affect the users’ interactions with the
product.  Thus, the intended environment of use is another important consideration in designing a
HF study.  Combination products may be used in various professional health care / clinical
settings that include emergency departments, intensive care units, inpatient bedsides, procedure
suites, outpatient clinics, mobile units, and stocking and storage locations.  Likewise, they can
also be used in non-clinical settings including homes, schools, offices, and various modes of
transportation (e.g., ambulances, airplanes).  These environments may vary with respect to
temperature, lighting and noise levels, ambient activity levels, number of people in the vicinity,
and the availability of associated/accessory medication or devices.  Also, a combination product
that is intended for home use may be confused with other family member or pet medications
stored in the same location.  Such environmental conditions may lead to use errors.  These
environmental factors should be considered in the use-related risk analysis, and included within
the design of the HF study as appropriate when they present a use hazard.

3.

Training

Training is often proposed as a way to mitigate or control risks.  However, before determining if
training is appropriate for the combination product, first it is important to eliminate risks that are
inherent to the product design.  If there are residual risks, the next step is to determine if training

Contains Nonbinding Recommendations

is needed.  For example, for a new product that is developed as similar to or an alternative to a
currently marketed product with use techniques that are well understood by the users, then
training may not be necessary.  Such an example might be a prefilled syringe with a staked
needle for use by a health care professional.  On the other hand, if there are residual risks for
which training may be appropriate, the next step is to consider whether there is an opportunity
for training, and if so, whether there is an expectation that training will routinely and consistently
occur, before the first use of the combination product.  In cases where training would be
appropriate but is not expected to routinely or consistently occur, the HF study should evaluate
the user interface in the absence of training.19

For combination products when training is expected or needed to control or mitigate residual
use-related hazards, it is important to determine what the training is likely to encompass and how
it will be performed, who is responsible for conducting the training, and how to ensure
consistency in the training method.  Consider, for example, a combination product being
developed for a hospital-based surgical procedure.  A risk analysis might determine that HCP
training is required prior to the first use of the product to minimize the risk of errors related to
assembling all the combination product constituent parts, preparing the treatment area and the
surgical device constituent part before beginning the procedure, administering the drug
constituent part(s), monitoring patient responses after using the product, and/or managing
interactions across multiple users during the procedure.  Due to the nature of the product and its
use environment, all users would be expected to receive training before using the product.   The
HF study would evaluate the adequacy of the training in minimizing these potential risks.  In this
case, it is likely that FDA would not expect the HF study to evaluate the absence of training.

In addition, when considering training to mitigate residual risks associated with the user
interface, it is important to consider how frequently the training will occur, as well as the length
of time between the training session(s) and product use.  For some combination products,
training and first product use is separated by days, weeks, or months.  As such, a significant
amount of time may elapse between the training session and product use.  Retention of
information from the first, and possibly the only, training a user receives can decrease over time
(i.e., training decay).  For example, for a combination product designed for once a week self-
injection, post-training information retention one week later can be anticipated to be lower than it
would one hour later.  If the risk analysis shows that training decay is a source of use-related
error, then the HF study design should evaluate the effect of training decay.  The HF Validation
study should simulate the effect training decay may have on the users; e.g., simulate the training
decay by separating the training and simulated use testing by several hours or days.  The protocol
should justify the interval to simulate the training decay.

C.

Human Factors Formative Studies

HF Formative studies are designed to evaluate early combination product prototypes, taking into
consideration the identified use-related hazards.  HF Formative study results guide prototype
design changes to eliminate or mitigate use-related hazards identified during the product
development process.  The use of iterative HF Formative studies optimizes the design of the

19 As appropriate, if user training is necessary, applicants should discuss what methods are appropriate to ensure the
provision of training.

Contains Nonbinding Recommendations

combination product user interface for safety, and minimizes the risk of first discovering use
problems during late stages of development (e.g., during an HF Validation study, during a major
clinical study, or after finalizing commercial plans.).

Iterative HF Formative studies and related design modifications are performed until the user
interface design appears to be sufficiently optimized for safety and ready for HF Validation
testing.  Iterative modifications to the user interface may include changes to the physical design
attributes, changes to the packaging and labeling (including instructions for use) and changes to a
training program.  The results of HF Formative studies should inform the design of the final
finished combination product.  None of the individual subjects in the HF Formative studies
should participate in the HF Validation studies to avoid the potential for bias.  For information
on HF Knowledge Task studies, see Section III.E; for information on HF Validation studies, see
Section III.D below.

D.

Human Factors Validation Studies

HF Validation studies demonstrate that the final finished combination product user interface
would maximize the likelihood that the product will be safely and effectively used by intended
users, for the intended uses in the intended use environments.  There are two types of HF
Validation studies: HF Simulated-Use and HF Actual-Use Validation.  For most combination
products, FDA expects that a HF Simulated-Use Validation study will be sufficient to assess the
adequacy of the user interface.

1.

Human Factors Simulated-Use Validation Studies

The HF Simulated-Use Validation study focuses on confirming that the design of the
final finished combination product (i.e., after iterative prototype design changes) user
interface adequately mitigates or eliminates the identified use-related risks.  Simulation
methods for these studies vary and may include the use of a manikin, injection pads,
placebo, and other elements intended to simulate the patient, the procedure, or the
environment of use.

The conditions of the HF Simulated-Use Validation study should be sufficiently realistic
so that the results HF-Simulated-Use Validation represent relevant aspects of actual use
of the product once introduced into the market.  Tasks to be performed in the HF
Simulated-Use Validation study should include those critical tasks identified in a use-
related risk analysis that may be associated with user interface problems.  The study
design should provide for the identification of any unanticipated hazards or unexpected
use behaviors that were not previously identified.

2.

Human Factors Actual-Use Validation Studies

As noted above, FDA expects that for most combination products, a HF Simulated-Use
Validation study will be sufficient to assess the adequacy of the user interface design.
However, there are rare circumstances when it is difficult to simulate the conditions of
use, physical characteristics of the product, or environment of use.  Thus, a HF Actual-
Use Validation study may be needed to confirm the adequacy of the user interface design.

Contains Nonbinding Recommendations

HF Actual-Use Validation studies either (1) use the final finished combination product
(including the drug, not a placebo) in a simulated use setting or (2) use the final finished
combination product in a real (not simulated) environment of use.

•  A HF Actual-Use Validation study of the combination product that includes the
actual drug in a simulated use setting may be necessary when the drug can affect
the user’s ability to perform a critical task.  For example, for a drug that causes
coughing on inhalation which could result in incomplete dosing, inhaler designs
to minimize the risk of not completing an inhalation could not be evaluated
without use of the actual drug.  This type of assessment using the drug-device
combination product would otherwise occur in a simulated-use setting.

•  The other type of HF Actual-Use Validation study in a real environment of use.
For example, based on the hazard analysis and results of an HF Simulated-Use
Validation, it may be appropriate to evaluate in a real environment of use use-
related risks associated with a complex combination product intended for use in
crisis/emergency settings or with a combination product that has a complex
operating procedure.  In these instances, the user’s tasks could be influenced by
the presence of noise, rapidly changing circumstances, distractions, etc.
Therefore, the need for a HF Actual-Use Validation study is determined on a
case-by-case basis.  FDA recommends that applicants for combination products
discuss with FDA the availability of simulation techniques and whether HF
Simulated-Use Validation and HF Actual-Use Validation studies are needed to
evaluate the user interface.20

Regardless of the type of HF Validation study, if use errors or problems (e.g., failures, “close
calls,” use difficulties, and/or new findings) are identified in an HF Validation study, these
should be evaluated to (1) identify the root cause(s), (2) determine the potential for harm
(including the clinical significance of such errors or problems and the potential for compromised
medical treatment), and (3) determine whether additional measures to eliminate or mitigate
hazards are necessary.  Regardless of the type of HF Validation study, if the HF Validation study
shows that additional measures are necessary to address the risk of failures that are deemed
clinically significant, then the HF Validation study will be considered failed.  Changes to the
user interface may be needed to eliminate or mitigate hazards and a new HF Validation study
should be performed to evaluate the changes, with the goal of demonstrating that the
modifications minimize the risk to acceptable levels without creating additional hazards.

Also, if the product design changes or the user population changes, then the completed HF
Validation study may or may not be applicable to the design change.  A use-related risk analysis
should be completed and, dependent upon the findings of the risk analysis, a new HF Validation
study may be advisable to support that the modifications continue to minimize the risk without

20 The term “HF Actual-Use Validation study” has a different meaning than similar terms such as “user study” or
“actual use study”.  The term “HF Actual-Use Validation study” applies to only the evaluation of the user interface
and associated critical tasks.  In contrast, the terms “actual use” or “user study” (without the “HF” qualifier) often
refer to clinical studies such as a major clinical study to evaluate safety and effectiveness of prolonged home use or
to an open label safety study.  Those studies have different purposes or mixed purposes and are outside the scope of
this document.  FDA recommends against referring to these different or mixed purpose studies as HF studies.

Contains Nonbinding Recommendations

creating additional hazards.  If the product design remains unchanged but the applicant seeks to
add a new user population, then as applicable, a new use-related risk analysis and new HF
Validation study should be performed.  See Section V for the relationship of the HF Validation
study to the major clinical study.

E.

Human Factors Knowledge Task Studies

In situations when the understanding of the information provided in a combination product’s
labels or labeling is a critical task to using a product safely and effectively, a study to assess the
user’s understanding of such information (Knowledge Task study) is appropriate.  Knowledge
Task studies may occur as part of the HF formative, or HF validation process.  However, in
comparison to other types of HF studies in which critical task performance is assessed by
observing user interaction with the product, Knowledge Task studies focus on the understanding
and interpretation of important information in the user interface that will be applied to make use-
related decisions.  The users’ understanding of the labeling is evaluated by questioning test
participants and assessing whether the information has been understood.

Knowledge Task studies may focus on particular aspects of labeling.  For example, a Knowledge
Task study could evaluate:

•  HCP’s understanding of their roles and responsibilities when introducing a

combination product as part of a new procedure, or associated with complex
medical/surgical procedures that involve many different HCPs;

•  The user’s ability to select the appropriate task from a lengthy set of instructions

that include different options;

•  The user’s understanding of how to identify defective or expired product;
•  The user’s awareness and understanding of the combination product’s pertinent

safety information provided in the instructions for use;

•  The user’s ability to recognize clinical signs, identified in the instructions for use,
that would prompt medical attention; e.g., shortness of breath, allergic reaction,
weakness, signs of disease progression; or

•  The user’s understanding of the diagrams provided in the labeling.

Certain types of Knowledge Task studies are also used in the development of non-prescription
products.21  Generally, these are quantitative studies that evaluate whether results are statistically
significant.

IV.  PROCESS CONSIDERATIONS

A.

Considerations for Submission of Combination Product Human Factors
Study Data

For the following two groups of combination products, generally human factors data should be
submitted:  (1) products for use outside the health care environment or by laypersons (e.g.,

21 For further information about such studies for non-prescription drug products, see Guidance to Industry Label
Comprehension Studies for Nonprescription Drug Products, accessible at
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm143834.pdf.

Contains Nonbinding Recommendations

home-use products, products for self-administration by patients or lay-caregivers) and (2)
combination products having a device constituent part for which human factors data should be
submitted.  For combination products that do not fall within these two categories, a risk analysis
for the combination product should be completed and the use-related risks reviewed to assess the
need for HF studies (see section III.B).  If the use-related risk analysis identifies the need for HF
studies, then a HF Validation study should be conducted and the results submitted for review.
For example, a syringe is not on the list of high priority devices for human factors review, and
the following illustrates certain considerations for when a HF Validation study may be needed
for a prefilled syringe.

•  A prefilled syringe with a staked needle and needle guard for use by HCPs in an acute

care setting:

o

o

If the syringe, needle and needle guard design is commonly used and well
understood (absent other use-related risk concerns for the combination product as
a whole), FDA would not expect a HF Validation study for such products.  During
the investigational phase when the applicant determines that a HF Validation
study may not be needed, the applicant should submit its risk analysis and
justification to support the basis of the applicant’s conclusion, and seek Agency
comment on the assessment.
If the syringe, needle and needle guard are of a unique/novel design, there are use
experience concerns with similar products, or there are other factors that increase
the use-related hazard, then an HF Validation study should be conducted.

•  The same prefilled syringe with needle guard for use by patients with neuromuscular

disorder or visual impairment:

o  Because the user characteristics and associated medical symptoms present unique
user profiles that may affect safe use of the product, an HF Validation study
should be conducted to demonstrate that the product design adequately mitigates
the risks for its intended use in these patients, and use environments.

•  The same prefilled syringe with needle guard and a unique application of color to

distinguish it from different drugs in similar prefilled syringes to help prevent medication
errors:

o  Even if factors such as indications for use, intended users, and use environment

remain unchanged, based on the use-related risk analysis, an HF Validation study
may be necessary to ensure that HCPs can readily distinguish the new syringe
from similar prefilled syringes containing different drugs.  As appropriate, such a
study might focus on knowledge-based tasks.

•  The same prefilled syringe with needle guard that is used with various tubing, connectors,

pumps and other device components in a high risk procedural setting:

o  A HF Validation study is likely necessary to assess the entire system.  As

applicable, the HF Validation study may include detailed assessments of the
instructions, diagrams, training or other aspects that might become part of a
postmarket safety program.

Contains Nonbinding Recommendations

Other scenarios and alternative approaches are possible.  As with all product development, FDA
encourages applicants to contact the Agency to discuss the specific product proposals.

B.

Considerations for Design Changes After HF Validation

FDA recognizes that combination product design changes may occur premarket or postmarket
after HF Validation studies have been completed.  For example, during premarket development
the results of a clinical trial may reveal design flaws that were not detected in HF Formative or
HF Validation studies.  Similarly, during postmarket development an applicant may plan a
design change to the marketed combination product, for example, to respond to use-related
safety reports, complaints/problems, to address a manufacturer-initiated postmarket corrective
and preventative action plan, or to meet the needs of an expanded indication or user population.

Some modifications to a product’s internal design or to some of its external features may not
need validation in a HF study (e.g., a change in a material that does not affect user interface).
However, design changes made after HF Validation that relate to identified critical tasks or may
result in new use-related errors or hazards that could lead to harm should have new HF
Validation study assessments.

When making design changes, the applicant should conduct an updated use-related risk
assessment of the new design.  FDA encourages applicants to follow the HF principles outlined
in this document.  Conceptually, this analysis should consider such things as:

•  Does the design change alter the user interface in any way (e.g., audible, tactile, color

recognition, user instructions, etc.)?

•  Does the design change alter an existing critical task or add a new critical task?
•  Does the design change alter the expected users or their knowledge base?

To facilitate discussion with FDA, the applicant should provide a proposal about what, if any,
additional HF testing is needed.  The proposal should include a detailed description of why the
change is being made, a description of what specifically is changing, a use-related risk analysis
of the new design, and where appropriate a proposal for evaluating potential risk mitigations of
the new design and the effects of the change.

When making a design change to a combination product, FDA encourages applicants to
expeditiously identify the change plans and to discuss with the Agency the types of HF and other
clinical or non-clinical studies that may be applicable before the applicant’s approval of the
design change.22  (Also, see Section IV.A for further information that may be useful in
considering the HF implications of a design change.)

C.

Review of Human Factors Information in Combination Product
Investigational Applications

The combination product’s specific use-related risk analysis generally informs the Agency’s
expectations for whether HF information on a combination product should be submitted in an

22 The use of other types (i.e., non-HF) of studies (e.g., clinical, pharmacokinetic, or non-clinical studies) to evaluate
combination product design changes is beyond the scope of this document.

Contains Nonbinding Recommendations

investigational application.  The risk analysis itself should be submitted in the investigational
application for the combination product.  If the applicant determines from the risk analysis that a
HF study is not needed, the applicant should provide the use-related risk analysis along with the
justification for this conclusion.  If the use-related risk analysis indicates that a HF study is
necessary, FDA encourages applicants to submit the following HF information for feedback
before commencing the HF Validation study:

•  Use-related risk analysis and any updated risk analysis of design changes;
•  A summary of HF Formative study results and analysis;
•  A summary of changes made to the product user interface after the HF Formative studies,
including how the results from the HF Formative studies were used to update the user
interface and use-related risk analysis;
•  The draft HF Validation study protocol; and
•

Intend-to-market labels and labeling (including instructions for use if any are proposed)
that will be tested in the HF Validation study.

When this information is submitted to the investigational application, FDA will review the
information, including the use-related risk analysis and the draft HF Validation study protocol,
and intends to provide comments or recommendations to increase the likelihood of an acceptable
HF study design that will adequately test for potential use failures.  Also, during Agency review
of draft HF Validation study protocols that include product labeling (e.g., instructions for use),
FDA intends to provide preliminary comments on the user interface labels and labeling being
However, final labeling is determined after review of the entire marketing application that
includes information beyond that in the HF Validation study.

D.

Review of HF Studies and Certain Labeling in Marketing Applications

As applicable, FDA will review HF Validation study results submitted in the marketing
application to assess whether the data confirm validation of the user interface and certain aspects
of the proposed labels and labeling (e.g., instructions for use).  FDA cautions applicants
leveraging a master file for HF data, that in some instances the master file data may suffice for
one constituent part alone, but not for the combination product as a whole (e.g., device with a
specific drug/biological product).  The applicant should determine whether sufficient information
would be available in the master file or whether the applicant should conduct and submit
additional HF studies for the combination product as a whole.

During FDA review of labeling23 in a marketing application, FDA may determine that the final
user interface labeling should differ from the HF Validated labeling.  This may occur, for
example, based on the results of the major clinical trial, other safety data or medication error
data, new nomenclature considerations, and labeling content and format requirements.  The
labeling assessment also considers current postmarket experience with the same or similar
products, which might indicate that modification of the instructions for use is appropriate to
mitigate a risk.  After review of the marketing application, depending on the potential impact of
resulting labeling differences on performance of critical tasks, an additional HF Validation study

23 Labeling review includes consideration of labeling claims that might be provided by a HF study (e.g., user
preference or ease of use) and whether the data support those claims.

Contains Nonbinding Recommendations

may be needed to ensure that the changes minimize the use-related risks without creating
additional hazards.

V.  RELATIONSHIP OF HUMAN FACTORS AND MAJOR CLINICAL STUDIES

OF THE COMBINATION PRODUCT

As explained in preceding sections of this document, HF studies of a combination product are
conducted as part of the product design controls process.  An appropriate HF development
program will maximize the likelihood that the combination product user interface is safe and
effective for use by the intended users, uses and use environments.  However, the HF Validation
study is not sufficient to establish the safety and effectiveness of the combination product for the
proposed indication.  Specifically, data from the major clinical study(ies) establish the
combination product’s safety and effectiveness for the proposed indication and the complete
labeling summarizes the essential scientific information needed for the safe and effective use of
the product.24

Therefore, ideally, before conducting the major clinical study(ies), the HF Validation study
should be conducted on the final finished combination product, including the user interface (e.g.,
instructions for use, training materials, and any other user labeling, if applicable).  The HF
Validated product would then be ready for further evaluation in the major clinical study(ies) that
will be submitted in the marketing application.  Noting that in some cases it may be appropriate
to conduct your human factors studies in parallel to your major clinical studies or after your
clinical studies to address modifications to your product.

FDA recognizes that in some circumstances the data to support safety and efficacy of the
combination product may adequate without the inclusion of the final finished combination in a
major clinical trial.  For certain products, the sequencing of the HF study prior to the clinical
study may be less critical to inform our understanding of the product’s safety and efficacy,
allowing for greater flexibility in the timing of the human factors validation study relative to a
major clinical studies.  In other cases, a sponsor may encounter a need to change the combination
product design in the course of the development program, even after clinical studies have been
completed.  The type and extent of data to support such changes depend on the nature of change,
development stage, and other contextual factors, and FDA would consider the totality of the data
provided to support the approvability of the combination product in any such circumstances.
However, for certain combination products, we might expect or encourage you to use the final
finished combination product in your major clinical studies.  In such cases, we recommend that
you conduct the HF-Validation study on the final finished combination product prior to the major
clinical studies.

And, in all cases, we encourage you to discuss your combination product development plans with
the Agency as appropriate and consider such discussion as a component of your development
meeting, including the pre-IND, IDE and EOP2 meetings

24 See 21CFR 201.56(a)(1).

Contains Nonbinding Recommendations

VI.  HOW TO OBTAIN ADDITIONAL INFORMATION

FDA encourages applicants to request early discussions with FDA regarding their HF program
and the type of HF studies that might be appropriate or necessary in the planned submission.
Additionally, if applicants anticipate design changes during product development before launch,
FDA strongly encourages meetings during the early planning stages.  Discussion topics might
include how to add a new configuration to the development plan and/or how to bridge to existing
data.  Such discussions should provide clarity on the applicant’s development plan and provide
transparency on FDA recommendations and expectations on HF studies and sequence of the
development program.  Where appropriate, the applicant may request focused meetings for more
detailed discussions.  For a combination product, applicants should submit meeting requests to
the lead center using the process and procedures of the lead center.  The meeting request should
indicate that the discussion is for a combination product and request participation of all relevant
centers and Office of Combination Products as appropriate.  Additional information on
requesting meetings is provided in the last two guidance documents listed below.

The following FDA documents may be useful:

•  Guidance for Industry and FDA Staff – Applying Human Factors and Usability

Engineering to Optimize Medical Device Design;
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument
s/ucm259748.htm

•  Draft Guidance for Industry – Safety Considerations for Product Design to Minimize

Medication Errors;
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM331810.pdf

•  Draft Guidance for Industry – Safety Considerations for Container Labels and Carton

Labeling Design to Minimize Medication Errors;
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm349009.pdf

•  Guidance for Industry – Label Comprehension Studies for Nonprescription Drug

Products;
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm143834.pdf

•  Draft Guidance for Industry – Format and Content of Proposed Risk Evaluation and

Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications;
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm184128.pdf

•  Guidance for Industry – Formal Meetings Between FDA and Sponsors or Applicants;

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc
es/ucm153222.pdf

•  Guidance for Industry and FDA Staff – Requests for Feedback on Medical Device
Submissions: The Pre-Submission Program and Meetings with Food and Drug
Administration Staff;
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedo
cuments/ucm311176.pdf

Contains Nonbinding Recommendations

## APPENDIX A: USER TASK FAILURE EXAMPLES

Table 1 and Table 2 below provide examples of some user task failures that typically apply to
injection and inhalation combination products.  Table 1 applies to combination products with
injectors (e.g., pen injectors, autoinjectors, prefilled syringes), and Table 2 applies to
combination products with certain inhalation systems (e.g., nebulizers and inhalers).

In addition to the examples in these tables, there may be knowledge tasks that require user
understanding of information that is not typically or easily evaluated through observation of
simulated use.  Knowledge tasks are derived from the product labeling (including user manual,
Medication Guide, labels on the device itself) and training package.

The tables do not present comprehensive all-inclusive lists.  If the combination product requires
users to perform tasks not contained in the tables that could result in harm if not performed
correctly, then those tasks should be included in the HF Validation study.  Also, depending upon
the product design, only certain tasks may be applicable to a specific combination product.   The
critical tasks may change depending on the indications, use environments, user populations that
have unique or novel risks, and other characteristics and features of the combination product.
Therefore, a use-related risk analysis should be performed before identifying tasks for evaluation
in a HF Validation study.  Once identified, those tasks should be used to construct the HF
Validation study.

(Intentionally blank)

Contains Nonbinding Recommendations

Table 1: Examples of Critical Tasks for Combination Products that Deliver Dose by Injection

User Task

Possible Task Failures and Use Errors

Understand how to dose
the product

•  Misunderstanding dosing instructions
•  Not aware of dosing instructions

Understand how to
administer the product

•

Improper technique while interacting
with the product during dosing

•  Cannot complete injection

Product differentiation
Open packaging

Evaluate device and drug
prior to dosing

Prepare injection site
Prepare/mix the dose for
injection

•  Select incorrect product
•  Damage to device
•  Loss of instructions or components
•

Inability to open package

•  Failure to check injector window for

drug condition

•  Expired or adulterated drug used
•  Use device that is not functional for

dose delivery

•  Use damaged needle
•  Not cleaning/disinfecting injection site
•  Mix or Measure the product incorrectly
•  Wrong drug amount drawn into the

syringe

Prime injector/syringe
for injection.
Select injection site

•  Not priming at all or priming

incorrectly
Identify incorrect injection site

•

Remove syringe needle
cover
Attach needle

•  Do not remove needle cover or injector

cap

•  Do not attach needle

Remove injector cap

•  Do not remove injector cap

Hold injector/syringe in
correct orientation

•  Hold injector/syringe incorrectly
•

Inject upside down

Depress syringe plunger/
activate autoinjector
(press injection button)
Hold syringe or injector
at injection site

•  Unable to depress the plunger
•  Unable to activate injector fully
•  Unable to determine if dose delivered
•  Premature removal of syringe/injector
•  Wet injection (drug solution on surface

Verify dose delivery

•  Not verifying complete dose delivery

of injection site)

Dispose/clean/store
syringe/injector

•
Improper disposal/storage
•
Inject degraded product
•  Do not clean reusable device

Possible Hazard / Harm Resulting
from Failures/Use Errors
•  Overdosing
•  Under dosing
•  Missed dose
•  Overdosing
•  Under dosing
•  Missed dose
•  Needlestick injury
•  Accidental exposure to others
•  Wrong drug delivered
•  Delay of therapy
•  Missed dose
•  Over or under dosing
•  User injury
•  Painful injection
•  Reduced drug efficacy
•  Delay of therapy
•  Missed dose
•
Infection

Infection

Inaccurate dosing

•
•  Reduced drug efficacy
•  Under dosing
•  Overdosing
•
•  Under dosing
•  Painful injection
•  Lack of drug efficacy
•  Local or systemic adverse events
•  Missed dose
•  Delay of therapy
•  Missed dose
•  Delay of therapy
•  Missed dose
•  Delay of therapy
•  Needle stick injuries
•  Delay of therapy
•  Reduced drug efficacy
•  No dose
•  Under dosing

•  Under dosing
•  Missed dose

•  Under dosing
•  Missed dose
•  Needle stick injuries
•  Contamination /transmission of

disease (infection)
•  Reduced drug efficacy
•  Delay of therapy
•  Drug diversion
•  Exposure of non-users

Contains Nonbinding Recommendations

Table 2: Examples of Critical Tasks for Combination Products that Deliver Dose by Inhalation

User Task

Possible Task Failures and Use Errors

Understand how to
administer the product

Understand how
the product

to dose

Open packaging

Assemble product

Evaluate device and drug
prior to dosing

Set up dose; prime
product

Use device to deliver
dose

Waiting a specific
amount of time between
doses for multiple breath
dosing
Disassemble, maintain,
store, and clean reusable
device components

Dispose of device as per
instructions.

•

•

•
•

•
•
•

•
•

•
•

•
•
•

•
•

Improper technique while using the
product during dosing
Cannot complete inhalation

Misunderstanding dosing instructions
Not aware of dosing instructions

Damage to device
Loss of instructions or components
Inability to open package

Assembled incorrectly
Unable to assemble

Expired or adulterated drug used
Use device that is not functional for dose
delivery
Use damaged product
Not preparing dose for inhalation
Not priming at all or priming incorrectly

Improper inhalation technique
Improper seal of mouth on mouthpiece

•  Not waiting long enough between doses

Possible Hazard / Harm Resulting
from Failures/Use Errors
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•

Overdosing
Under dose
Missed dose
Accidental exposure to others
Overdosing
Under dosing
Missed dose
Delay of therapy
Missed dose
Wrong dose
User injury
Choking on device components
Delay of therapy
Missed dose or dosing error
Reduced drug efficacy
Delay of therapy
Missed dose or dosing error

•
•

•
•

•
•
•
•

Under dosing or overdosing
Choking on dose capsule (if
present)
Missed dose
Under dosing  or over-dosing

Missed dose  or dosing error
Coughing
Under dose
Lack of efficacy

•  Failing to clean or maintain.
•  Storing at wrong temperature or under

other incorrect conditions

•  Failing to properly dispose of device

•  Delay of therapy
•  Under dosing or overdosing
•
•
•
•

Infection
Reduced drug efficacy
Diversion of drug
Exposure to non-users

---

### Document: FDA ContainerClosure Complete (FDA)

# FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics — CMC Documentation (1999)

Guidance for Industry
Container Closure Systems for Packaging
Human Drugs and Biologics
CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 1999
Guidance for Industry
Container Closure Systems for Packaging
Human Drugs and Biologics
CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
Additional copies are available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
Center for Drug Evaluation and Research (CDER)
5600 Fishers Lane
Rockville, Maryland  20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
or
Office of Communications
Training and Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research (CBER)
1401 Rockville Pike
Rockville, Maryland  20852-1448
(Fax) 888-CBERFAX or 301-827-3844
(Voice Information) 800-835-4709 or 301-827-1800
(Internet) http://www.fda.gov/cber/guidelines.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
May 1999
Table of Contents
I.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II.
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
A.
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
B.
CGMP, CPSC and USP Requirements on Containers and Closures . . . . . . . . . . . 3
C.
Additional Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
III.
QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS . 5
A.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
B.
General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
C.
Information That Should Be Submitted in Support of an Original
Application for Any Drug Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
D.
Inhalation Drug Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
E.
Drug Products for Injection and Ophthalmic Drug Products . . . . . . . . . . . . . . . 23
F.
Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems . . 27
G.
Solid Oral Dosage Forms and Powders for Reconstitution . . . . . . . . . . . . . . . . 33
H.
Other Dosage Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
IV.
POSTAPPROVAL PACKAGING CHANGES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
V.
TYPE III DRUG MASTER FILES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
A.
General Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
B.
Information in a Type III DMF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
VI.
BULK CONTAINERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
A.
Containers for Bulk Drug Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
B.
Containers for Bulk Drug Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
ATTACHMENT A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  A-1
REGULATORY REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  A-1
ATTACHMENT B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  B-1
COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING . . . . . . . . . .  B-1
ATTACHMENT C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  C-1
EXTRACTION STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  C-1
ATTACHMENT D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  D-1
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  D-1
ATTACHMENT E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  E-1
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  E-1
 This guidance has been prepared by the Packaging Technical Committee of the Chemistry, Manufacturing, and
Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) and in
conjunction with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.  This
guidance document represents the Agency's current thinking on container closure systems for the packaging of human
drugs and biological products.  It does not create or confer any rights for or on any person and does not operate to bind
FDA or the public.  An alternative approach may be used if such approach satisfies the requirements of the applicable
statute, regulations, or both.
 In general, this guidance does not suggest specific test methods and acceptance criteria (except for references to The
United States Pharmacopia methods), nor does it suggest comprehensive lists of tests.  These details should be
determined based on good scientific principles for each specific container closure system for particular drug product
formulations, dosage forms, and routes of administration.  Acceptance criteria should be based on actual data for
particular packaging components and container closure systems, and they should be set to ensure batch-to-batch
uniformity of packaging components.
 As used in this guidance, the terms drug and drug product include biologics unless otherwise noted.
 The policy statement is a document titled Container/Closure Information Which Should Be Provided In An
ANDA/AADA which was written by the Office of Generic Drugs/Packaging Advisory Group.
GUIDANCE FOR INDUSTRY1
CONTAINER CLOSURE SYSTEMS FOR PACKAGING
HUMAN DRUGS AND BIOLOGICS
CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
I.
INTRODUCTION
This document is intended to provide guidance on general principles  for submitting information
on packaging materials used for human drugs and biologics.   This guidance supersedes the FDA
Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics, issued
in February 1987 and the packaging policy statement issued in a letter to industry dated June 30,
1995 from the Office of Generic Drugs.   This guidance is not intended to describe the
information that should be provided about packaging operations associated with drug product
manufacture.
Approaches which differ from those described in this guidance may be followed, but the applicant
is encouraged to discuss significant variations in advance with the appropriate CDER chemistry
review staff or CBER review staff.  This is to prevent applicants or sponsors from spending
unnecessary time and effort in preparing a submission that the FDA may later determine to be
unacceptable.
 These definitions are intended to clarify the use of certain terms in this guidance only and are not intended to supersede
the definitions of container and package as provided for in 21 CFR 600.3.
 This term is used in a general sense for the basic material, which should be defined in the application in terms of its
specific chemical composition for a given drug application (e.g., the specific polymer and any additives used to make the
material).
II.
BACKGROUND
The Federal Food, Drug, and Cosmetic Act (the Act) mandates the need for adequate information
related to packaging materials.  Section 501(a)(3) of the Act states that a drug is deemed to be
adulterated "if its container is composed, in whole or in part, of any poisonous or deleterious
substance which may render the contents injurious to health...."  In addition, section 502 of the
Act states that a drug is considered misbranded if there are packaging omissions.  Also, section
505 of the Act requires a full description of the methods used in, and the facilities and controls
used for, the packaging of drugs (see Attachment A).
Section 505(b)(1)(D) of the Act states that an application shall include a full description of the
methods used in, the manufacturing, processing and packing of such drug.  This includes facilities
and controls used in the packaging a drug product.
A.
Definitions5
Materials of construction  refer to the substances (e.g., glass, high density polyethylene
(HDPE) resin, metal) used to manufacture a packaging component.
A packaging component means any single part of a container closure system.  Typical
components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube
liners), closures (e.g., screw caps, stoppers), closure liners, stopper overseals, container
inner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps,
administration accessories, and container labels.  A primary packaging component means
a packaging component that is or may be in direct contact with the dosage form.  A
secondary packaging component means a packaging component that is not and will not be
in direct contact with the dosage form.
A container closure system refers to the sum of packaging components that together
contain and protect the dosage form.  This includes primary packaging components and
secondary packaging components, if the latter are intended to provide additional
protection to the drug product.  A packaging system is equivalent to a container closure
system.
 The materials of construction used in the labeling are a concern from a packaging perspective if they affect the
protection and/or safety of the drug product.
A package or market package  refers to the container closure system and labeling,
associated components (e.g., dosing cups, droppers, spoons), and external packaging
(e.g., cartons or shrink wrap).  A market package is the article provided to a pharmacist or
retail customer upon purchase and does not include packaging used solely for the purpose
of shipping such articles.
Quality refers to the physical, chemical, microbiological, biological, bioavailability, and
stability attributes that a drug product should maintain if it is to be deemed suitable for
therapeutic or diagnostic use.  In this guidance, the term is also understood to convey the
properties of safety, identity, strength, quality, and purity (see 21 CFR 211.94(a)).
An extraction profile refers to the analysis (usually by chromatographic means) of extracts
obtained from a packaging component.  A quantitative extraction profile is one in which
the amount of each detected substance is determined.
B.
CGMP, CPSC and USP Requirements on Containers and Closures
Current good manufacturing practice (CGMP) requirements for the control of drug
product containers and closures are included in 21 CFR Parts 210 and 211.  A listing of
the relevant sections is provided in Attachment A.  In addition, a listing of Compliance
Policy Guides that deal with packaging issues is provided in Attachment B.  References in
this guidance to CGMP regulations are provided for completeness.  For additional
information, refer to the FDA Compliance Program Guidance Manual for Pre-Approval
Inspections/Investigations (7346.832) which describes specific responsibilities for CDER
scientists and for field investigators.
The FDA requirement for tamper-resistant closures is included in 21 CFR 211.132 and the
Consumer Product Safety Commission (CPSC) requirements for child-resistant closures
are included in 16 CFR 1700.  An outline of these and other applicable regulatory
requirements is provided in Attachment A.
The United States Pharmacopeial Convention has established requirements for containers
which are described in many of the drug product monographs in The United States
Pharmacopeia/National Formulary (USP/NF).  For capsules and tablets, these
requirements generally relate to the design characteristics of the container (e.g., tight,
well-closed or light-resistant).  For injectable products, materials of construction are also
addressed (e.g., "Preserve in single-dose or in multiple-dose containers, preferably of Type
I glass, protected from light").  These requirements are defined in the "General Notices
and Requirements" (Preservation, Packaging, Storage, and Labeling) section of the USP.
The requirements for materials of construction are defined in the "General Chapters" of
the USP (see Attachment A).
C.
Additional Considerations
1.
Submissions of INDs
The packaging information in the chemistry, manufacturing, and controls section
of an IND usually includes a brief description of the components, the assembled
packaging system and any precautions needed to ensure the protection and
preservation of the drug substance and drug product during their use in the clinical
trials.
For general guidance regarding the container closure system information to be
submitted for phase 1 studies, refer to the FDA guidance for industry Content and
Format of investigational New Drug Applications(INDs) for Phase 1 Studies of
Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived
Products (November 1995).
General guidance regarding the container closure system information to be
submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for
industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified
Therapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, and
Controls Content and Format, when finalized (draft guidance published April 21,
1999).
2.
Submissions on Packaging of a Drug Product by Another Firm
a.
Contract Packager
A contract packager is a firm retained by the applicant to package a drug
product.  The applicant remains responsible for the quality of the drug
product during shipping, storage, and packaging.
The information regarding the container closure system used by a contract
packager that should be submitted in the CMC section of an application
(NDA, ANDA, or BLA), or in a DMF which is referenced in the
application, is no different from that which would be submitted if the
applicant performed its own packaging operations.  If the information is
provided in a DMF, then a copy of the letter of authorization (LOA) for
the DMF should be provided in the application (see section V.A).
 This discussion does not apply to the repackaging of drug products for dispensing under the practice of pharmacy.
 FDA Compliance Policy Guides, “Expiration Dating of Unit Repackaged Drugs,” 480.200, February 1, 1984, rev.
March 1995 (CPG 7132b.11).
 FDA Compliance Policy Guides, "Regulatory Action Regarding Approved New Drugs and Antibiotic Drug Products
Subjected to Additional Processing or Other Manipulation," 446.100, January 18, 1991 (CPG 7132c.06).
b.
Repackager8
A repackager is a firm that buys drug product from the drug product
manufacturer or distributor and repackages it for sale under a label
different from that of the manufacturer.  The repackager is responsible for
ensuring the quality and stability of the repackaged drug prpoduct.  The
repackaging operation is required to e in compliance with CGMPs (21 CFR
Part 211), and there are limits to the expiration period that may be used
with the repackaged product unless the repackager conducts stability
studies.   Packaging qualification information is not required if the
repackager uses the same container closure system approved in the original
application.
All significant phases of the manufacturing and processing of a drug
product (including packaging) should be described as part of the CMC
section of an application (NDA, ANDA or BLA), or in a DMF referenced
in the application.  The only exception is the repackaging of solid oral drug
products for which an approved application already exists.   For biologics,
repackaging is considered a step in the manufacturing process for which
licensing is required (21 CFR 600.3(u) and 601).
III.
QUALIFICATION AND QUALITY CONTROL OF PACKAGING
COMPONENTS
A.
Introduction
CDER and CBER approve a container closure system to be used in the packaging of a
human drug or biologic as part of the application (NDA, ANDA or BLA) for the drug or
biologic.  A packaging system found acceptable for one drug product is not automatically
assumed to be appropriate for another.  Each application should contain enough
information to show that each proposed container closure system and its components are
suitable for its intended use.
The type and extent of information that should be provided in an application will depend
on the dosage form and the route of administration.  For example, the kind of information
that should be provided about a packaging system for an injectable dosage form or a drug
product for inhalation is often more detailed than that which should be provided about a
packaging system for a solid oral dosage form.  More detailed information usually should
be provided for a liquid-based dosage form than for a powder or a solid, since a liquid-
based dosage form is more likely to interact with the packaging components.
Table 1 illustrates the correlation between the degree of concern regarding the route of
administration with the likelihood of packaging component-dosage form interactions for
different classes of drug products.
Table 1
Examples of Packaging Concerns for Common Classes of Drug Products
Degree of Concern
Likelihood of Packaging Component-Dosage Form Interaction
Associated with the
Route of
Administration
High
Medium
Low
Highest
Inhalation Aerosols
Sterile Powders and
and Solutions;
Powders for
Injections and
Injection; Inhalation
Injectable
Powders
Suspensionsa
High
Ophthalmic Solutions
and Suspensions;
Transdermal
Ointments and
Patches; Nasal
Aerosols and Sprays
Low
Topical Solutions and
Topical Powders;
Oral Tablets and Oral
Suspensions; Topical
Oral powders
(Hard and Soft
and Lingual Aerosols;
Gelatin) Capsules
Oral Solutions and
Suspensions
For the purposes of this table, the term suspension is used to mean a mixture of two
a
immiscible phases (e.g., solid in liquid or liquid in liquid).  As such, it encompasses a wide
variety of dosage forms such as creams, ointments, gels, and emulsions, as well as
suspensions in the pharmaceutical sense.
For the purpose of this guidance, container closure systems for the most common types of
dosage forms will be discussed in terms of five general categories:  Inhalation Drug
Products (section III.D); Drug Products for Injection and Ophthalmic Drug Products
(Section III.E); Liquid-based Oral and Topical Drug Products and Topical Delivery
Systems (section III.F); Solid Oral Dosage Forms and Powders for Reconstitution (section
III.G); and Other Dosage Forms (section III.H).
B.
General Considerations
Suitability refers to the tests and studies used and accepted for the initial qualification of a
component or a container closure system for its intended use.  Quality control (QC) refers
to the tests typically used and accepted to establish that, after the application is approved,
the components and the container closure system continue to possess the characteristics
established in the suitability studies.  The subsections on associated components and
secondary components describe the tests and studies for establishing suitability and quality
control for these types of components.  However, the ultimate proof of the suitability of
the container closure system and the packaging process is established by full shelf life
stability studies.
1.
Suitability for the Intended Use
Every proposed packaging system should be shown to be suitable for its intended
use:  it should adequately protect the dosage form; it should be compatible with
the dosage form; and it should be composed of materials that are considered safe
for use with the dosage form and the route of administration.  If the packaging
system has a performance feature in addition to containing the product, the
assembled container closure system should be shown to function properly.
Information intended to establish suitability may be generated by the applicant, by
the supplier of the material of construction or the component, or by a laboratory
under contract to either the applicant or the firm.  An adequately detailed
description of the tests, methods, acceptance criteria, reference standards, and
validation information for the studies should be provided.  The information may be
submitted directly in the application or indirectly by reference to a DMF.  If a
DMF is used, a letter authorizing reference (i.e., letter of authorization (LOA)) to
the DMF must be included in the application (see section V.A).
General issues concerning protection, compatibility, safety and performance of
packaging components and/or systems are discussed below.  In this guidance,
component functionality and drug delivery will also be addressed in connection
with specific dosage forms and routes of administration (see sections III.D, III.E,
III.F, III.G, and III.H).
a.
Protection
A container closure system should provide the dosage form with adequate
protection from factors (e.g., temperature, light) that can cause a
degradation in the quality of that dosage form over its shelf life.  Common
causes of such degradation are: exposure to light, loss of solvent, exposure
 For further information regarding photostability studies, see the FDA Guideline for the Photostability Testing of New
Drug Substances and Products (May 1997).
to reactive gases (e.g., oxygen), absorption of water vapor, and microbial
contamination.  A drug product can also suffer an unacceptable loss in
quality if it is contaminated by filth.
Not every drug product is susceptible to degradation by all of these factors.
Not all drug products are light sensitive.  Not all tablets are subject to loss
of quality due to absorption of moisture.  Sensitivity to oxygen is most
commonly found with liquid-based dosage forms.  Laboratory studies can
be used to determine which of these factors actually have an influence on a
particular drug product.
Light protection  is typically provided by an opaque or amber-colored
container or by an opaque secondary packaging component (e.g., cartons
or overwrap).  The USP test for light transmission (USP <661>) is an
accepted standard for evaluating the light transmission properties of a
container.  Situations exist in which solid and liquid-based oral drug
products have been exposed to light during storage because the opaque
secondary packaging component was removed, contrary to the approved
labeling and the USP monograph recommendation.  A firm, therefore, may
want to consider using additional or alternate measures to provide light
protection to these drug products when necessary.
Loss of solvent can occur through a permeable barrier (e.g., a polyethylene
container wall), through an inadequate seal, or through leakage.  Leaks can
develop through rough handling or from inadequate contact between the
container and the closure (e.g., due to the buildup of pressure during
storage).  Leaks can also occur in tubes due to a failure of the crimp seal.
Water vapor or reactive gases (e.g., oxygen) may penetrate a container
closure system either by passing through a permeable container surface
(e.g., the wall of a low density polyethylene (LDPE) bottle) or by diffusing
past a seal.  Plastic containers are susceptible to both routes.  Although
glass containers would seem to offer better protection, because glass is
relatively impermeable, glass containers are more effective only if there is a
good seal between the container and the closure.
Protection from microbial contamination is provided by maintaining
adequate container integrity after the packaging system has been sealed.
An adequate and validated procedure should be used for drug product
manufacture and packaging.
b.
Compatibility
Packaging components that are compatible with a dosage form will not
interact sufficiently to cause unacceptable changes in the quality of either
the dosage form or the packaging component.
Examples of interactions include loss of potency due to absorption or
adsorption of the active drug substance, or degradation of the active drug
substance induced by a chemical entity leached from a packaging
component; reduction in the concentration of an excipient due to
absorption, adsorption or leachable-induced degradation; precipitation;
changes in drug product pH; discoloration of either the dosage form or the
packaging component; or increase in brittleness of the packaging
component.
Some interactions between a packaging component and dosage form will
be detected during qualification studies on the container closure system and
its components.  Others may not show up except in the stability studies.
Therefore, any change noted during a stability study that may be
attributable to interaction between the dosage form and a packaging
component should be investigated and appropriate action taken, regardless
of whether the stability study is being conducted for an original application,
a supplemental application, or as fulfillment of a commitment to conduct
postapproval stability studies.
c.
Safety
Packaging components should be constructed of materials that will not
leach harmful or undesirable amounts of substances to which a patient will
be exposed when being treated with the drug product.  This consideration
is especially important for those packaging components which may be in
direct contact with the dosage form, but it is also applicable to any
component from which substances may migrate into the dosage form (e.g.,
an ink or adhesive).
Making the determination that a material of construction used in the
manufacture of a packaging component is safe for its intended use is not a
simple process, and a standardized approach has not been established.
There is, however, a body of experience which supports the use of certain
approaches that depend on the route of administration and the likelihood of
interactions between the component and the dosage form (see Table 1).
For a drug product such as an injection, inhalation, ophthalmic, or
transdermal, a comprehensive study is appropriate.  This involves two
 See Attachment C for discussion of extraction studies.
 FDA/CFSAN, Recommendations for Chemistry Data for Indirect Food Additive Petitions, Version 1.2, Chemistry
Review Branch, Office of Pre-Market Approval, June 1995.
parts:  first, an extraction study  on the packaging component to determine
which chemical species may migrate into the dosage form (and at what
concentration); and, second, a toxicological evaluation of those substances
which are extracted to determine the safe level of exposure via the label
specified route of administration.  This technique is used by the Center for
Food Safety and Applied Nutrition (CFSAN) to evaluate the safety of
substances that are proposed as indirect food additives (e.g., polymers or
additives that may be used in for packaging foods).13
The approach for toxicological evaluation of the safety of extractables
should be based on good scientific principles and take into account the
specific container closure system, drug product formulation, dosage form,
route of administration, and dose regimen (chronic or short-term dosing).
For many injectable and ophthalmic drug products (see sections III.E and
III.F), data from the USP Biological Reactivity Tests and USP Elastomeric
Closures for Injections tests will typically be considered sufficient evidence
of material safety.
For many solid and liquid oral drug products, an appropriate reference to
the indirect food additive regulations (21 CFR 174-186) promulgated by
CFSAN for the materials of construction used in the packaging component
will typically be considered sufficient.  Although these regulations do not
specifically apply to materials for packaging drug products, they include
purity criteria and limitations pertaining to the use of specific materials for
packaging foods that may be acceptable for the evaluation of drug product
packaging components.  Applicants are cautioned that this approach may
not be acceptable for liquid oral dosage forms intended for chronic use (see
section III.F.1).
For drug products that undergo clinical trials, the absence of adverse
reactions traceable to the packaging components is considered supporting
evidence of material safety.
Safety assessments for specific dosage forms are discussed further in
section III of this guidance.
d.
Performance
Performance of the container closure system refers to its ability to function
in the manner for which it was designed.  A container closure system is
often called upon to do more than simply contain the dosage form.  When
evaluating performance, two major considerations are container closure
system functionality and drug delivery.
i.
Container Closure System Functionality
The container closure system may be designed to improve patient
compliance (e.g., a cap that contains a counter), minimize waste
(e.g., a two-chamber vial or IV bag), improve ease of use (e.g., a
prefilled syringe), or have other functions.
ii.
Drug Delivery
Drug delivery refers to the ability of the packaging system to
deliver the dosage form in the amount or at the rate described in the
package insert.  Some examples of a packaging system for which
drug delivery aspects are relevant are a prefilled syringe, a
transdermal patch, a metered tube, a dropper or spray bottle, a dry
powder inhaler, and a metered dose inhaler.
Container closure system functionality and/or drug delivery are
compromised when the packaging system fails to operate as
designed.  Failure can result from misuse, faulty design,
manufacturing defect, improper assembly, or wear and tear during
use.  Tests and acceptance criteria regarding dosage form delivery
and container closure system functionality should be appropriate to
the particular dosage form, route of administration, and design
features.
e.
Summary
Table 2 summarizes typical packaging suitability considerations for
common classes of drug products.
Table 2
Typical Suitability Considerations for Common Classes of Drug Products
(This table is a general guide, and is not comprehensive.  See sections III.C through III.H for a
more detailed discussion.)
Route of
Administration/
Dosage Form
SUITABILITYa
Protection
Compatibility
Safety
Drug
Performance/
Delivery
Inhalation Aerosols and
Solutions, Nasal Sprays
L, S, M, W, G
Case 1c
Case 1s
Case 1d
Inhalation Powders
L, W, M
Case 3c
Case 5s
Case 1d
Injections, Injectable
Suspensionsb
L, S, M, G
Case 1c
Case 2s
Case 2d
Sterile Powders and
Powders for Injection
L, M, W
Case 2c
Case 2s
Case 2d
Ophthalmic Solutions
and Suspensions
L, S, M, G
Case 1c
Case 2s
Case 2d
Topical Delivery
Systems
L, S
Case 1c
Case 3s
Case 1d
Topical Solutions and
Suspensions, and
Topical and Lingual
Aerosols
L, S, M
Case 1c
Case 3s
Case 2d
Topical Powders
L, M, W
Case 3c
Case 4s
Case 3d
Oral Solutions and
Suspensions
L, S, M
Case 1c
Case 3s
Case 2d
Oral Powders
L, W
Case 2c
Case 3s
Case 3d
Oral Tablets and Oral
(Hard and Soft Gelatin)
L, W
Case 3c
Case 4s
Case 3d
Capsules
If there is a special performance function built into the drug product (e.g., counter cap), it
a
is of importance for any dosage form/route of administration to show that the container
closure system performs that function properly.
For definition of the term suspension, see footnote a to Table 1.
b
Explanation of Codes in Table 2:
Protection:
L (protects from light, if appropriate)
S (protects from solvent loss/leakage)
M (protects sterile products or those with microbial limits from
microbial contamination)
W (protects from water vapor, if appropriate)
G (protects from reactive gases, if appropriate)
Compatibility:
Case 1c:  Liquid-based dosage form that conceivably could interact with its
container closure system components (see examples described in section
III.B.1).
Case 2c:  Solid dosage form until reconstituted; greatest chance
for interacting with its container closure system components
occurs after it is reconstituted.
Case 3c:  Solid dosage form with low likelihood of interacting
with its container closure system components.
Safety:
Case 1s:  Typically provided are USP Biological Reactivity Test
data, extraction/toxicological evaluation, limits on extractables,
and batch-to-batch monitoring of extractables.
Case 2s:  Typically provided are USP Biological Reactivity Test
data and possibly extraction/toxicological evaluation.
Case 3s:  Typically, an appropriate reference to the indirect food
additive regulations is sufficient for drug products with aqueous-
based solvents.  Drug products with non-aqueous based solvent
systems or aqueous based systems containing co-solvents
generally require additional suitability information (see section
III.F).
Case 4s:  Typically, an appropriate reference to the indirect food
additive regulations is sufficient.
Case 5s:  Typically, an appropriate reference to the indirect food
additive regulations for all components except the mouthpiece for
which USP Biological Reactivity Test data is provided.
Performance:
Case 1d:  Frequently a consideration.
Case 2d:  May be a consideration.
Case 3d:  Rarely a consideration.
2.
Quality Control of Packaging Components
In addition to providing data to show that a proposed container closure system is
suitable for its intended use, an application should also describe the quality control
measures that will be used to ensure consistency in the packaging components (see
section III.C.3).  These controls are intended to limit unintended postapproval
 These are substances not previously determined to be safe by extraction/toxicological evaluation studies (e.g., the USP
Biological Reactivity Tests or another appropriate method conducted on the packaging component as part of the
qualifying process).
variations in the manufacturing procedures or materials of construction for a
packaging component and to prevent adverse affects on the quality of a dosage
form.
Principal consideration is usually given to consistency in physical characteristics
and chemical composition.
a.
Physical Characteristics
The physical characteristics of interest include dimensional criteria (e.g.,
shape, neck finish, wall thickness, design tolerances), physical parameters
critical to the consistent manufacture of a packaging component (e.g., unit
weight), and performance characteristics (e.g., metering valve delivery
volume, or the ease of movement of syringe plungers).  Unintended
variations in dimensional parameters, if undetected, may affect package
permeability, drug delivery performance, or the adequacy of the seal
between the container and the closure.  Variation in any physical parameter
is considered important if it can affect the quality of a dosage form.

b.
Chemical Composition
The chemical composition of the materials of construction may affect the
safety of a packaging component.  New materials  may result in new
substances being extracted into the dosage form or a change in the amount
of known extractables.  Chemical composition may also affect the
compatibility, functional characteristics or protective properties of
packaging components by changing rheological or other physical properties
(e.g., elasticity, resistance to solvents, or gas permeability).
A composition change may occur as a result of a change in formulation or
in a processing aid (e.g., using a different mold release agent) or through
the use of a new supplier of a raw material.  A change in the supplier of a
polymeric material or a substance of biological origin is more likely to bring
with it an unexpected composition change than a change in the supplier of
a pure chemical compound, because polymeric and natural materials are
often complex mixtures.  A composition change may also occur with a
change in the manufacturing process, such as the use of different operating
conditions (e.g., a significantly different curing temperature), different
equipment, or both.
A change in formulation is considered a change in the specifications for the
packaging component.  This change in the formulation of a packaging
component by its manufacturer should be reported to the firm that
purchases that component and to any appropriate DMF.  The firm that
purchases the component should, in turn, report the change to its
application as required under 21 CFR 314.70(a) or 601.12.  Manufacturers
who supply a raw material or an intermediate packaging component should
inform their customers of any intended changes to formulations or
manufacturing procedures and update the DMF in advance of implementing
such a change.  Changes which seem innocuous may have unintended
consequences on the dosage form marketed in the affected packaging
system.
The use of stability studies for monitoring the consistency of a container
closure system in terms of compatibility with the dosage form and the
degree of protection provided to the dosage form is accepted.  Currently
there is no general policy concerning the monitoring of a packaging system
and components with regard to safety.  One exception involves inhalation
drug products for which batch-to-batch monitoring of the extraction profile
for the polymeric and elastomeric components is routine.
3.
Associated Components
Associated components are packaging components that are typically
intended to deliver the dosage form to the patient but are not stored in
contact with the dosage form for its entire shelf life.  These components are
packaged separately in the market package and are either attached to the
container upon opening or used only when a dose is to be administered.
Measuring spoons, dosing cups, measuring syringes, and vaginal delivery
tubes are examples of associated components that typically contact the
dosage form only during administration.  A hand pump or dropper
combined into a closure are examples of an associated component that
would contact the dosage form from the time the packaging system is
opened until the dosing regimen is completed.
The complete and assembled component and its parts should meet
suitability criteria appropriate for the drug product and the actual use of the
component (see sections III.B.1 and III.B.2).  Safety and functionality are
the most common factors to be established for suitability.  The length of
time that the associated component and the dosage form are in direct
contact should also be taken into consideration when assessing the
suitability of an associated component.
4.
Secondary Packaging Components
Unlike primary and associated packaging components, secondary
packaging components are not intended to make contact with the dosage
form.  Examples are cartons, which are generally constructed of paper or
plastic, and overwraps, which may be fabricated from a single layer of
plastic or from a laminate made of metal foil, plastic, and/or paper.
A secondary packaging component generally serves one or more of the
following additional functions:
a.
Provides protection from excessive transmission of moisture or
solvents into or out of the packaging system
b.
Provides protection from excessive transmission of reactive gases
(atmospheric oxygen, inert headspace filler gas, or other organic
vapors) into or out of the packaging system
c.
Provides light protection for the packaging system
d.
Provides protection for a packaging system that is flexible or needs
extra protection from rough handling
e.
Provides an additional measure of microbiological protection (i.e.,
by maintaining sterility or by protecting the packaging system from
microbial intrusion)
When information on a container closure system is submitted in an application, the
emphasis would normally be on the primary packaging components.  For a
secondary packaging component, a brief description will usually suffice unless the
component is intended to provide some additional measure of protection to the
drug product.  In this case, more complete information should be provided, along
with data showing that the secondary packaging component actually provides the
additional protection (see sections III.B.1 and III.B.2).
Because secondary packaging components are not intended to make contact with
the dosage form, there is usually less concern regarding the materials from which
they are constructed.  However, if the packaging system is relatively permeable,
the possibility increases that the dosage form could be contaminated by the
migration of an ink or adhesive component, or from a volatile substance present in
the secondary packaging component.  (For example, a solution packaged in a
LDPE container was found to be contaminated by a volatile constituent of the
secondary packaging components that enclosed it.).  In such a case, the secondary
packaging component should be considered a potential source of contamination
and the safety of its materials of construction should be taken into consideration.
 See Table 3 for additional information.  This section applies to primary packaging components and to those associated
and secondary packaging components that provide protection to the drug product or for which there may be a safety
concern (see section III.B).
 Where possible, this information should be included in the application.  Alternatively, it may be provided in a drug
master file (see section V) and a letter of authorization (LOA) to the DMF submitted in the application.  The LOA
permits the Agency to review the information in support of a particular application.
 For further information see the FDA guidance for industry Submission of Documentation for the Sterilization Process
Validation in Applications of Human and Veterinary Drug Products (November 1994).
C.
Information That Should Be Submitted in Support of an Original
Application for Any Drug Product15
Additional discussion and information regarding the CMC information to be
provided in an application (NDA, ANDA, or BLA) can be found in the guidances
and guidelines listed in Attachment E.
1.
Description
A general description of the entire container closure system should be provided in
the CMC section of the application.  In addition, the following information should
be provided by the applicant for each individual component of the packaging
system:
a.
Identification by product name, product code (if available), the
name and address of the manufacturer, and a physical description
of the packaging component (e.g., type, size, shape, and color)
b.
Identification of the materials of construction (i.e., plastics, paper,
metal, glass, elastomers, coatings, adhesives, and other such
materials) should be identified by a specific product designation
(code name and/or code number) and the source (name of the
manufacturer).   Alternate materials of construction should also be
indicated.  Postconsumer recycled plastic should not be used in the
manufacture of a primary packaging component.  If used for a
secondary or associated component, then the safety and
compatibility of the material for its intended use should be
addressed appropriately.
c.
Description of any operations or preparations that are performed on
a packaging component by the applicant (such as washing, coating,
sterilization, or depyrogenation)17
2.
Information About Suitability
a.
To establish safety and to ensure consistency, the complete
chemical composition should be provided for every material used in
the manufacture of a packaging component.
b.
Test results from appropriate qualification and characterization
tests should be provided.  Adequate information regarding the tests,
methods, acceptance criteria, reference standards, and validation
information should be provided.
To address protection, use of USP tests (see Attachment A) for
light transmission, moisture permeation, microbial limits, and
sterility are generally considered sufficient.  Testing for properties
other than those described in USP (e.g., gas transmission, solvent
leakage container integrity) may also be necessary.
To address safety and compatibility, the results of
extraction/toxicological evaluation studies should be provided for
drug products that are likely to interact with the packaging
components and introduce extracted substances into the patient
(see Table 1).  For drug products less likely to interact, other tests
(e.g., USP Biological Reactivity Test) or information (e.g.,
appropriate reference to the indirect food additive regulations at 21
CFR 174-186) could be used to address the issue of safety and
compatibility (see Table 2).  For example, an appropriate reference
to an indirect food additive regulation is generally sufficient for a
solid oral dosage form product.
To address performance, the results of USP and non-USP
functionality tests are considered sufficient if the test and
acceptance criteria are appropriate for the intended purpose.
Tests described in the USP are typically considered sufficient
standards for establishing specified properties and characteristics of
specified materials of construction or packaging components.
For non-USP tests, an applicant should provide justification for the
use of the test, a complete and detailed description of how the test
was performed, and an explanation of what the test is intended to
establish.  If a related USP test is available, comparative data
should be provided using both methods.  Supporting data should
include a demonstration of the suitability of the test for its intended
use and its validation.
Testing on an assembled container closure system is usually
performed by the applicant (or a testing laboratory commissioned
by the applicant) and the test results provided in the application.
Such tests may include vacuum leak testing, moisture permeation,
and weight loss or media fill.
Testing on an individual packaging component is typically
performed by the manufacturer of the component and reported via a
DMF (see section V).
3.
Information About Quality Control
The fabricator/manufacturer of a packaging component and the drug product
manufacturer who uses this firm share the responsibility for ensuring the quality of
packaging components.  These firms should have a quality control program in
place so that consistent components are produced.  The drug product
manufacturer must have an inspection program for incoming packaging
components and materials (21 CFR 211.22, 211.84 and 211.122).  For most drug
products, a drug product manufacturer may accept a packaging component lot
based on receiving a Certificate of Analysis (COA) or Certificate of Certification
(COC) from the component supplier and the performance of an appropriate
identification test, provided the supplier’s test data are periodically validated (21
CFR 211.84(d)(3)).  Acceptance of a packaging component lot based on a
supplier's COA or COC may not be appropriate in all cases (e.g., some packaging
components for certain inhalation drug products).
a.
Applicants
The tests and methods used by the applicant for acceptance of each batch
of a packaging component that they receive should be described.  If a batch
is to be accepted based on a supplier's COA or COC, then the procedure
for supplier validation should be described.  The data from the supplier’s
COA or COC should clearly indicate that the lot meets the applicant’s
acceptance criteria.  Acceptance criteria for extractables should also be
included, if appropriate.
Dimensional and performance criteria should be provided.  Dimensional
information is frequently provided via a detailed schematic drawing
complete with target dimensions and tolerances and may be provided via
the packaging component manufacturer's DMF.  A separate drawing may
not be necessary if the packaging component is part of a larger unit for
which a drawing is provided or if the component is uncomplicated in design
(e.g., a cap liner).
b.
Manufacturers of Packaging Components Sold to Drug Product
 Statistical process control is defined as "[t]he application of statistical techniques for measuring and analyzing the
variation in processes." Juran, J.M., ed., 1988, Quality Control Handbook, 4th ed., McGraw-Hill, p. 24.2.
Manufacturers
Each manufacturer of a packaging component sold to a drug product
manufacturer should provide a description of the quality control measures
used to maintain consistency in the physical and chemical characteristics of
the component.  These generally include release criteria (and test methods,
if appropriate) and a description of the manufacturing procedure.  If the
release of the packaging component is based on statistical process
control,  a complete description of the process (including control criteria)
and its validation should be provided.
The description of the manufacturing process is generally brief and should
include any operations performed on the packaging component after
manufacture but prior to shipping (e.g., washing, coating, and/or
sterilization).  In some cases it may be desirable for the description to be
more detailed and to include in-process controls.
This information may be provided via a DMF (see section V).
c.
Manufacturers of Materials of Construction or of Packaging
Components Used to Make Other Packaging Components
The quality control procedures of the manufacturer of a packaging
component may sometimes rely in whole or in part on the quality control
procedures of a manufacturer who makes an intermediate packaging
component that is used to create the component.  If so, each contributor to
the final packaging system should provide a description of the quality
control measures used to maintain consistency in the physical and chemical
characteristics of the separate components and of the assembled packaging
system that they provide.
The manufacturer of each material of construction should be prepared to
describe the quality control measures used to maintain consistency in the
chemical characteristics of their product.
This information may be provided via a DMF (see section V).
4.
Stability Data (Packaging Concerns)
Stability testing of the drug product should be conducted using the container
closure systems proposed in the application.  The packaging system used in each
stability study should be clearly identified.
The container closure system should be monitored for signs of instability.  When
appropriate, an evaluation of the packaging system should be included in the
stability protocol.  Even when a formal test for quality of the packaging system is
not performed, the applicant should investigate any observed change in the
packaging system used in the stability studies.  The observations, results of the
investigation, and corrective actions should be included in the stability report.  If
the corrective action requires a change in an approved container closure system, a
supplemental application should be submitted.
For general guidance on conducting stability studies, refer to the FDA Guideline
for Submitting Documentation for the Stability of Human Drugs and Biologics
(February 1987).  The stability guideline is undergoing revision and will be
superseded by the FDA’s draft guidance for industry Stability Testing of Drug
Substance and Drug Products (June 1998), once it is issued in final form.
Table 3
Information That Should Be Submitted in an Original Application for Any Drug Product
Description
Overall general description of the container closure system, plus:
For Each Packaging Component:
C
Name, product code, manufacturer, physical description
C
Materials of construction (for each:  name, manufacturer, product code)
C
Description of any additional treatments or preparations
Suitability
Protection:  (By each component and/or the container closure system, as appropriate)
C
Light exposure
C
Reactive gases (e.g., oxygen)
C
Moisture permeation
C
Solvent loss or leakage
C
Microbial contamination(sterility/container integrity, increased bioburden,
microbial limits)
C
Filth
C
Other
Safety:  (for each material of construction, as appropriate)
C
Chemical composition of all plastics, elastomers, adhesives, etc.a
C
Extractables, as appropriate for the materialb
Extraction/toxicological evaluation studies, as appropriate
Appropriate USP testing
Appropriate reference to the indirect food additive regulations (21 CFR
174-186)
C
Other studies as appropriate
Compatibility:  (for each component and/or the packaging system, as appropriate)
C
Component/dosage form interaction, USP methods are typically accepted
C
May also be addressed in post-approval stability studies
Performance:  (for the assembled packaging system)
C
Functionality and/or drug delivery, as appropriate
Quality Control
For Each Packaging Component Received by the Applicant:
C
Applicant's tests and acceptance criteriac
C
Dimensional (drawing) and performance criteria
C
Method to monitor consistency in composition, as appropriate
For Each Packaging Component Provided by the Supplier:
C
Manufacturer's acceptance criteria for release, as appropriate
C
Brief description of the manufacturing process
Stability
C
See section III.C.4
Including any additives used in the manufacture of a packaging component
a
See Attachment C for further discussion of extraction studies.  Testing of plastics should be performed on the
b
packaging component, not on the unformed resin.  For a blow/fill/seal product, extractables should be evaluated on
the formed drug product container itself.  This also applies to a container closure system which is manufactured as
part of the drug product manufacturing process.
Note that an applicant's acceptance tests may include, among others, test parameters indicated under the description,
c
suitability, and quality control sections of this table.
 The terms SVP and LVP as used in this guidance correspond to the definitions of small-volume injection and large-
volume injection, respectively, in USP 23, page 1650.
D.
Inhalation Drug Products
Inhalation drug products include inhalation aerosols (metered dose inhalers); inhalation
solutions, suspensions, and sprays (administered via nebulizers); inhalation powders (dry
powder inhalers); and nasal sprays.  The CMC and preclinical considerations for inhalation
drug products are unique in that these drug products are intended for respiratory-tract
compromised patients.  This is reflected in the level of concern given to the nature of the
packaging components that may come in contact with the dosage form or the patient (see
Table 1).
Guidance regarding the container closure system information to support the approval of
applications for inhalation drug products will be provided in two guidance documents
when finalized:  the guidance for industry Metered Dose Inhaler (MDI) and Dry Powder
Inhaler (DPI) Drug Products; Chemistry, Manufacturing and Controls Documentation (a
draft was issued in October 1998) and the guidance for industry Nasal Spray and
Inhalation Solution, Suspension, and Spray Drug Products; Chemistry, Manufacturing
and Controls Documentation, which is currently under development.
E.
Drug Products for Injection and Ophthalmic Drug Products
These dosage forms share the common attributes that they are generally solutions,
emulsions, or suspensions, and are all required to be sterile.  Injectable dosage forms
represent one of the highest risk drug products (see Table 1).  Any contaminants present
(as a result of contact with a packaging component or due to the packaging system’s
failure to provide adequate protection) can be rapidly and completely introduced into the
patient's general circulation.  Although the risk factors associated with ophthalmics are
generally considered to be lower than for injectables, any potential for causing harm to the
eyes demands caution.
1.
Injectable Drug Products
Injectable drug products may be liquids in the form of solutions, emulsions,
suspensions, or dry solids that are to be combined with an appropriate vehicle to
yield a solution or suspension.  Injections are classified as small-volume parenterals
(SVPs), if they have a solution volume of 100 mL or less, or as large-volume
parenterals (LVPs), if the solution volume exceeds 100 mL.   For solids that must
be dissolved or dispersed in an appropriate diluent before being injected, the
diluent may be in the same container closure system (e.g., a two-part vial) or be
part of the same market package (e.g., a kit containing a vial of diluent).
An SVP may be packaged in a disposable cartridge, a disposable syringe, a vial, an
ampule or a flexible bag.  An LVP may be packaged in a vial, a flexible bag, a glass
bottle or, in some cases, as a disposable syringe.
Cartridges, syringes, vials, and ampules are usually composed of Type I or II glass,
or polypropylene.  Flexible bags are typically constructed with multilayered plastic.
Stoppers and septa in cartridges, syringes, and vials are typically composed of
elastomeric materials.  The input (medication) and output (administration) ports
for flexible bags may be plastic and/or elastomeric materials.  An overwrap may be
used with flexible bags to retard solvent loss and to protect the flexible packaging
system from rough handling.
The potential effects of packaging component/dosage form interactions are
numerous.  Hemolytic effects may result from a decrease in tonicity and pyrogenic
effects may result from the presence of impurities.  The potency of the drug
product or concentration of the antimicrobial preservatives may decrease due to
adsorption or absorption.  A cosolvent system essential to the solubilization of a
poorly soluble drug can also serve as a potent extractant of plastic additives.  A
disposable syringe may be made of plastic, glass, rubber, and metal components,
and such multicomponent construction provides a potential for interaction that is
greater than when a container consists of a single material.
Injectable drug products require protection from microbial contamination (loss of
sterility or added bioburden) and may also need to be protected from light or
exposure to gases (e.g., oxygen).  Liquid-based injectables may need to be
protected from solvent loss, while sterile powders or powders for injection may
need to be protected from exposure to water vapor.  For elastomeric components,
data showing that a component meets the requirements of USP Elastomeric
Closures for Injections will typically be considered sufficient  evidence of safety.
For plastic components, data from USP Biological Reactivity Tests will typically
be considered sufficient evidence of safety.  Whenever possible, the extraction
studies should be performed using the drug product.  If the extraction properties of
the drug product vehicle may reasonably be expected to differ from that of water
(e.g., due to high or low pH or due to a solubilizing accipient), then drug product
should be used as the extracting medium. If the drug substance significantly affects
extraction characteristics, it may be necessary to perform the extractions using the
drug product vehicle.  If the total of extracts significantly exceeds the amount
obtained from water extraction, then an extraction profile should be obtained.  It
may be advisable to obtain a quantitative extraction profile of an elastomeric or
plastic packaging component and to compare this periodically to the profile from a
new batch of the packaging component.  Extractables should be identified
whenever possible.  For a glass packaging component, data from USP Containers:
Chemical Resistance — Glass Containers will typically be considered sufficient
evidence of safety and compatibility.  In some cases (e.g., for some chelating
agents), a glass packaging component may need to meet additional criteria to
ensure the absence of significant interactions between the packaging component
and the dosage form.
Performance of a syringe is usually addressed by establishing the force to initiate
and maintain plunger movement down the barrel, and the capability of the syringe
to deliver the labeled amount of the drug product.
2.
Ophthalmic Drug Products
These drug products are usually solutions marketed in a LDPE bottle with a
dropper built into the neck (sometimes referred to as droptainer), or ointments
marketed in a metal tube with an ophthalmic tip (see section III.F.2 for a more
detailed discussion of tubes).  A few solution products use a glass container due to
stability concerns regarding plastic packaging components.  Ophthalmic ointments
that are reactive toward metal may be packaged in a tube lined with an epoxy or
vinyl plastic coating.  A large volume intraocular solution (for irrigation) may be
packaged in a glass or polyolefin (polyethylene and/or polypropylene) container.
The American Academy of Ophthalmology (AAO) recommended to the Agency
that a uniform color coding system be established for the caps and labels of all
topical ocular medications.  An applicant should either follow this system or
provide an adequate justification for any deviations from the system.  The AAO
color codes, as revised and approved by the AAO Board of Trustees in June 1996,
are shown in Table 5.
Although ophthalmic drug products can be considered topical products (section
III.F.2), they have been grouped here with injectables because they are required to
be sterile (21 CFR 200.50(a)(2)) and the descriptive, suitability, and quality control
information is typically the same as that for an injectable drug product.  Since
ophthalmic drug products are applied to the eye, compatibility and safety should
also address the container closure system's potential to form substances which
irritate the eye or introduce particulate matter into the product (see USP <771>
Ophthalmic Ointments).
See Table 4 for additional information.
Table 4
Information That Typically Should Be Submitted for Injectable
or Ophthalmic Drug Products
Description
Overall general description of container closure system, plus:
For Each Packaging Component:
C
Name, product code, manufacturer, physical description
C
Materials of construction (for each:  name, manufacturer and product code)
C
Description of any additional treatments (e.g., procedures for sterilizing and
depyrogenating packaging components)
Suitability
Protection:  (By each component and/or the container closure system, as appropriate)
C
Light exposure, when appropriate
C
Reactive gases (e.g., oxygen)
C
Moisture permeation (powders)
C
Solvent loss (liquid-based dosage forms)
C
Sterility (container integrity) or increased bioburden
C
Seal integrity or leak testing of tubes (ophthalmics)
Safety:  (for each material of construction, as appropriate)
C
Chemical composition of all plastics, elastomers, adhesives, etc.a
C
For elastomeric closures:  USP Elastomeric Closures for Injections testing
C
For glass components:  USP Containers:  Chemical Resistance — Glass
Containers
C
For plastic components and coatings for metal tubes:  USP Biological Reactivity
Tests
C
If the extraction properties of the drug product vehicle may reasonably be
expected to differ from that of water (e.g., due to high or low pH or due to a
solubilizing excipient), then drug product should be used as the extracting
medium.
C
If the total weight of extracts significantly exceeds the amount obtained from
water extraction, then an extraction profile should be obtained.
C
For plastic or elastomeric components undergoing heat sterilization, it is current
practice to request that the extraction profile be obtained at 121EC/1 hour using
an appropriate solvent.
Compatibility:  (for each component and/or the packaging system, as appropriate)
C
For coatings on metal tubes:  Coating integrity testing
C
For elastomeric components:  Evaluation of swelling effects
C
For plastic components (including tube coatings):  USP Containers:
Physicochemical Tests - Plastics testing
C
For ophthalmics: Particulate matter and eye irritants
C
Stability studies also support compatibility
Performance:   (For the assembled packaging system)
C
Functionality and/or drug delivery
Quality Control
For Each Packaging System Received by the Applicant:
C
Applicant’s tests and acceptance criteriac
C
Dimensional (drawing) and performance criteria
C
Method to monitor consistency in composition of most plastic and elastomeric
components (e.g., periodic comparison to the original extraction profile is
recommended)
For Each Packaging Component Provided by the Supplier:
C
Manufacturer’s acceptance criteria for release, as appropriate
C
Description of the manufacturing process, as appropriate (e.g.,
procedure/validation for sterilization and depyrogenation)
Stability
C
See section III.C.4
Including any additives used in the manufacture of a packaging component
a.
Testing for plastics should be performed on the packaging component, not on the unformed resin.
b.
Note that applicant's acceptance tests may include, among others, test parameters indicated under the
c.
description, suitability, and quality control sections of this table.
Refer to the Guidance for Industry for the Submission of Documentation for Sterilization Process Validation
d
in Applications for Human and Veterinary Drug (November 1994).
Table 5
AAO Recommended Color Coding of Caps and Labels
 for Topical Ophthalmic Medications
Class
Color
Pantone® Number
Anti-Infectives
Tan
Anti-Inflammatories/Steroids
Pink
197, 212
Mydriatics and Cycloplegics
Red
485C
Nonsteroidal Anti-Inflammatories
Gray
4C
Miotics
Green
374, 362, 348
Beta-Blockers
Yellow or Blue
290, 281
a
Yellow C
Adrenergic Agonists (e.g., Propine)
Purple
2583
Carbonic Anhydrase Inhibitors
Orange
1585
Prostaglandin Analogues
Turquoise
326C
The AAO notes that as new classes of drugs are developed this coding system may be modified in the future by
a
reassigning the blue color to a new class of drugs while keeping yellow for beta-blockers.
F.
Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems
A wide variety of drug products fall into this category.  The presence of a liquid phase
implies a significant potential for the transfer of materials from a packaging component
into the dosage form.  The higher viscosity of semisolid dosage forms and transdermal
systems may cause the rate of migration of leachable substances into these dosage forms
 See Attachment A for a listing of the FDA regulations for indirect food additives.
to be slower than for aqueous solutions.  Due to extended contact, the amount of
leachables in these drug products may depend more on a leachable material’s affinity for
the liquid/semisolid phase than on the rate of migration.
1.
Liquid-Based Oral Drug Products
Typical liquid-based oral dosage forms are elixirs, emulsions, extracts, fluid
extracts, solutions, gels, syrups, spirits, tinctures, aromatic waters, and
suspensions.  These products are usually nonsterile but may be monitored for
changes in bioburden or for the presence of specific microbes.
These dosage forms are generally marketed in multiple-unit bottles or in unit-dose
or single-use pouches or cups.  The dosage form may be used as is or admixed first
with a compatible diluent or dispersant.  A bottle is usually glass or plastic, often
with a screw cap with a liner, and possibly with a tamper-resistant seal or an
overcap that is welded to the bottle.  The same cap liners and inner seals are
sometimes used with solid oral dosage forms.  A pouch may be a single-layer
plastic or a laminated material.  Both bottles and pouches may use an overwrap,
which is usually a laminated material.  A single-dose cup may be metal or plastic
with a heat-sealed lid made of a laminated material.
A liquid-based oral drug product typically needs to be protected from solvent loss,
microbial contamination, and sometimes from exposure to light or reactive gases
(e.g., oxygen).
For glass components, data showing that a component meets the requirements of
USP Containers:  Glass Containers are accepted as sufficient evidence of safety
and compatibility.  For LDPE components, data from USP Containers tests are
typically considered sufficient evidence of compatibility.  The USP General
Chapters do not specifically address safety for polyethylene (HDPE or LDPE),
polypropylene (PP), or laminate components.  A patient's exposure to substances
extracted from a plastic packaging component (e.g., HDPE, LDPE, PP, laminated
components) into a liquid-based oral dosage form is expected to be comparable to
a patient's exposure to the same substances through the use of the same material
when used to package food.  Based on this assumption, an appropriate reference
to the indirect food additive regulations (21 CFR 174-186)  is typically considered
sufficient to establish safety of the material of construction, provided any
limitations specified in the regulations are taken into consideration.  This
assumption is considered valid for liquid-based oral dosage forms which the patient
will take only for a relatively short time (acute dosing regimen).
 See Attachment C for a discussion of extraction studies.
For liquid-based oral drug products which the patient will continue to take for an
extended period (i.e., months or years (chronic drug regimen)), a material of
construction that meets the requirements for indirect food additives will be
considered safe — on that basis alone — only if the patient's exposure to
extractables can be expected to be no greater than the exposure through foods, or
the length of exposure is supported by toxicological information.  For example, if
the dosage form is aqueous-based and contains little or no cosolvent (or other
substance, including the active drug substance, liable to cause greater extraction of
substances from plastic packaging components than would be extracted by water),
meeting the requirements of the indirect food additive regulations will usually
satisfy the issue of safety.
If the dosage form contains cosolvents (or if, for any reason, it may be expected to
extract greater amounts of substances from plastic packaging components than
water), then additional extractable information  may be needed to address safety
issues.
Performance is typically not a factor for liquid-based oral drug products.
See Table 6 for additional information.
2.
Topical Drug Products
Topical dosage forms include aerosols, creams, emulsions, gels, lotions, ointments,
pastes, powders, solutions, and suspensions.  These dosage forms are generally
intended for local (not systemic) effect and are generally applied to the skin or oral
mucosal surfaces.  Topical products also include some nasal and otic preparations
as well as some ophthalmic drug products.  Ophthalmic drug products are
discussed in section III.E.2.  Vaginal and rectal drug products may be considered
to be topical if they are intended to have a local effect.  Some topical drug
products are sterile or may be subject to microbial limits.  In these cases, additional
evaluation may be necessary when determining the appropriate packaging.
A liquid-based topical product typically has a fluid or semi-solid consistency and is
marketed in a single- or multiple-unit container (e.g., a rigid bottle or jar, a
collapsible tube, or a flexible pouch).  A powder product may be marketed in a
sifter-top container.  An antibacterial product may be marketed as part of a sterile
dressing.  There are also a number of products marketed as a pressurized aerosol
or a hand-pumped spray.
A rigid bottle or jar is usually made of glass or polypropylene with a screw cap.
The same cap liners and inner seals are sometimes used as with solid oral dosage
forms.
A collapsible tube is usually constructed from metal or is metal-lined, from LDPE
or from a laminated material.  Tubes are identified as either blind-end or open-end.
In the former, there is no product contact with the cap on storage.  Usually, the
size of the tube is controlled by trimming it to an appropriate length for the target
fill volume.  Fill volume is commonly determined as an in-process measurement
using bulk density.  Usually there is no cap liner, although the tube may have a
liner.  Aluminum tubes usually include a liner.  A tube liner is frequently a lacquer
or shellac whose composition should be stated.  A tube is closed by folding or
crimping the open end.  The type of fold (roll or saddle) should be described, as
well as the type and composition of any sealant.  If the tube material is self-sealing
through the application of heat alone, this should be stated.  If the market package
includes a separate applicator device, this should be described.  Product contact is
possible if the applicator is part of the closure, and therefore an applicator's
compatibility with the drug product should be established, as appropriate.
Dressings consist of dosage form on a bandage material (e.g., Absorbent Gauze
USP or Gauze Bandage USP) within a flexible pouch.  The pouch should maintain
the sterility and physical stability of the dressing.
Unlike inhalation aerosols, topical aerosols are not intended to be inhaled.  The
droplet size of the spray does not need to be carefully controlled, nor is the dose
usually metered.  The spray may be used to apply dosage form to the skin (topical
aerosol) or mouth (lingual aerosol) and functionality of the sprayer should be
addressed.  A topical aerosol may be sterile or may conform to acceptance criteria
for microbial limits.
The packaging system for a liquid-based topical product should deter solvent loss
and should provide protection from light when appropriate.  Because these dosage
forms may be placed in contact with mucosal membranes or with skin that has
been broken or otherwise compromised, the safety of the materials of construction
for the packaging components should be evaluated.  For liquid and semisolid
dosage forms, the same information as described in section III.F.1 is accepted for
establishing safety and compatibility.  For solid dosage forms, an appropriate
reference to the indirect food additive regulations is typically considered sufficient
to establish safety.
See Table 6 for additional information.
3.
Topical Delivery Systems
Topical delivery systems are self-contained, discrete dosage forms that are
designed to deliver drug via intact skin or body surface.  USP Pharmaceutical
Dosage Forms defines three types of topical delivery systems:  transdermal, ocular,
and intrauterine.
Transdermal systems are usually applied to the skin with an adhesive and may be in
place for an extended period.  Ocular systems are inserted under the lower eyelid,
typically for seven days.  Intrauterine systems are held in place without adhesive
and may stay in place for a year.
A transdermal system is usually comprised of an outer barrier, a drug reservoir
(with or without a rate-controlling membrane), a contact adhesive, and a
protective liner.  An ocular system usually consists of the drug formulation
contained in a rate-controlling membrane.  An intrauterine system may be
constructed of a plastic material impregnated with active ingredients or a coated
metal.  It is shaped to remain in place after being inserted in the uterus.
Each of these systems is generally marketed in a single-unit soft blister pack or a
preformed tray with a preformed cover or overwrap.
Compatibility and safety for topical delivery systems are addressed in the same
manner as for topical drug products.  Performance and quality control should be
addressed for the rate-controlling membrane.  Appropriate microbial limits should
be established and justified for each delivery system.  Microbiological standards are
under development; therefore the review division for a specific application should
be consulted.
See Table 6 for additional information.
Table 6
Information That Typically Should Be Submitted for Liquid-Based Oral
and Topical Drug Products and for Topical Drug Delivery Systems
Description
Overall general description of container closure system, plus:
For Each Packaging Component:
C
Name, product code, manufacturer, physical description
C
Materials of construction (for each:  name, manufacturer and product code)
C
Description of any additional treatments (e.g., procedure for washing
components)
Suitability
Protection:  (by each component and/or the container closure system, as appropriate)
C
Light exposure
C
Reactive gases (e.g., oxygen)
C
Solvent loss
C
Moisture permeation (liquid-based oral products would typically meet USP
requirements for a tight or class A container)
C
Microbial contamination (container integrity, increased bioburden, microbial
limits, as appropriate)
C
Seal integrity or leak testing of tubes (topical drug products) and unit dose
containers (liquid-based oral drug products)
Safety:  (for each material of composition, as appropriate)
C
Chemical composition of all plastics, elastomers, adhesives, etc.a
C
For most liquid-based oral drug products:  appropriate reference to the indirect
food additive regulations
C
For liquid-based oral drug products with chronic dosing regimens that contain
alcohol or a cosolvent:  information to establish that exposure to extractables
will be no greater than that expected to result from the use of similar packaging
components when used with foods,  or that the exposure is acceptable based on
b
toxicological data.
C
For topical drug products (plastic coatings for metal tubes), and plastic drug
delivery system components:  USP Containers testing
C
For topical delivery systems:  appropriate reference to indirect food additive
regulations
Compatibility:  (for each component of the packaging system, as appropriate)
C
For LDPE and glass components, USP Containers testingc
C
For coatings for metal tubes:  coating integrity testing
Performance:  (for the assembled packaging system)
C
Functionality and/or drug delivery should be addressed, as appropriate.
Quality Control
For Each Packaging Component Received by the Applicant:
C
Applicant's tests and acceptance criteriad
C
Dimensional (drawing) and performance criteria
C
Method to monitor consistency in composition, as appropriate
For Each Packaging Component Provided by the Supplier:
C
Manufacturer's acceptance criteria for release, as appropriate
C
Description of the manufacturing process, as appropriate
Stability
C
See section III.C.4
Including any additives used in the manufacture of a packaging component
a
The materials of construction should be acceptable for contact with foods that have extraction characteristics similar
b
to those of the drug product (e.g., aqueous, acidic, alcoholic, or fatty).
Plastics testing should be performed on the packaging component, not on the unformed resin.
c
Note that applicant's acceptance tests may include, among others, test parameters indicated under the description,
d
suitability, and quality control sections of this table.
G.
Solid Oral Dosage Forms and Powders for Reconstitution
The most common solid oral dosage forms are capsules and tablets.  For the purpose of
this guidance, oral powders and granules for reconstitution are also included in this group.

The risk of interaction between packaging components and a solid oral dosage form is
generally recognized to be small.  Powders that are reconstituted in their market container,
however, have an additional possibility of an interaction between the packaging
components and the reconstituting fluid.  Although the contact time will be relatively short
when compared to the component/dosage form contact time for liquid-based oral dosage
forms, it should still be taken into consideration when the compatibility and safety of the
container closure system is being evaluated.
A typical container closure system is a plastic (usually HDPE) bottle with a screw-on or
snap-off closure and a flexible packaging system, such as a pouch or a blister package.  A
typical closure consists of a cap, often with a liner, and frequently with an inner seal.  If
used, fillers, desiccants, and other absorbent materials are considered primary packaging
components.
The most common forms of flexible packaging are the blister package and the pouch.  A
blister package usually consists of a lidding material and a forming film.  The lidding
material is usually a laminate which includes a barrier layer (e.g., aluminum foil) with a
print primer on one side and a sealing agent (e.g., a heat-sealing lacquer) on the other side.
The sealing agent contacts the dosage form and the forming film.  The forming film may
be a single film, a coated film, or a laminate.  A pouch typically consists of film or laminate
which is sealed at the edges by heat or adhesive.  Leak testing is usually performed on
flexible packages as part of the in-process controls.
Solid oral dosage forms generally need to be protected from the potential adverse affects
of water vapor.  Protection from light and reactive gases may also be needed. For example
the presence of moisture may affect the decomposition rate of the active drug substance or
the dissolution rate of the dosage form.  The container should have an intrinsically low
rate of water vapor permeation, and the container closure system should establish a seal to
protect the drug product.  Three standard tests for water vapor permeation have been
established by the USP for use with solid oral dosage forms.
 Hartauer, K.J. et al., "The Effects of Rayon Coiler on the Dissolution Stability of Hard Shelled Gelatin Capsules,"
Pharmaceutical Technology, 17:76-83 (1993).
1.
Polyethylene Containers (USP <661>):  This test is conducted on
containers heat-sealed with foil laminate; therefore only the properties of
the container are evaluated.  The level of protection from water vapor
permeation provided by a packaging system marketed with a heat-sealed
foil laminate inner seal (up to the time the inner seal is removed) is
expected to be approximately the same as that determined by this test.  The
acceptance criteria are those established in USP <671>.
2.
Single-Unit Containers and Unit-Dose Containers for Capsules and Tablets
(USP <671>):  This test measures the water vapor permeation of a single-
unit or unit-dose container closure system and establishes acceptance
criteria for five standards (Class A-E containers).
3.
Multiple-Unit Containers for Capsules and Tablets (USP <671>):  This test
is intended for drugs being dispensed on prescription, but has also been
applied to the drug product manufacturer’s container closure system.  If
the container closure system has an inner seal, it should be removed prior
to testing.  The results from this study reflect the contributions to water
vapor permeation through the container, and through the seal between the
container and the closure.  Acceptance criteria have been established for
two standards (tight and well-closed containers).
For solid oral dosage forms, a reference to the appropriate indirect food additive
regulation for each material of construction is typically considered sufficient evidence of
safety.  However, for a powder for reconstitution dosage form, reference only to the
indirect food additive regulations as evidence of safety for the materials of construction is
not recommended.  Compatibility for solid oral dosage forms and for powders for
reconstitution is typically addressed for plastics and glass by meeting the requirements of
the USP Containers test.
The USP monographs for Purified Cotton and Purified Rayon will typically be considered
sufficient standards to establish the safety of these materials as fillers in the packaging of
tablets or capsules, with the following caveats:  cotton need not meet the monograph
requirements for sterility, fiber length, or absorbency; and rayon need not meet the
monograph requirements for fiber length or absorbency.  Appropriate tests and acceptance
criteria for identification and for moisture content should be provided for both cotton and
rayon filler.  Rayon has been found to be a potential source of dissolution problems for
gelatin capsules and gelatin-coated tablets and this characteristic should be considered
when choosing a filler.   The use of other fillers may be considered with appropriate tests
and acceptance criteria.
If a desiccant or other absorbent material is used, the composition should be provided (or
an appropriate DMF referenced).  The component should differ in shape and/or size from
the tablets or capsules with which it is packaged.  This will help distinguish between the
component and the dosage form.  Because these are considered primary packaging
components, appropriate tests and acceptance criteria to establish suitability should be
provided (see Table 7 for additional information).
Table 7
Information That Typically Should Be Submitted for Solid Oral
Drug Products and Powders
Description
Overall general description of container closure system, plus:
For Each Packaging Component:
C
Name, product code, manufacturer
C
Materials of construction
C
Description of any additional treatments
Suitability
Protection:  (by each component and/or the container closure system, as appropriate)
C
Light exposure
C
Moisture permeation
C
Seal integrity or leak tests for unit-dose packaging
Safety:  (for each material of construction, as appropriate)
C
Chemical composition of all plastics, elastomers, adhesives, etc.a
C
For tablets, capsules, and powders, appropriate reference to the indirect food
additive regulation may be submitted, but may not be appropriate for Powders
for Reconstitution.
C
For rayon and cotton fillers, data from USP monographs.  For non-USP
materials, data and acceptance criteria should be provided.
C
For dessicants and other absorbent materials:  the size and shape should differ
from that of the dosage form.
Compatibility:  (on each component or the packaging system)
C
For glass and plastic containers, data from USP Containers  testing.
b
Performance:  (on each component or the packaging system, as appropriate)
C
Functionality and/or drug delivery, as appropriate
Quality Control
For Each Packaging Component Received by the Applicant:
C
Applicant's tests and acceptance criteriac
C
Dimensional (drawing) and performance criteria
C
Method to monitor consistency in composition, as appropriate
For Each Packaging Component Provided by the Supplier:
C
Manufacturer's acceptance criteria for release, as appropriate
C
Description of manufacturing process, as appropriate
Stability
C
See section III.C.4
Including any additives used in the manufacture of a packaging component
a
Testing of plastics should be performed on the packaging component, not on the unformed resin.
b
Note that applicant's acceptance tests may include, among others, test parameters indicated under the description,
c
suitability, and quality control sections of this table.
H.
Other Dosage Forms
The CGMP requirements for container closure systems for compressed medical gases are
described in 21 CFR 210 and 211.  The containers are regulated by the U.S. Department
of Transportation.  For more detailed information refer to the CDER Compressed Medical
Gas Guideline (February 1989).
When submitting information for a drug product or dosage form not specifically covered
by the sections above, a firm should take into consideration: (1) the compatibility and
safety concerns raised by the route of administration of the drug product and the nature of
the dosage form (e.g., solid or liquid-based); (2) the kinds of protection the container
closure system should provide to the dosage form; and (3) the potential effect of any
treatment or handling that may be unique to the drug product in the packaging system.
Quality control procedures for each packaging component should ensure the maintenance
of the safety and quality of future production batches of the drug product.
IV.
POSTAPPROVAL PACKAGING CHANGES
For an approved application (NDA, ANDA or BLA), a change to a container closure system, to a
component of the container closure system, to a material of construction for a component, or to a
process involving one of the above must be reported to the application.  The filing requirements
are specified under 21 CFR 314.70 (supplements and other changes to an approved application)
for an NDA or ANDA, and under 21 CFR 601.12 (changes to an approved application) for a
BLA.  The submission should address the items described and discussed in sections III.B and
III.C of this guidance.  The Agency intends to provide additional guidance on postapproval
changes in container closure systems in the future.
V.
TYPE III DRUG MASTER FILES
A.
General Comments
The responsibility for providing information about packaging components rests foremost
with the applicant of an NDA, ANDA or BLA, or the sponsor of an IND.  This
information may be provided to the applicant by the manufacturer of a packaging
component or material of construction and may be included directly in the application.
Any information that a manufacturer does not wish to share with the applicant or sponsor
(i.e., because it is considered proprietary) may be placed in a Type III DMF and
incorporated into the application by a letter from the manufacturer to the applicant which
authorizes reference to the DMF.  The letter of authorization should specify the firm to
whom authorization is granted, the component or material of construction being
described, and where the information and/or data is located in the file by page number
and/or date of submission.  This last item is especially important for files that contain
information on multiple components or have several volumes.
Information in a Type III DMF is not restricted to data of a proprietary nature.  DMF
holders may include in their files as much or as little information as they choose.  In
addition, a manufacturer of a packaging component is not required to maintain a Type III
DMF.  Without a DMF there is no procedure for the Agency to review proprietary
information except by submission to the application.
The Agency ordinarily reviews a DMF only in connection with an application (IND, NDA,
ANDA, or BLA).  If the combined information from the application and the DMF is not
adequate to support approval of the application or safety for the IND, then the Agency
may request additional information from the applicant and/or the DMF holder, as
appropriate.
In the event of a change in the DMF, the holder of a DMF must notify the holder of each
application supported by the DMF (21 CFR 314.420(c)).  Notice should be provided well
before the change is implemented to allow the applicant or sponsor enough time to file a
supplement or an amendment to the affected application.
General information on format and content of a DMF and a LOA may be found in the
CDER Guideline for Drug Master Files (September 1989).
B.
Information in a Type III DMF
Section III of this guidance describes the kind of descriptive, suitability, and quality
control information which the Agency usually reviews concerning packaging components
and materials of construction for drug products.  The following are examples of the items
that have been submitted via a Type III DMF.
1.
Descriptive Information:
a.
General description of the component and the address of the
manufacturing site
b.
Description of the manufacturing process for a packaging
component and operations performed after manufacture, but prior
to shipment (washing, coating, sterilization or depyrogenation)
c.
Description of the acceptance, in-process, and release controls for
materials of construction, the manufacturing process, and the
finished product (component part or assembled component)
d.
Characterization of the key properties
2.
Information About Suitability
a.
Protection provided by the component
b.
Safety information on the materials of construction or the finished
component
c.
Compatibility of the materials of construction or the finished
component with the specific dosage form, the specific drug
product, or equivalent materials
3.
Information About Quality Control:
a.
Dimensional (an engineering drawing) and performance criteria for
the component
b.
A description of the quality control measures used to maintain
consistency in the physical and chemical characteristics of
packaging components
c.
A summary of the quality assurance/quality control criteria when
release of the component is based on statistical process control
VI.
BULK CONTAINERS
A.
Containers for Bulk Drug Substances
Drug substances are generally solids, but some are liquids or gases.
The container closure system for storage or shipment of a bulk solid drug substance is
typically a drum with double LDPE liners that are usually heat sealed or closed with a
twist tie.  A desiccant may be placed between the bags.
The drum provides protection from light and mechanical strength to protect the liner
during shipment and handling.  The majority of the protection from air and moisture is
provided by the liner.  Because LDPE is not a particularly good moisture barrier, a drug
substance that is moisture sensitive may need additional protection.  An alternative to a
LDPE bag is a heat-sealable laminate bag with a comparatively low rate of water vapor
transmission.
Qualification of the packaging system is usually based on establishing compatibility and
safety of the liner but may also include characterization for solvent or gas transmission
(see section III.B).
The container closure system for the storage or shipment of a bulk liquid drug substance is
typically plastic, stainless steel, a glass-lined metal container, or an epoxy-lined metal
 The 1987 stability guidance will be superseded by the FDA guidance for industry Stability Testing of Drug
Substances and Drug Products, issued in draft for comment in June 1998, once it is issued in final form.
container with a rugged, tamper-resistant closure.  Qualification of the container closure
system may include characterization for solvent and gas permeation, light transmittance,
closure integrity, ruggedness in shipment, protection against microbial contamination
through the closure, and compatibility and safety of the packaging components as
appropriate (see section III.B).
The application (or Type II DMF) should include a detailed description of the complete
container closure system for the bulk drug substance as well as a description of the
specific container, closure, all liners, inner seal, and desiccant (if any), and the composition
of each component.  A reference to the appropriate indirect food additive regulation is
typically considered sufficient to establish the safety of the materials of construction (also
note the discussion on this subject in section III).  The tests, methods, and criteria for the
acceptance and release of each packaging component should be provided.
Stability studies to establish a retest period for bulk drug substance in the proposed
container closure system should be conducted with fillers or desiccant packs in place (if
used).  Smaller versions which simulate the actual container closure system may be used.
Stability recommendations for container closure systems of different types are described in
the Guideline for Submitting Documentation for the Stability of Human Drugs and
Biologics (February 1987).23
Container closure systems for compressed medical gases are discussed in section III.H.
B.
Containers for Bulk Drug Products
A container closure system for bulk drug products may be used for storage prior to
packaging or for shipment to repackagers or contract packagers.  In all cases, the
container closure system should adequately protect the dosage form and should be
constructed of materials that are compatible and safe.
Container closure systems for on-site storage have generally been considered a CGMP
issue under 21 CFR 211.65.  However, if a firm plans to hold bulk drug products in
storage, then the container closure system and the maximum storage time should be
described and justified in the application.  In addition, stability data should be provided to
demonstrate that extended storage in the described containers does not adversely affect
the dosage form.  Even when the storage time before packaging will be short, a firm
should use a container closure system that provides adequate protection and that is
manufactured from materials that are compatible and safe for the intended use (see section
III.B).
 FDA Compliance Policy Guides, "Regulatory Action Regarding Approved New Drugs and Antibiotic Drug Products
Subjected to Additional Processing or other Manipulation," Section 446.100, January 18, 1991 (CPG 7132c.06).
A container closure system for the transportation of bulk drug products to contract
packagers (section II.C.3) should be described in the application.  The container closure
system should be adequate to protect the dosage form, be constructed with materials that
are compatible with product being stored, and be safe for the intended use.  The protective
properties of the shipping container are verified by the practice of including annual batches
of the packaged product in postapproval stability studies.
A container closure system specifically intended for the transportation of a large volume of
drug product to a repackager (section II.C.3), whether for a solid or liquid dosage form, is
considered a market package.  The package should meet the same requirements for
protection, compatibility, and safety as a smaller market package;  should be included in
the stability studies for application approval and in the long term stability protocol; and
should be fully described in the application.  The length of time that the dosage form will
spend in the bulk container may be a factor in determining the level of detail of the
supporting information.  Two examples of a large-volume shipping package are a 10,000-
tablet HDPE pail with tamper-evident closure, and a 10-liter polyethylene terephthalate
(PET) container with a screw cap closure with dispenser attachment for a liquid drug
product.  Both are intended for sale to a mass distribution pharmacy.  A special case is the
pharmacy bulk package which is described in USP <1>.
 Applicants should check the appropriate sources directly for the most up-to-date information.
 A-1
ATTACHMENT A25
REGULATORY REQUIREMENTS
1.
The Federal Food, Drug, and Cosmetic Act
a.
Section 501
A drug or device shall be deemed to be adulterated “if its container is composed, in
whole or in part, of any poisonous or deleterious substance which may render the
contents injurious to health” (section 501(a)(3)); or “if it is a drug and the methods
used in, or the facilities or controls used for, its manufacture, processing, packing,
or holding do not conform to or are not operated or administered in conformity
with current good manufacturing practice to assure that such drug meets the
requirements of this Act as to safety and has the identity and strength, and meets
the quality and purity characteristics, which it purports or is represented to possess
(section 501(a)(2)(B)).
b.
Section 502
A drug or device shall be deemed to be misbranded:
C  “[i]f it purports to be a drug the name of which is recognized in an official
compendium, unless it is packaged and labeled as prescribed therein” (section
502(g))
C  “[i]f it is a drug and its container is so made, formed, or filled as to be
misleading” (section 502(i)(1))
C  “[i]f it is a drug and its packaging or labeling is in violation of an applicable
regulation issued pursuant to section 3 or 4 of the Poison Prevention Packaging
Act of 1970" (section 502(p))
c.
Section 505
“No person shall introduce or deliver for introduction into interstate commerce any
new drug, unless an approval of an application filed pursuant to subsection (b) or
(j) is effective with respect to such drug” (section 505(a)).
Section 505(b)(1)(D) requires "a full description of the methods used in, and the
 A-2
facilities and controls used for, the manufacture, processing, and packing of such
drug."
2.
The Code of Federal Regulations
a.
21 CFR 211 - Current Good Manufacturing Practice for Finished Pharmaceuticals
i.
Subpart E, Control of Components and Drug Product Containers and
Closures (21 CFR 211.80 - 211.94)
In particular, 21 CFR 211.94 outlines the requirements for drug product
containers and closures:
(a)
Drug product containers and closures shall not be reactive, additive,
or absorptive so as to alter the safety, identity, strength, quality, or
purity of the drug beyond the official or established requirements.
(b)
Container closure systems shall provide adequate protection against
foreseeable external factors in storage and use that can cause
deterioration or contamination of the drug product.
(c)
Drug product containers and closures shall be clean and, where
indicated by the nature of the drug, sterilized and processed to
remove pyrogenic properties to ensure that they are suitable for
their intended use.
(d)
Standards or acceptance criteria, test methods, and, where
indicated, methods of cleaning, sterilizing, and processing to
remove pyrogenic properties shall be written and followed for drug
product containers and closures.
ii.
Subpart F, Production and Process Controls (21 CFR 211.100 - 211.115)
iii.
Subpart G, Packaging and Labeling Control (21 CFR 211.122 - 211.137)
In particular, 21 CFR 211.132 describes the tamper-resistant packaging
requirements for over-the-counter (OTC) human drug products.  Most
OTC drug products must be packaged in tamper-resistant containers.
b.
16 CFR 1700-1702 - Special Packaging
The U.S. Consumer Product Safety Commission (CPSC) is responsible for
enforcing the Poison Prevention Packaging Act of 1970 (PPPA).  The PPPA
requires special packaging of hazardous household substances to protect children
 Federal Register, Volume 49, March 5, 1984, page 8008 (49 FR 8008), “Prescribed Drugs Distributed to Prescribing
Practitioners; Withdrawal of Proposed Statement of Policy and Interpretation.”
 A-3
from serious personal injury or serious illness from handling, using, or ingesting the
substances.  Drug products containing controlled substances, most human oral
prescription drug products (including oral investigational drugs used in outpatient
trials), and OTC drug preparations containing aspirin, acetaminophen,
diphenhydramine, liquid methyl salicylate, ibuprofen, loperamide, lidocaine,
dibucaine, naproxen, iron, or ketoprofen, require special packaging (16 CFR
1700.14).
Special packaging is defined under 15 U.S.C. 1471(2)(4), 16 CFR 1700.1(b)(4),
and 21 CFR 310.3(l).  Regulations issued under the PPPA establish performance
standards and test methods that determine if a packaging system is child-resistant
and adult-use-effective (16 CFR 1700.15 and 16 CFR 1700.20, respectively).
Except as noted below, all PPPA-regulated substances must be in packaging
systems that comply with these special packaging standards.  The standards apply
to both reclosable and nonreclosable packaging systems (unit-dose packaging).
There are several situations where child-resistant packaging for drug products is
not required.  Manufacturers and packagers of bulk-packaged prescription drug
products do not have to use special packaging if the drug is intended to be
repackaged by the pharmacist.  However, the manufacturer or packager is
responsible for child-resistant packaging if the drug product is intended to be
dispensed to the consumer as packaged without repackaging by the pharmacist (16
CFR 1701.1).  Prescribed drugs that are dispensed for use within institutions such
as hospitals and nursing homes do not require child-resistant packaging.  However,
any prescriptions dispensed to patients upon their release for their use at home
would be subject to the PPPA packaging requirements.  In addition, drug product
manufacturers are not required to provide child-resistant packaging for
prescription drug samples that are distributed to physicians and other prescribing
practitioners (i.e., physician samples).26
For OTC preparations, manufacturers or packagers are allowed to market one size
in non-child-resistant packaging as long as child-resistant packages are also
supplied.  The non-child-resistant package requires special labeling (16 CFR
1700.5).
16 CFR 1702 establishes the procedures for petitioning the CPSC for an
exemption from the PPPA requirements.  Several prescription drugs (e.g., oral
contraceptives in mnemonic packages, powdered colestipol, and
medroxyprogesterone acetate) have been exempted from the special packaging
requirements (16 CFR 1700.14(10)(I)-(xix)).  The CPSC is permitted to grant an
 A-4
exemption if it finds that packaging is not required to protect children from serious
injury, or that special packaging is not technically feasible, practicable, or
appropriate for that product.
For additional information regarding these packaging requirements and the
protocol test methods, please contact the CPSC.  Their website is located at
www.cpsc.gov and their hotline is 1-800-638-2772.
c.
21 CFR 174-186 - Indirect Food Additive Regulations
Regulations that are applicable to packaging components are:
i.
Part 174 - Indirect Food Additives:  General
ii.
Part 175 - Indirect Food Additives:  Adhesives and Components of
Coatings
e.g.,

### 175.105 Adhesives

### 175.300 Resinous and polymeric coatings

iii.
Part 176 - Indirect Food Additives:  Paper and Paperboard Components
e.g.,

### 176.170 Components of paper and paperboard in contact

with aqueous and fatty foods

### 176.180 Components of paper and paperboard in contact

with dry food
iv.
Part 177 - Indirect Food Additives:  Polymers
e.g.,

### 177.1380 Fluorocarbon resins

### 177.1520 Olefin polymers

### 177.1630 Polyethylene phthalate polymers

v.
Part 178 - Indirect Food Additives:  Adjuvants, Production Aids, and
Sanitizers
vi.
Part 180 - Food Additives Permitted in Food or in Contact with Food on
an Interim Basis Pending Additional Studies
e.g.,

### 180.22 Acrylonitrile copolymers

vii.
Part 182 - Substances Generally Recognized as Safe
e.g.,

### 182.70 Substances migrating from cotton and cotton fabrics

 A-5
used in dry food packaging

### 182.90 Substances migrating to food from paper and

paperboard products
viii.
Part 186 - Indirect Food Substances Affirmed as Generally Recognized as
Safe (GRAS)
e.g.,

### 186.1673 Pulp

d.
Biologics Provisions, 21 CFR 600, Subpart B, Establishment Standards
i.
21 CFR 600.11(h) - Containers and Closures
ii.
21 CFR 601.2 - Applications for Licenses; Procedures for Filing
e.
Other Sections
i.
21 CFR 201 - Labeling
ii.
21 CFR 310.509 - Parenteral drug products in plastic containers
iii.
21 CFR 200.50(a)(3) - Containers of ophthalmic preparations
3.
U.S. Pharmacopeia/National Formulary
The following sections are applicable to packaging components:
a.
General Notices - PRESERVATION, PACKAGING, STORAGE, AND
LABELING
b.
General Tests and Assays
<1>
Injections
<51>
Antimicrobial Preservatives - Effectiveness
<61>
Microbial Limit Tests
<71>
Sterility Tests
<87>
Biological Reactivity Tests, in vitro
<88>
Biological Reactivity Tests, in vivo
<161>
Transfusion and Infusion Assemblies
<381>
Elastomeric Closures for Injections
C Biological Test Procedures
C Physicochemical Test Procedures
<601>
Aerosols
<661>
Containers
 A-6
C
Light Transmission
C
Chemical Resistance - Glass Containers
C
Biological Tests - Plastics and Other Polymers
C
Physicochemical Tests - Plastics
C
Containers for Ophthalmics - Plastics
C
Polyethylene Containers
C
Polyethylene Terephthalate Bottles and Polyethylene
Terephthalate G Bottles
C
Single-Unit Containers and Unit-Dose Containers for Nonsterile
Solid and Liquid Dosage Forms
C
Customized Patient Medication Packages
<671>
Containers - Permeation
C
Multiple-Unit Containers for Capsules and Tablets
C
Single-Unit Containers and Unit-Dose Containers for Capsules
and Tablets
<691>
Cotton (or the monograph for Purified Rayon USP)
<771>
Ophthalmic Ointments
<1041>
Biologics
<1151>
Pharmaceutical Dosage Forms
 B-1
ATTACHMENT B
COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING
(August 1996)
Compliance Policy Guides are issued by the Division of Compliance Policy (in the Office of
Enforcement/Office of Regulatory Affairs).  The following is a list of Compliance Policy Guides
that concern packaging.  Any questions or concerns about the content of any Compliance Policy
Guide should be addressed to the Office of Enforcement/Office of Regulatory Affairs/Division of
Compliance Policy at 301-827-0420 (telephone), 301-827-0482 (FAX) or
www.fda.gov/ora/compliance_ref/cpg/default.html (Internet).
Sub Chapter 410
BULK DRUGS
Sec. 410.100
Finished Dosage Form Drug Products in Bulk Containers -
Applications of Current Good Manufacturing Practice Regulations
(CPG 7132a.06)
Sub Chapter 430
LABELING and REPACKAGING
Sec. 430.100
Unit Dose Labeling for Solid and Liquid Oral Dosage Forms (CPG
7132b.10)
Sec. 430.200
Repacking of Drug Products - Testing/Examination Under CGMPs
(CPG 7132.13)
Sub Chapter 440-448
NEW DRUGS
Sec. 446.100
Regulatory Action Regarding Approved New Drugs and Antibiotic
Drug Products Subjected to Additional Processing or Other
Manipulations (CPG 7132c.06)
Sub Chapter 450-457
OTC
Sec. 450.500
Tamper-Resistant Packaging Requirements for Certain Over-the-
Counter (OTC) Human Drug Products (CPG 7132a.17)
Sec. 450.550
Control and Accountability of Labeling Associated with Tamper-
Resistant Packaging of Over-the-Counter Drug Products (CPG
7132.14 )
Sub Chapter 480
STABILITY/EXPIRATION
 B-2
Sec. 480.100
Requirements for Expiration Dating and Stability Testing (CPG
7132a.04)
Sec. 480.200
Expiration Dating of Unit Dose Repackaged Drugs (CPG
7132b.11)
Sec. 480.300
Lack of Expiration Date of Stability Data (CPG 7132a.10)
 C-1
ATTACHMENT C
EXTRACTION STUDIES
An extraction study of a packaging component typically involves exposing a sample of the
component, often subdivided into small pieces to increase surface area, to an appropriate solvent
system at elevated temperatures, followed by chemical analysis.  The purpose of elevated
temperature is to increase the rate of extraction, so that a short experimental time may simulate a
longer exposure time at room temperature, or to maximize the amount of extractables obtained
from a sample.
The methods employed to analyze the resulting extracts vary, depending on the purpose of the
extraction study and the nature of the packaging component.  The extraction solvent may be
evaporated to concentrate the extracts or to determine the total weight of nonvolatile
extractables.  Appropriate methods, such as HPLC or gas chromatography, may be used to obtain
qualitative or quantitative extraction profiles of volatile or nonvolatile extractables.
Extraction studies may be conducted during the qualification of packaging components for any of
the following purposes:
C
To perform USP characterization tests on plastics (USP <661>) or elastomers
(USP <381>)
C
To perform USP Biological Reactivity Tests (USP <87> and <88>) on plastics or
elastomers
C
To obtain qualitative extraction profiles of plastics or elastomers
C
To obtain quantitative extraction profiles of plastics or elastomers
C
To evaluate whether the FDA indirect food additive regulations provide an
adequate indicator of safety
Extraction studies may also be conducted on a routine basis as a quality control measure to
monitor the chemical compositions of elastomeric or other packaging components.
The solvent that should be used in an extraction study depends on the purpose of the study.  The
ideal situation is for the extracting solvent to have the same propensity to extract substances as
the dosage form, thus obtaining the same quantitative extraction profile.  For this study, the
preferred solvent would be the drug product or placebo vehicle.  When feasible, the dosage form
itself would be used.  A stronger extracting solvent than the drug product would be used to obtain
a qualitative extraction profile that would be used to establish quality control criteria.
 D-1
ATTACHMENT D
ABBREVIATIONS
AAO
American Academy of Ophthalmology
ANDA
Abbreviated New Drug Application
BLA
Biologics License Application
CBER
Center for Biologics Evaluation and Research
CDER
Center for Drug Evaluation and Research
CFR
Code of Federal Regulations
CFSAN
Center for Food Safety and Applied Nutrition
CGMP
Current Good Manufacturing Practice
CMC
Chemistry, Manufacturing, and Control
COA
Certificate of Analysis
CPSC
Consumer Product Safety Commission
DMF
Drug Master File
DPI
Dry Powder Inhaler
FDA
U.S. Food and Drug Administration (the Agency)
HDPE
High Density Polyethylene
IND
Investigational New Drug Application
LDPE
Low Density Polyethylene
LOA
Letter of Authorization
LVP
Large-Volume Parenteral
MDI
Metered Dose Inhaler
NDA
New Drug Application
PET
Polyethylene Terephthalate
PETG
Polyethylene Terephthalate G
PP
Polypropylene
PVC
Polyvinyl Chloride
QA
Quality Assurance
QC
Quality Control
SVP
Small-Volume Parenteral
USP/NF
U.S. Pharmacopeia/National Formulary
 A list of CDER and CBER guidances and guidelines is provided on the Internet at
www.fda.gov/cder/guidances.index.htm and www.fda.gov/cber/guidelines.htm, respectively.
 E-1
ATTACHMENT E
REFERENCES27
Center for Drug Evaluation and Research (CDER) Compressed Medical Gases Guideline
(February 1989)
FDA Guideline for Drug Master Files (September 1989)
FDA Guidance for Industry on the Submission of Documentation for the Sterilization Process
Validation in Applications for Human and Veterinary Drug Products (November 1994)
FDA Guidance for Industry on the Content and Format on Investigational New Drug
Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic,
Biotechnology-Derived Products (November 1995)
FDA Guidance for Industry on the Submission of Chemistry, Manufacturing, and Controls
Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody
Product for In Vivo Use (August 1996)
FDA Guidance for Industry on the Submission of Chemistry, Manufacturing, and Controls
Information and Establishment Description for Autologous Somatic Cell Therapy Products
(January 1997)
FDA Guidance for the Photostability Testing of New Drug Substance and Products (May 1997)
FDA Guidance for Industry on the Submission of Chemistry, Manufacturing, and Controls
Information for Synthetic Peptide Substances (January 1998)
FDA Guidance for Industry on the Content and Format of Chemistry, Manufacturing, and
Controls and Establishment Description Information for a Vaccine or Related Product (January
1999)
FDA Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls and
Establishment Description Information for Human Plasma-Derived Biological Product or
Animal Plasma or Serum-Derived Products (February 1999)
FDA Guidance for Industry on the Content and Format of Chemistry, Manufacturing, and
 E-2
Controls and Establishment Description Information for a Biological In Vitro Diagnostic
Product (March 1999)
FDA Guidance for Industry on the Content and Format of Chemistry, Manufacturing, and
Controls and Establishment Description Information for Allergenic Extract or Allergen Patch
Test (April 1999)
FDA Guidance for Industry for the Submission of Chemistry, Manufacturing, and Controls and
Establishment Description Information for Human Blood and Blood Components Intended for
Transfusion or for Further Manufacture and for the Completion of the FDA Form 356h,
Application to Market a New Drug, Biologic, or an Antibiotic Drug for Human Use (May 1999)

---

### Document: FDA GlassVial Complete (FDA)

# FDA Guidance for Industry: Container Closure System and Component Changes: Glass Vials and Stoppers (2024)

Container Closure
System and Component
Changes: Glass Vials
and Stoppers
Guidance for Industry

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

July 2024
Pharmaceutical Quality/Manufacturing Standards

Container Closure
System and Component
Changes: Glass Vials
and Stoppers
Guidance for Industry

Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
 Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)

July 2024
Pharmaceutical Quality/Manufacturing Standards

Contains Nonbinding Recommendations

i
TABLE OF CONTENTS

I.
INTRODUCTION............................................................................................................. 1
II.
REGULATORY APPROACHES TO CMC CHANGES ............................................. 2
III.
COMMON CHANGES RELATED TO GLASS VIALS AND STOPPERS .............. 4
IV.
TOOLS TO FACILITATE CHANGES TO CCS COMPONENTS ............................ 5
A.
Risk-Based Considerations for Supplement Reporting Categories ........................................... 5
B.
Comparability Protocols ............................................................................................................... 6
REFERENCES .............................................................................................................................. 7
APPENDIX: TABLES DESCRIBING CCS CHANGES FOR PRODUCTS WITH
APPROVED ANDAS, NDAS, OR BLAS ................................................................................. 10
Contains Nonbinding Recommendations

Container Closure System and Component Changes: Glass Vials
and Stoppers
Guidance for Industry1

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.

I.
INTRODUCTION

FDA is issuing this guidance to collate recommendations for appropriate reporting categories and
the content of postapproval change submissions across numerous FDA guidance documents.2
This guidance conveys recommendations to holders of approved new drug applications (NDAs),
biologics license applications (BLAs), and abbreviated new drug applications (ANDAs)
regarding the reporting and implementation of some common changes to container closure
system (CCS) components consisting of glass vials and stoppers for approved3 sterile drug
products, including biological products, administered parenterally. This guidance also discusses
pathways available to application holders to obtain Agency feedback. Additionally, this guidance
discusses risk-based tools available to facilitate the implementation of changes to CCSs
consisting of glass vials and stoppers. This guidance does not apply to CCS types other than
glass vials and stoppers.

1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug
Administration. You may submit comments on this guidance at any time.  Submit comments to Docket No. FDA-
2017-D-6821 (available at https://www.regulations.gov/docket?D=FDA-2017-D-6821). See the instructions in
that docket for submitting comments on this and other Level 2 guidances.
2 In March 2021, FDA published the guidance for industry COVID-19 Container Closure System and Component
Changes: Glass Vials and Stoppers, which provided recommendations regarding the reporting and implementation
of some common changes to container closure system (CCS) components consisting of glass vials and stoppers for
approved sterile drugs. That guidance was intended to remain in effect only for the duration of the public health
emergency related to COVID-19 declared by the Secretary of Health and Human Services under section 319 of the
Public Health Service Act (section 319 public health emergency), which has now expired. FDA is issuing this final
guidance because many of the recommendations set forth in the 2021 guidance are applicable outside the context of
the section 319 public health emergency.
3 Although this guidance does not principally address data recommendations for original applications pending
approval, the risk-based regulatory approaches discussed in this guidance, other guidance documents referenced in
References, and the data recommendations provided in the tables in Appendix may be useful during product
development and for original application submission. Should an applicant need to change CCS components before
product approval, the applicant should proactively seek feedback from the appropriate FDA review division to
mitigate the effect of the change on the review timeline of the pending application.
Contains Nonbinding Recommendations

In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.

II.
REGULATORY APPROACHES TO CMC CHANGES

As described in section 506A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 356a), 21
CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12, an applicant must notify FDA about changes
in each condition (e.g., the product, production process, quality controls, equipment, facilities, or
labeling) established in an approved application beyond the variations already provided for in the
application. The reporting category for such changes depends on the potential to have an adverse
effect on the identity, strength, quality, purity, or potency of the product as these factors may
relate to the safety or effectiveness of the product. Therefore, changes can range from those that
require approval before implementation (prior approval supplement (PAS)), those that require
notification 30 days before (changes being effected in 30 days (CBE-30)), or upon
implementation (changes being effected), and those where notification can be provided after
implementation (annual report). Some of these identified changes, depending on the
circumstances, may be more appropriately submitted as an original application instead of as
supplements.4

FDA has conveyed additional clarification regarding reporting of CMC changes to an NDA,
BLA, and ANDA in guidance documents specific to various application types and product
dosage forms (see References). The content in section IV. Common Changes Related to Glass
Vials and Stoppers related to changes to glass vials and stoppers for finished drug and biological
products includes content derived from the referenced guidance documents.

FDA applies a risk-based approach to the evaluation of proposed CMC changes to a CCS (e.g.,
changes in components, composition, container type, suppliers, and manufacturers), taking into
consideration the characteristics of the specific product. The suitability and compatibility of a
CCS depends not only on the properties of a container, but also on the properties of other CCS
components and their interactions with the drug product formulation over its intended shelf life.
Applicants must validate the effects of the change prior to distribution of the drug,5 and, as
appropriate, conduct additional qualification tests or submit information to address product-
specific risks as part of that assessment. For example, this additional information to be submitted
to FDA could include studies to assess: the effect of formulation attributes such as high pH; the
effect of factors that increase the potential for glass delamination, particulate matter, leachables,
or interactions of labile molecules with leachables (such as susceptibility of some proteins to
interact with metal ions); or the effect of the lyophilization process on product quality. Finally,

4 Applicants can consult the appropriate Center for Drug Evaluation and Research or Center for Biologics
Evaluation and Research review division for questions regarding circumstances where an original application or
supplement should be submitted.
5 See section 506A(b) of the FD&C Act and pertinent regulations at 21 CFR 314.70(a)(2), 21 CFR 314.97(a)
(incorporating 21 CFR 314.70 by reference), and 21 CFR 601.12(a)(2).
Contains Nonbinding Recommendations

applicable tests and studies as outlined in United States Pharmacopeia (USP) chapters6 should be
conducted to demonstrate the suitability of the glass vial following a change; such tests must be
conducted where needed to ensure continued compliance with compendial standards for strength,
quality, or purity of the drug.7 FDA encourages applicants to submit the appropriate
postapproval supplement type as recommended by the existing guidance documents for proposed
changes to the CCS.

FDA may consider available risk evaluations and product quality risk mitigation strategies to
support a lower reporting category for specific changes. FDA recommends applicants use the
risk management principles described in the ICH guidance for industry Q9(R1) Quality Risk
Management (May 2023), and tools described in ICH guidance for industry Q12 Technical and
Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021),
where appropriate. Whether or not a change is required to be reported to FDA, in accordance
with applicable regulations,8 FDA expects all changes to be appropriately managed by an
establishment’s/facility’s pharmaceutical quality system under the applicable current good
manufacturing practice regulations in 21 CFR parts 210, 211, and 600. Applicants should also
refer to the recommendations in the ICH guidance for industry Q10 Pharmaceutical Quality
System (April 2009).

A supplement for a CCS-related change should include information to support the proposed
change and can incorporate certain information by reference to a drug master file (DMF), where
appropriate. However, when incorporating information by reference to a DMF, the supplement
should also include sufficient product-specific information to support the change.

Applicants are ultimately responsible for assessing the effects of the proposed change(s) on
product quality, and ensuring that information to support the change is provided for a complete
submission of a supplement or annual report.9 DMF holders must notify affected authorized
parties of any DMF changes, additions, or deletions.10 DMF holders also should provide
application holders with sufficient information to determine the appropriate reporting category
for their applications based on the potential to have an adverse effect on the identity, strength,
quality, purity, or potency of the product as these factors may relate to the safety or effectiveness
of the product. This notification should occur well before making any changes to permit
authorized parties to submit application changes within an appropriate time frame. For additional
information on DMF submission guidelines, refer to 21 CFR 314.420, 21 CFR 601.51(a), and the
draft guidance for industry Drug Master Files (October 2019).11

6 See USP General Chapters <381> Elastomeric Closure for Injections, <660> Glass Containers Used in
Pharmaceutical Packaging/Delivery Systems, <1207> Package Integrity Evaluation — Sterile Products, <1660>
Evaluation of the Inner Surface Durability of Glass Containers.
7 See section 501(b) of the FD&C Act.
8 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
9 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
10 21 CFR 314.420(c).
11 In June 2014, FDA issued the guidance for industry Drug Master Files: Guidelines. In October 2019, FDA issued
the revised draft guidance for industry Drug Master Files. When final, this guidance will represent FDA’s current
thinking on this topic. We update guidances periodically. For the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
Contains Nonbinding Recommendations

This guidance is not intended to alter existing submission processes; applicants should follow the
recommendations in current guidance documents for reporting CMC changes to an approved
application (see References).

III.
COMMON CHANGES RELATED TO GLASS VIALS AND STOPPERS

The tables in the Appendix of this guidance include information derived from existing FDA
guidance documents that contain recommendations for reporting category and submission
content related to common CMC changes to CCS components (glass vials and stoppers) for
finished drug and biological products. The tables include the type of data recommended to
support a specific change (as discussed in the guidance for industry Container Closure Systems
for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls
Documentation (May 1999)), as well as the recommended reporting category. Some
recommendations regarding data submission and reporting categories may differ based on the
nature of the product and the potential risk to product quality as it may relate to safety and
effectiveness of the product. The quantity of data that should be included in the submission
depends on the application type and available body of knowledge.12 Changes should be
supported with confirmatory13 batch data. To assess the change, FDA may request that the
applicant provide additional information in the supplement or referenced DMF.

An applicant seeking to make more than one related change concurrently should submit a
supplement with data appropriate to address the potential risk from the cumulative effect of
multiple changes. Where the recommended reporting categories for the individual changes differ,
the submission category selected should be the one associated with the highest risk change (e.g.,
PAS) of the categories recommended for the individual changes.

When the CCS changes described in the Appendix tables necessitate a corresponding change in
finished product specifications,14 the applicant should provide all studies and data appropriate to
support the affected specification change(s). The reporting category depends on the potential to
have an adverse effect on the identity, strength, quality, purity, or potency of the product as these
factors may relate to the safety or effectiveness of the product. For example, tightening the
acceptance criteria for a quality attribute may warrant a lower reporting category than widening
the acceptance criteria.

12 The quantity of data recommended in the Appendix tables for NDAs, ANDAs, and BLAs is derived from related
guidance documents. For example, the number of batches is derived from principles outlined in scale-up and
postapproval changes guidance documents (e.g., 1 to 3 batches for ANDAs and NDAs depending on the body of
knowledge). Where guidance documents do not provide specific information on the quantity of data expected to
support the change, the applicant may contact FDA to obtain feedback.
13 For the purposes of this guidance, confirmatory data means comparative product batch data (on product
manufactured prior to and after the proposed change) that is sufficient to demonstrate no adverse effect on product
quality due to the proposed CCS change.
14 The ICH guidances for industry Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances (December 2000) and Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnological/Biological Products (August 1999) define specifications
as “a list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits,
ranges, or other criteria for the tests described.”
Contains Nonbinding Recommendations

Before introducing a new CCS component that differs from the specified CCS component
type/grade in product labeling (e.g., “packaged in type 1 glass”), a supplement to change product
labeling may be appropriate. When the CCS new component differs from that specified in the
applicable USP monograph, appropriate engagement with USP regarding an update to the
product monograph15 may be necessary to ensure continued compliance with the monograph.16

IV.
TOOLS TO FACILITATE CHANGES TO CCS COMPONENTS

For CCS and component changes that are the subject of this guidance, FDA intends to consider
risk-based approaches using existing tools and capabilities to facilitate providing timely
feedback, guidance, and assessment of proposed changes as discussed below.

FDA may expedite the assessment of a supplement or determine that a different reporting
category is appropriate, taking into account public health priorities17 and the applicant’s rationale
and associated risk assessment and mitigation strategy for the proposed change. Should a
different reporting category be determined to be appropriate, FDA will notify the applicant and
convey its rationale for the determination.18

A.
Risk-Based Considerations for Supplement Reporting Categories

Consistent with applicable regulations and existing guidance documents related to postapproval
CMC changes for NDAs, ANDAs, and BLAs, FDA may consider available information and
approaches to mitigate the risk to product quality when determining whether a lower reporting
category for supplements is appropriate. Applicants should consider using tools in ICH Q12
(e.g., established conditions, postapproval change management protocols (PACMPs)) to support
proposals for reduced reporting categories based on an increased understanding of the risk to
product quality when making a change related to the glass vial or stopper.

Before submitting a supplement with a lower reporting category than what is required in existing
regulations and recommended in existing guidance, applicants should contact FDA for feedback
and concurrence. For Center for Drug Evaluation and Research (CDER)-regulated products,
applicants should contact the regulatory project management staff (regulatory project manager or

15 For additional information, see the draft guidance for industry Harmonizing Compendial Standards With Drug
Application Approval Using the USP Pending Monograph Process (July 2019). When final, this guidance will
represent FDA’s current thinking on this topic.
16 See section 501(b) of the FD&C Act.
17 For additional information, see 21 CFR 314.70(b)(4). For FDA policies describing expedited review requests
related to prior approval supplements to NDAs and BLAs, see MAPP 5310.3 Rev 1 Requests for Expedited Review
of New Drug Application and Biologics License Application Prior Approval Supplements Submitted for Chemistry,
Manufacturing, and Controls Changes; for FDA policies describing prioritization of the review related to original
ANDAs, amendments, and supplements thereof, see MAPP 5240.3 Rev. 5 Prioritization of the Review of Original
ANDAs, Amendments, and Supplements; for FDA policies on drug shortage management, see MAPP 4190.1 Rev. 3
Drug Shortage Management. MAPPs are available at https://www.fda.gov/about-fda/center-drug-evaluation-and-
research-cder/cder-manual-policies-procedures-mapp.
18 Depending on the regulatory jurisdiction of the product, the applicant can contact the responsible review division
within CDER or CBER (as applicable) to gain additional feedback on specific changes, the information needed to
support the change, and the filing approach, as needed.
Contains Nonbinding Recommendations

regulatory business process manager) within the appropriate CDER review office responsible for
the subject product application. For Center for Biologics Evaluation and Research (CBER)-
regulated products, applicants should contact the appropriate CBER review office. Additionally,
if the CDER- or CBER-regulated product could enter, or is currently in, drug shortage, then the
respective applicant should include drugshortages@fda.hhs.gov for products regulated by CDER
and cbershortage@fda.hhs.gov for products regulated by CBER on those communications.

B.
Comparability Protocols

As explained in the guidance for industry Comparability Protocols for Postapproval Changes to
the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA (October
2022), a comparability protocol (CP) is a comprehensive, prospectively written plan for
assessing the effect of a proposed CMC postapproval change(s) on the identity, strength, quality,
purity, and potency of a drug product or a biological product. It is a tool for applicants to obtain
feedback from FDA on prospective scientific approaches, submitted as a part of an original
application or PAS, to facilitate expeditious implementation of postapproval changes. CPs allow
FDA to review a description of one or more proposed CMC postapproval changes, supporting
information (including any analysis and risk assessment activities), the plan for implementing the
change(s), and, if appropriate, the proposed reduced reporting category for the change(s). By
delineating the specific approach to be used to evaluate one or more future changes and the
rationale for that approach, the applicant can gain the Agency’s approval of the plan well in
advance of the need to implement the change(s). This process can facilitate a more efficient
submission process for the applicant and review process for FDA.

If the original application or PAS containing the CP is approved, the change usually can be
implemented under a lower reporting category than would normally be expected based on
recommendations in guidance (e.g., changes otherwise requiring a prior approval supplement
could be implemented under a CBE-30). A CP can then be used for a one-time change(s) or be
used repeatedly for a specified type of change over the life cycle of a product. A CP can also be
submitted to cover an identical change(s) that affects multiple applications (grouped
supplements, trans-BLA submissions).19 A CP is a well-suited tool for making changes to glass
vials and stoppers, because a change to one component can be implemented to many products
sharing that container or closure, and the protocol could be used multiple times as the need arises
for additional changes to accommodate the dynamic supply chain evolution.

19 See the guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application:
Certain Biological Products (June 2021).
Contains Nonbinding Recommendations

REFERENCES20

Draft and Final Guidances21

• Changes to an Approved Application for Specified Biotechnology and Specified Synthetic
Biological Products (July 1997)

• Changes to an Approved NDA or ANDA (April 2004)

• Changes to an Approved NDA or ANDA; Questions and Answers (January 2001)

• Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain
Biological Products (June 2021)

• Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing,
and Controls Information in an NDA, ANDA, or BLA (October 2022)

• Container Closure Systems for Packaging Human Drugs and Biologics (May 1999)

• CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports
(March 2014)

• CMC Postapproval Manufacturing Changes for Specified Biological Products To Be
Documented in Annual Reports (December 2021)

• Drug Master Files (October 2019)22

• Harmonizing Compendial Standards With Drug Application Approval Using the USP
Pending Monograph Process (July 2019)23

• ICH Q12 Implementation Considerations for FDA-Regulated Products (May 2021)24

• Manufacturing Changes and Comparability for Human Cellular and Gene Therapy
Products (July 2023)25

• PAC-ATLS: Postapproval Changes — Analytical Testing Laboratory Sites (April 1998)

20 MAPPs can be found on the CDER Manual of Policies & Procedures web page at https://www.fda.gov/about-
fda/center-drug-evaluation-and-research/cder-manual-policies-procedures-mapp, and SOPPs can be found on the
Biologics Procedures (SOPPs) web page at https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-procedures-sopps.
21 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
22 When final, this guidance will represent the FDA’s current thinking on this topic.
23 Ibid.
24 Ibid.
25 Ibid.
Contains Nonbinding Recommendations

• Submission Documentation for Sterilization Process Validation in Applications for
Human and Veterinary Drug Products (November 1994)

Scale-Up and Postapproval Changes Guidances

• SUPAC: Manufacturing Equipment Addendum (December 2014)26

• SUPAC-IR: Questions and Answers about SUPAC-IR Guidance (February 1997)

• SUPAC-MR: Modified Release Solid Oral Dosage Forms; Scale-Up and Postapproval
Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing and In
Vivo Bioequivalence Documentation (September 1997)

• SUPAC-IR: Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval
Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In
Vivo Bioequivalence Documentation (November 1995)

• SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and Postapproval Changes:
Chemistry, Manufacturing, and Controls; In Vitro Release Testing and In Vivo
Bioequivalence Documentation (May 1997)

ICH Guidances

• Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances (December 2000)

• Q6B Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products (August 1999)

• Q9(R1) Quality Risk Management (May 2023)

• Q10 Pharmaceutical Quality System (April 2009)

• Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management (May 2021)

Manual of Policies and Procedures27

• MAPP 4190.1 Rev. 3 Drug Shortage Management

26 When final, this guidance will represent the FDA’s current thinking on this topic.
27 MAPPs can be found on the CDER Manual of Policies & Procedures web page at https://www.fda.gov/about-
fda/center-drug-evaluation-and-research/cder-manual-policies-procedures-mapp.
Contains Nonbinding Recommendations

• MAPP 5240.3 Rev. 6 Prioritization of the Review of Original ANDAs, Amendments, and
Supplements

• MAPP 5310.3 Rev. 2 Requests for Expedited Review of New Drug Application and
Biologics License Application Prior Approval Supplements Submitted for Chemistry,
Manufacturing, and Controls Changes

Standard Operating Procedures and Policies28

• SOPP 8506 Management of Shortages of CBER-Regulated Products

28 SOPPs can be found on the CBER Biologics Procedures (SOPPs) web page at https://www.fda.gov/vaccines-
blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-procedures-sopps.
Contains Nonbinding Recommendations

APPENDIX: TABLES DESCRIBING CCS CHANGES FOR PRODUCTS WITH
APPROVED ANDAS, NDAS, OR BLAS

The following tables include information derived from existing FDA guidance documents
containing FDA recommendations for reporting categories and submission content for common
chemistry, manufacturing, and controls changes to glass vials and stoppers, the container closure
system (CCS) components of finished pharmaceuticals and biological products. These tables
provide baseline recommendations for the information to be submitted and the reporting category
for specific changes, and do not consider the cumulative effect of concurrent changes. As stated
in sections III and IV of the guidance, FDA may request more information to support the change,
and determine that a different reporting category is appropriate based on risk assessment
information related to the specific change proposed.

These tables do not include all possible CCS changes that would necessitate a submission as
described in applicable regulations.1 Application holders should consult existing guidance
documents for further information on CCS change recommendations. Depending on regulatory
jurisdiction of the product application, the applicant can contact the responsible review division
within the Center for Drug Evaluation and Research (CDER)2 or the Center for Biologics
Evaluation and Research (CBER) (as applicable) to gain additional feedback on specific
changes, the information needed to support the change, and the filing approach, as needed.

For the following tables, the term confirmatory data means comparative data that demonstrate no
adverse impact on product quality due to the proposed CCS change.

1 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12.
2 When the submission is an abbreviated new drug application (ANDA), submit questions through the pre-ANDA
meeting or controlled correspondence processes. See the guidances for industry Formal Meetings Between FDA and
ANDA Applicants of Complex Products Under GDUFA (November 2020) and Controlled Correspondence Related
to Generic Drug Development (December 2020).
Contains Nonbinding Recommendations

Table A: Changes to the Properties of Glass Vials and Stoppers: New Drug Applications/Abbreviated New Drug Applications*
continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Change from glass to a
new material (e.g.,
plastic)
Confirmatory batch data, including
release and stability data
(accelerated and real time•), and
data to support sterility assurance

Extractables and leachables risk
assessment and supporting data
PAS

Section IX.B.4. of
Changes to an
Approved NDA or
ANDA (April 2004)

Change to different
composition or type of
glass2

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance

PAS

Sections IX.B.4.
and IX.C.1.a. of
Changes to an
Approved NDA or
ANDA
FDA may consider a lower
reporting category based
on the circumstances of
the specific change2
Contains Nonbinding Recommendations

Table A, continued
continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Change between
molded and tubing
glass

Description, composition, drawing,
and specification of vial

CCS suitability tests and
determinations as recommended
in USP General Chapter <660> and
principles of USP General Chapter
<1660> (required for compendial
products)3

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance

CCIT data

Lyophilization cycle verification or
validation if process is modified
(refer to Specific Considerations for
Reporting Category)
CBE-30

PAS for
lyophilized
products (refer
to Specific
Considerations
for Reporting
Category)

Section IX.C.1.a.
of Changes to an
Approved NDA or
ANDA

Changes in vial properties
that affect manufacturing
processes (e.g., thicker
glass affecting
lyophilization processes)
pose a higher risk to
quality and therefore may
trigger a higher reporting
category with additional
data needed to assess the
effects of the change
Contains Nonbinding Recommendations

Table A, continued
continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Change in vial
dimensions
CCIT data

Representative media
fill/bracketing data

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance
PAS

Section IX.B.4. of
Changes to an
Approved NDA or
ANDA

For vials with the same
nominal fill volume but
slight changes to
dimensions, a CBE-30 may
be appropriate

Switch from amber
glass to clear glass (with
or without additional
photoprotective
measures)

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance

Additional tests based on results of
comparative photostability study

Labeling change accounting for
different storage conditions (e.g.,
protect from light)
PAS
Section IX.B.6. of
Changes to an
Approved NDA or
ANDA

Contains Nonbinding Recommendations

Table A, continued
continued

Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Change in primary CCS
type (e.g., switching
from vial to ampule)4
Description of the container
properties and composition

Container suitability5

Manufacturing and controls

CCIT data

Sterilization validation

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance
PAS

Section IX.B.4. of
Changes to an
Approved NDA or
ANDA

Contains Nonbinding Recommendations

Table A, continued
continued

Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Change in stopper
rubber/elastomer
material6

Description of new stopper

Composition

Manufacturing and controls

Closure suitability7

CCIT data

Confirmatory batch data, including
release and stability data
(accelerated and real time),
including vial orientations where
formulation is in contact with
stopper, and data to support
sterility assurance
PAS
Section IX.B.4. of
Changes to an
Approved NDA or
ANDA

Change in stopper
dimensions

CCIT data

Confirmatory batch data, including
release and stability data
(accelerated and real time), and
data to support sterility assurance
CBE-30
Section IX.C.1.a.
of Changes to an
Approved NDA or
ANDA

Contains Nonbinding Recommendations

Table A, continued
* PAS = prior approval supplement; CCIT = Container Closure Integrity Test; CBE-30 = changes being effected in 30 days; RTS = ready to sterilize; RTU =
ready to use; COA = certificate of analysis; BET = bacterial endotoxins testing
• Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
2 A change in glass supplier without a change in glass type or coating and without a change in container/closure dimensions can be filed as an annual report as
described in section 5.4 of Appendix in the guidance for industry CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (March
2014).
3 United States Pharmacopeia (USP) General Chapter <660> Glass Containers Used in Pharmaceutical Packaging/Delivery Systems, and USP General Chapter
<1660> Evaluation of the Inner Surface Durability of Glass Containers.
4 Some of these identified changes, depending on the circumstances, may be more appropriately submitted as an original application instead of as supplements.
This type of change may also warrant a labeling change supplement to account for a new presentation. Application holders should follow existing FDA guidance.
Applicants can consult the appropriate review division within CDER or CBER if there are questions.
5 Information about the suitability of proposed glass with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables) and
performance. Application holders should refer to USP General Chapter <660> and USP General Chapter <1660> for further information.
6 When alternate suppliers of stoppers are proposed, and if there are differences in stopper properties or manufacturing processes changes between the currently
approved and proposed supplier, because of the increased risk to quality, a higher reporting category — PAS — is warranted. However, if the differences in
stopper properties and manufacturing processes are minimal then a lower reporting category may be considered.
7 Information about the suitability of proposed stopper with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables)
and performance. Application holders should refer to USP General Chapter <381> Elastomeric Closure for Injections, for additional information.

Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to
Current
Guidance1
Specific Considerations for
Reporting Category
Changes in how the
stopper is supplied
(e.g., unprocessed, RTS,
and RTU)
Sterilization and depyrogenation
validation

Representative COA, which would
include sterility and BET data if
stoppers are supplied RTU and BET
data if stoppers are supplied RTS
CBE-30
Section IX.C.1.a.
of Changes to an
Approved NDA or
ANDA

Contains Nonbinding Recommendations

Table B: Changes to the Properties for Glass Vials and Stoppers: Biologics License Applications*
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change from glass to a
new material (e.g.,
plastic)
Extractables and leachables risk
assessment and supporting data

Confirmatory batch data,
including release and stability
data (accelerated and real time•),
and data to support sterility
assurance

PAS
Changes to an
Approved
Application for
Specified
Biotechnology and
Specified Synthetic
Biological Products
(July 1997)

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products
(June 2021)

continued
Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change to different
composition or type of
glass2
Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance

PAS

BLA: Changes to an
Approved
Application for
Specified
Biotechnology and
Specified Synthetic
Biological Products

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products
FDA may consider a
lower reporting category
based on the
circumstances of the
specific change (e.g., if
the new vial type or
composition was
previously used in a
licensed product)
continued
Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change between molded
and tubing glass

Description, composition,
drawing, and specification of vial

CCS suitability tests and
determinations as recommended
in USP General Chapter <660>
and principles of USP General
Chapter <1660> (required for
compendial products)3

CCIT data

Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance

Lyophilization cycle verification or
validation if process is modified
(refer to Specific Considerations
for Reporting Category)

AR

PAS for
lyophilized
products with
molded vials
(refer to
Specific
Considerations
for Reporting
Category)

Section 3.2.P.7., due
to expected change in
properties, of the
Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products

Section 5.2 of the

## Appendix in: CMC

Postapproval
Manufacturing
Changes for Specified
Biological Products To
Be Documented in
Annual Reports
(December 2021)

Changes to an
Approved Application
for Specified
Biotechnology and
Specified Synthetic
Biological Products
Changes in vial
properties that affect
manufacturing processes
(e.g., thicker glass
affecting lyophilization
processes) pose a higher
risk to quality and
therefore may trigger a
higher reporting
category with need for
additional data to assess
the effects of the change
continued

Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change in vial
dimensions
CCIT data

Representative media fill

Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance

Additional accelerated and real
time stability data as needed
(e.g., concurrent stopper change)

PAS
BLA: Changes to an
Approved Application
for Specified
Biotechnology and
Specified Synthetic
Biological Products

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products
For vials with the same
nominal fill volume but
slight changes to
dimensions, a CBE-30
may be considered
Switch from amber glass
to clear glass (with or
without additional
photoprotective
measures)

Confirmatory batch data, including
release and stability data
(accelerated and real time), and data
to support sterility assurance

Additional tests based on results of
comparative photostability study

Labeling change accounting for
different storage conditions (e.g.,
protect from light)
PAS
Same as above

continued

Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change in primary CCS
type (e.g., switching from
vial to ampule)4

Description of the container
properties and composition

Container suitability5

Manufacturing and controls

Sterilization validation

CCIT data

Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance
PAS
BLA: Changes to an
Approved
Application for
Specified
Biotechnology and
Specified Synthetic
Biological Products

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products

continued
Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Change in stopper
rubber/elastomer
material6

Description of new stopper

Composition

Closure suitability7

Manufacturing and controls

CCIT data

Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance
PAS
BLA: Changes to an
Approved
Application for
Specified
Biotechnology and
Specified Synthetic
Biological Products

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products

Change in stopper
dimensions

Confirmatory batch data,
including release and stability
data (accelerated and real time),
and data to support sterility
assurance

CCIT data
CBE-30
Same as above

continued
Contains Nonbinding Recommendations

Table B, continued
Proposed Change
Recommended Information to
Support the Change
Recommended
Reporting
Category
Reference to
Current Guidance1
Specific Considerations
for Reporting Category
Changes in how the
stopper is supplied (e.g.,
unprocessed, RTS, and
RTU)

Sterilization and depyrogenation
validation
Confirmatory batch data,
including data to support sterility
assurance

CBE-30

Section 3.2.P.7. of
the Appendix in
Chemistry,
Manufacturing, and
Controls Changes to
an Approved
Application: Certain
Biological Products
Changes to an
Approved
Application for
Specified
Biotechnology and
Specified Synthetic
Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances of
the change (e.g., change
is occurring at a vendor
that provides pre-
processed stoppers)
* PAS = prior approval supplement; BLA = biologics license application; CCIT = Container Closure Integrity Test; AR = annual report; CBE-30 = changes
being effected in 30 days; RTS = ready to sterilize; RTU = ready to use
• Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
2 This change can be reported in an annual report if there is no change in the product-contact material or dimensions (size and shape) per 3.2.P.7 of the Appendix
in the guidance for industry Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products.
3 United States Pharmacopeia (USP) General Chapter <660> Glass Containers Used in Pharmaceutical Packaging/Delivery Systems, and USP General Chapter
<1660> Evaluation of the Inner Surface Durability of Glass Containers.
4 Some of these identified changes, depending on the circumstances, may be more appropriately submitted as an original application instead of as supplements.
This type of change may also warrant a labeling change supplement to account for a new presentation. Application holders should follow existing FDA guidance.
Applicants can consult the appropriate review division within CDER or CBER if there are questions.
5 Information about the suitability of proposed glass with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables) and
performance. Application holders should refer to USP General Chapter <660> and USP General Chapter <1660> for further information.
Contains Nonbinding Recommendations

6 When alternate suppliers of stoppers are proposed, and if there are differences in stopper properties or manufacturing processes changes between the currently
approved and proposed supplier, because of the increased risk to quality, a higher reporting category — PAS — is warranted. However, if the differences in
stopper properties and manufacturing processes are minimal then a lower reporting category may be considered.
7 Information about the suitability of proposed stopper with respect to protection (e.g., container integrity for sterility), safety (e.g., extractables and leachables)
and performance. Application holders should refer to USP General Chapter <381> Elastomeric Closure for Injections, for additional information.

Contains Nonbinding Recommendations

Table C: Changes to the Source or Site of Manufacture for Glass Vials and Stoppers: New Drug Applications/Abbreviated
New Drug Applications*
Proposed Change
Recommended
Information to Support the
Change
Recommended
Reporting
Category
Reference to Current
Guidance1

Specific
Considerations for
Reporting Category
Site of vial or stopper
manufacture or
processing (no change in
supplier)

Name and address of the
new site
Comparative information
on the CCS between the
old and the new source
Commitment to place
batches on stability
AR

Section VI.A. of Changes to
an Approved NDA or ANDA
(April 2004)

Site of vial or stopper
sterilization

Name and address of the
new site
Validation data to support
the vial/stopper
sterilization

AR (when the
process is not
materially
different from
that provided
for in the
approved
application)
Section VI.D.4. of Changes
to an Approved NDA or
ANDA

Site of vial or stopper
testing

Name and address of the
new site
Full description of the
testing to be performed by
the new facility
CBE-30
Section VI.C.1.d. of
Changes to an Approved
NDA or ANDA

PAC-ATLS: Postapproval
Changes — Analytical
Testing Laboratory Sites
(April 1998)

* AR = annual report; CBE-30 = changes being effected in 30 days
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
Contains Nonbinding Recommendations

Table D: Changes to the Source or Site of Manufacture for Glass Vials and Stoppers: Biologics License Applications*
Proposed Change
Recommended
Information to Support the
Change
Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Site of vial or stopper
manufacture or
processing (no change in
supplier)

Name and address of the
new site

Comparative information
on the CCS between the
old and the new source

Commitment to place
batches on stability

AR

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain
Biological Products (June
2021)

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
(July 1997)
For certain biological
products, a higher
reporting category may
be appropriate if vial or
stopper manufacturing
or processing will be
done by the drug
product manufacturer
continued
Contains Nonbinding Recommendations

Table D, continued
Proposed Change
Recommended
Information to Support the
Change
Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Site of vial or stopper
sterilization

Name and address of the
new site

Validation data to support
the vial/stopper
sterilization

CBE-30

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain
Biological Products

Section 5.2 of the Appendix
in CMC Postapproval
Manufacturing Changes for
Specified Biological Products
To Be Documented in Annual
Reports (December 2021)

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g.,
vendor provides pre-
sterilized stoppers and
is changing site of
sterilization).

Site of vial or stopper
testing

Name and address of the
new site

Full description of the
testing to be performed by
the new facility
AR
CMC Postapproval
Manufacturing Changes for
Specified Biological Products
To Be Documented in Annual
Reports

* AR = annual report; CBE-30 = changes being effected in 30 days
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents.
Contains Nonbinding Recommendations

Table E: Changes to the Manufacturing or Processing of Glass Vials and Stoppers: New Drug Applications/Abbreviated New
Drug Applications*
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific
Considerations for
Reporting Category
Changes in vial
sterilization or
depyrogenation
method (e.g., changing
from moist to dry heat)

Validation data to support the
sterilization or depyrogenation
method change

Extractables and leachables data

Accelerated and real time• stability
data
PAS
Section VII.B.2. of
Changes to an
Approved NDA or ANDA
(April 2004)

Changes in vial
sterilization or
depyrogenation
process parameters
Validation data to support the
sterilization/depyrogenation
process change

CBE-30

Section VII.C.1.d. of
Changes to an
Approved NDA or ANDA

Stopper washing
process
Validation data to support the
depyrogenation process change
CBE-30

Section VII.C.1.a. of
Changes to an
Approved NDA or ANDA

Stopper siliconization
process

CCIT data if a new coating is used

Extractables and leachables data

Accelerated and real time stability
data
PAS

Section IX.B.4. of
Changes to an
Approved NDA or ANDA

continued

Contains Nonbinding Recommendations

Table E, continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific
Considerations for
Reporting Category
Changing the method
of stopper sterilization
(e.g., from moist heat
to irradiation)
Validation data to support the
sterilization/depyrogenation
process change

Extractables and leachables data

Accelerated and real time stability
data
PAS
Section VII.B.2. of
Changes to an
Approved NDA or ANDA

Stopper sterilization
process parameters
Validation data to support the
sterilization/depyrogenation
process change
CBE-30

Section VII.C.1.a. of
Changes to an
Approved NDA or ANDA

* PAS = prior approval supplement; CBE-30 = changes being effected in 30 days; CCIT = Container Closure Integrity Test
• Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
Contains Nonbinding Recommendations

Table F: Changes to the Manufacturing or Processing of Glass Vials and Stoppers: Biologics License Applications*
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Changes in vial
sterilization or
depyrogenation
method (e.g.,
changing from
moist to dry heat)

Validation data to support the
sterilization or depyrogenation
method change

Extractables and leachables
data

Accelerated and real time•
stability data
PAS
Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
(July 1997)2

Changes in vial
sterilization or
depyrogenation
process
parameters

Validation data to support the
sterilization or depyrogenation
process change

CBE-30

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain Biological
Products (June 2021)

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g., vial
vendor is changing the
sterilization or
depyrogenation
process parameters)

continued
Contains Nonbinding Recommendations

Table F, continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Stopper washing
process

Depyrogenation validation data
to support the stopper washing
process change

CBE-30

Section 5.2 of the Appendix in
CMC Postapproval
Manufacturing Changes for
Specified Biological Products
To Be Documented in Annual
Reports (December 2021)

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain Biological
Products

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g.,
vendor provides pre-
washed stoppers and is
changing the washing
process)

continued
Contains Nonbinding Recommendations

Table F, continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Stopper
siliconization
process

CCIT data if a new coating is
used

Extractables and leachables
data

Accelerated and real time
stability data

CBE-30

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain Biological
Products

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g.,
vendor provides pre-
siliconized stoppers
and is changing the
siliconization process)

Changing the
method of
stopper
sterilization (e.g.,
from moist heat
to irradiation)
Validation data to support the
stopper sterilization method
change

Extractables and leachables
data

Accelerated and real time
stability data
PAS
Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products3

For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g.,
vendor is changing the
sterilization method)
continued

Contains Nonbinding Recommendations

Table F, continued
Proposed Change
Recommended Information to
Support the Change

Recommended
Reporting
Category
Reference to Current
Guidance1

Specific Considerations
for Reporting Category
Stopper
sterilization
process
parameters

Validation data to support the
stopper sterilization process
change

CBE-30

Section 3.2.P.7. of the

## Appendix in: Chemistry,

Manufacturing, and Controls
Changes to an Approved
Application: Certain Biological
Products

Changes to an Approved
Application for Specified
Biotechnology and Specified
Synthetic Biological Products
For certain biological
products, FDA may
consider AR depending
on the circumstances
of the change (e.g.,
vendor provides pre-
sterilized stoppers and
is changing the
sterilization process)
* PAS = prior approval supplement; CBE-30 = changes being effected in 30 days; AR = annual report; CCIT = Container Closure Integrity Test
• Accelerated and real time refers to batch stability data from accelerated and long-term studies, respectively.
1 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-
information/search-fda-guidance-documents.
2 See also 21 CFR 601.12(b)(2)(vi).
3 Ibid.

---

### Document: FDA ParametricRelease Complete (FDA)

# FDA Guidance for Industry: Submission of Documentation for Parametric Release of Drug Products Terminally Sterilized by Moist Heat (2010)

Guidance for Industry
Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug
Products Terminally Sterilized by Moist Heat
Processes

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Center for Biologics Evaluation and Research (CBER)

February 2010
CMC

Guidance for Industry
Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug
Products Terminally Sterilized by Moist Heat
Processes

Additional copies are available from:

Office of Communications
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Bldg. 51, rm. 2201
 Silver Spring, MD  20993-0002
(Tel) 301-796-3400
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Communications Staff, HFV-12
Center for Veterinary Medicine
Food and Drug Administration
7519 Standish Place, Rockville, MD  20855
(Tel) 240-276-9300
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
and/or
Office of Communication, Outreach, and
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Center for Biologics Evaluation and Research (CBER)

February 2010
CMC

Contains Nonbinding Recommendations
TABLE OF CONTENTS

I.
INTRODUCTION............................................................................................................. 1
II.
BACKGROUND ............................................................................................................... 2
III.
CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE ............................ 3
A.
Control Strategy for the Terminal Sterilization Program .........................................................4
B.
Risk Assessment, Process Understanding, and Prior Knowledge .............................................5
C.
Documentation for Parametric Release Process .........................................................................5
IV.
FILING REQUIREMENTS ............................................................................................ 6
V.
REFERENCES.................................................................................................................. 7

Contains Nonbinding Recommendations

Guidance for Industry1
Submission of Documentation in Applications for Parametric
Release of Human and Veterinary Drug Products Terminally
Sterilized by Moist Heat Processes

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I.
INTRODUCTION

This guidance provides recommendations to applicants on information to include in support of
parametric release for sterile products2 terminally sterilized by moist heat when submitting a new
drug application (NDA), abbreviated new drug application (ANDA), new animal drug
application (NADA), abbreviated new animal drug application (ANADA), biologics license
application (BLA), or supplement or other postmarketing report.

the market.3, 4  In many cases, the requirements for batch release are fulfilled by conducting a
sterility test on finished units drawn from the batch.  Parametric release is defined as a sterility
assurance release program where demonstrated control of the sterilization process enables a firm
to use defined critical process controls, in lieu of the sterility test, to fulfill the intent of 21 CFR
211.165(a), and 211.167(a).5  Under this strategy, market release of terminally sterilized products
can be based upon meeting the defined sterilization parameters and not on performing an
approved sterility test.  Meeting the requirements of the parametric release process can provide
greater assurance that a batch meets the sterility requirement than can be achieved with a sterility
test of finished units drawn from the batch.

1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and
Research (CDER) in cooperation with CDER’s Office of Compliance, the Center for Veterinary Medicine (CVM),
and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 The term product includes final products that are regulated by CDER, CVM, and CBER.
3 See 21 CFR 314.50(d)(1)(ii)(a) or 21 CFR 514.1(b)(5)(vii)(b).
4 See 21 CFR 211.167(a) for drug products or 21 CFR 610.12 for biologic products.  In addition, refer to United
States Pharmacopeia (USP) General Chapters: <1> (Injections), <71> (Sterility), and <1041> (Biologics).  Short-
lived radiopharmaceuticals, including positron emission tomography (PET) drugs, are subject to sterility testing;
however, they may be released prior to completion of this test (21 CFR 211.165(a)).
5 For information on how current good manufacturing practices will be applied for products subject to parametric
release that are within the scope of this guidance, see the FDA Compliance Policy Guide (CPG) 460.800.

Contains Nonbinding Recommendations

This guidance does not provide information on procedures, studies, or data concerning efficacy
and qualification/validation of moist heat sterilization processes.  This guidance also does not
provide information on sterility assurance validation programs.  However, you may find
information relating to such topics in the Agency’s guidance for industry on Submission of
Documentation for Sterilization Process Validation in Applications for Human and Veterinary
Drug Products.6, 7   Current Good Manufacturing Practices (CGMP) requirements for process
validation are found at 21 CFR 211.100 and, for sterile products in particular, at 21 CFR
211.113(b).  Adherence to CGMPs is required for all marketed products.

The principles in the guidance may also be applicable to products sterilized by other terminal
sterilization processes, such as radiation sterilization, which may be suitable for parametric
release.  For these types of applications, we recommend the applicant discuss with the review
division whether applying the guidance would be appropriate.

FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited.  The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.

II.
BACKGROUND

Sterility testing by cultivation of finished units drawn from the batch is limited in its ability to
detect contamination because of the following: (1) the small number of samples required for
testing, which restricts the ability to capture those microorganisms dispersed in a large volume,
and (2) the limited ability of the prescribed culture media to stimulate growth of all potential
microorganisms.  Typically, these tests will detect only major errors in the manufacturing
process that result in contamination of a large number of product units.  However, data derived
from in-process controls of a validated terminal sterilization process can provide more accurate
information regarding product sterility because the probability of product bioburden surviving
the sterilization process in any single unit of a product can be calculated to be less than one in a
million.

Parametric release allows manufacturers to replace sterility testing of samples drawn from the
finished product as a release criterion with acceptance criteria for the control of identified
process parameters.  These parameters, called critical parameters, are critical to a successful
sterilization process and are based on an in-depth knowledge of the process, the product, the

6 This guidance outlines the submission documentation for microbiological product quality of sterile products.
7 CDER guidance documents can be found on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  We update guidances
periodically.  To make sure you have the most recent version of a guidance, check the CDER guidance Web site.
CVM guidance documents can be found at
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm, and CBER
guidance documents can be found at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

Contains Nonbinding Recommendations

effects of the sterilization process on the product itself, and any microorganisms that become
associated with the product during the manufacturing process.  Parametric release of the batch is
then based on documented evidence of the control of critical parameters, removing the need to
test samples drawn from the finished product.

A sterilization load monitor,8 either in the form of a physical, chemical (ANSI 2008), or
biological indicator, is included with each load to satisfy the requirement for a laboratory test.9
In addition, the sterilization load monitor is always considered a critical process parameter.  A
successful load monitor result, the meeting of the acceptance criteria of the critical parameters,
and having a well validated sterility assurance program demonstrate that there is a state of
control of the manufacturing process for the product.  The load monitor(s) should be placed in
appropriate positions to indicate that the load was exposed to a sterilization process which was
measured and recorded for conformance with defined criteria for parametric release.  This
position(s) is determined based on the evaluation of development and qualification data.  The
location and number of monitors should be described and justified in the application.  Alternative
procedures for demonstrating that a load or part of a load was exposed to a sterilization process
should be discussed with the review division(s) prior to submitting a plan for parametric release.

FDA conducts scientific evaluation of the parametric release program as part of a cooperative
effort among our review staff, compliance staff, and field investigators.

FDA has accepted the practice of parametric release for drug products terminally sterilized by
moist heat since 1985.  Parametric release, described in the International Conference on
Harmonisation (ICH) Q6A (ICH 2000),10 is endorsed by regulatory and/or pharmaceutical
manufacturing groups in the US (PDA 1999, USP 2009), EU (PIC/S 2007, EMEA 2001), and
Japan (Sasaki 2002).

III.
CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE

Section IV describes what submissions are required to obtain approval for parametric release.11
The approval of parametric release practices is based on an assessment of the applicant’s
proposed critical process parameters and how they are controlled.  Demonstrated reliability of
the production terminal sterilization cycle, microbiological control, and monitoring and control
of production cycle parameters within established validated limits are part of this assessment.
The terminal sterilization process for the product proposed for parametric release should be
validated according to the Agency’s guidance for industry on Submission of Documentation for
Sterilization Process Validation in Applications for Human and Veterinary Drug Products.12

8 See section III. C., bullet 5.
9 See 21 CFR 211.167(a).
10  See footnote 7.
11 See 21 CFR 314.50(d)(1)(ii)(a) and 21 CFR 314.70(b)(2)(iii) for human drug products; 21 CFR
514.1(b)(5)(vii)(b) and 21 CFR 514.8(b)(2)(ii)(C) for veterinary drug products; or 21 CFR 601.2(a) for biologic
products.
12 See footnotes 6 and 7.

Contains Nonbinding Recommendations

FDA approval of the parametric release program will be based on how well the firm has
addressed the risks to product sterility.  A risk assessment statement consistent with the
principles of ICH Q9 (ICH 2006) should be provided that describes the following:

• Current strategies for control of the terminal sterilization program;

• Risk that these strategies might fail to ensure sterility; and

• How prior manufacturing experience and knowledge were incorporated into the risk
assessment.13

A.
Control Strategy for the Terminal Sterilization Program

A control strategy is used to ensure that the acceptance criteria of the parametric release process
and terminal sterilization cycle are met in order to ensure product sterility.

The control strategy should include the following:

• The rationale for the methods implemented to monitor and control the terminal
sterilization process used for the product release (the critical process parameters);

• The rationale for the selection of critical process parameter(s);

• A description of the acceptance criteria for parametric release;

• A description of the drug product and container closure system (including secondary
packaging, as applicable) that will be part of the parametric release program;

• A description of the proposed production loading patterns and verification that they are
within the validated limits for the terminal sterilization cycle, or a statement that they
have not changed since last approved and validated (as applicable); and

• A description of the microbiological monitoring plan for the product and components
prior to terminal sterilization or a statement that the plan has not changed since last
validated.  Spore detection and heat resistance studies should be emphasized for
bioburden based sterilization cycles.

If you are referencing information previously submitted to meet these recommendations, it
should include the application number and submission date, and any other relevant citations to
the Agency’s records where the information can be found.14

13 Knowledge management and quality risk management can be used to continually improve manufacturing
capabilities throughout the life cycle for a terminal sterilization program.

14 See 21 CFR 314.50(g)(1) or 21 CFR 601.2.

Contains Nonbinding Recommendations

B.
Risk Assessment, Process Understanding, and Prior Knowledge

Successful parametric release systems are based on the reliability of the control strategy of the
sterility assurance program.  We recommend that your risk assessment focus on the risk of
failure to achieve the minimum required probability of a non-sterile unit for each unit of every
batch.  The risk assessment should include the following:

• Consistency of performance of the terminal sterilization cycle within the validated limits.
• A discussion of risk to the sterility of the product relative to the following:  (1) the
production terminal sterilization cycle, (2) the production loading patterns, (3) the
container closure system (including secondary packaging), and (4) any potential
contamination risks from the environment (as appropriate).  For an approved application,
you should indicate any changes to the above items and provide an assessment of the risk
to the sterility of the product associated with those changes.  For example, although the
established minimum sterilization time cannot be lowered, the maximum sterilization
time can be increased if the appropriate stability data are provided to support the increase.
• Experience with the proposed or similar product (and container closure system) and
proposed or similar sterilization process, the overall risks to sterility, and the steps you
have taken to assess and control these risks.  For new products, prior knowledge from
developmental and registration/exhibit batches may suffice.
• A discussion of your overall prior knowledge and production and testing experience
relevant to the drug product that will be subject to parametric release.

C.
Documentation for Parametric Release Process

The following information specific to the proposed parametric release process should also be
included in your submission:

• A citation to a complete and detailed description of the current relevant terminal
sterilization cycle.

• Identification of the critical process parameters (process/cycle parameters and appropriate
load monitors essential for product release) for the product(s) proposed for parametric
release, including the minimum and maximum limits for these critical parameters.  The
critical process parameters should be within the limits that have been validated and
approved for sterility assurance of the subject product(s).

• Acknowledgement that adherence to the critical parameters of the parametric release
program will substitute for the performance of a sterility test as the primary release
criterion for the product and that sterility test results from the finished product will not be
used to overrule any failure to meet the acceptance criteria of the parametric release

Contains Nonbinding Recommendations

program.  In the event of failure, the specific sterilizer load will be rejected by the quality
control unit and will not be released unless there is a provision for reprocessing.

• Acknowledgement that regardless of the batch release technique used, any specimen
tested according to the reference test method for sterility (e.g., compendium or FDA
regulations) will meet the criteria for sterility (such as during testing for stability or
postmarketing investigations).

• A description of the sterilization load monitor that indicates the following:  (1) the type of
monitor being proposed, (2) how the load monitor will be used and analyzed, (3) what
functions are being measured by the monitor, and (4) the rationale for the location of the
monitor.  Additionally, for indirect monitors, we recommend that you include a statement
justifying the classification of the indirect indicator that you are using as defined by the
American National Standard Institute (ANSI 2008).  In certain circumstances a Class 3
indicator may be appropriate; however, a Class 5 indicator is recommended for most
situations.

• Documentation of the control system to verify exposure of the load to the sterilization
process.

• Revision of the certificates of analysis or batch release records for each product subject to
parametric release to indicate that parametric release is now the method used to provide
assurance of the requirement of sterility.  We recommend that you provide a reference to
show the link between batch release criteria and the commitments in the application.

IV.
FILING REQUIREMENTS

To request parametric release in an original application submission, the request should include
information specific to parametric release along with sterilization validation information and
product release criteria.  For changes to an approved application, the request for parametric
release should be submitted in a prior approval supplement under 21 CFR 314.70, 21 CFR
601.12 or 21 CFR 514.8(b)(2).  The change to parametric release requires FDA approval before
its implementation.  If the applicant has current experience using parametric release with a
comparable sterilization cycle at the same manufacturing site, and the proposed product's
manufacturing process fits into the same validation protocol for parametric release (e.g.,
container closure system, load patterns, cycle process parameters, and cycle acceptance criteria),
then the applicant should meet the filing requirements with a special report for a human drug
product,15 or an annual report for a veterinary drug product16 or a biologic product.17  If your
product fits into one of these filing categories, contact the review division for your product to
verify submission requirements.

15 21 CFR 314.81(b)(3)(ii)
16 21 CFR 514.8 (b)(4)
17 21 CFR 601.12(d)

Contains Nonbinding Recommendations

V.
REFERENCES

American National Standard Institute (ANSI), Association for the Advancement of Medical
Instrumentation (AAMI), International Organization for Standardization (ISO) 15882, 2008,
Sterilization of Health Care Products-Chemical Indicators-Guidance for Selection, Use and
Interpretation of Results.

The European Agency for the Evaluation of Medicinal Product (EMEA), 2001; Committee for
Proprietary Medicinal Products: Note for Guidance on Parametric Release, March 2001,
CPMP/QWP/3015/99.

Food and Drug Administration, 1987, Parametric Release - Terminally Heat Sterilized Drug
Products, Compliance Policy Guide (CPG) 460.800 (CPG 7132a.14), October 2, 1987.

International Conference Harmonisation (ICH), 2000, Guidance on Q6A Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:
Chemical Substances, Guidance for Industry, Federal Register, Vol. 65, No. 251, December 29,
2000.

ICH, 2006, Q9 Quality Risk Management, Guidance for Industry, Federal Register, Vol. 71, No.
106, June 2006.

ICH, 2009, Q10 Pharmaceutical Quality System, Guidance for Industry, Federal Register, Vol.
74, No. 66, April 2009.

PDA Journal of Pharmaceutical Science and Technology, Technical Report No. 30: Parametric
Release of Pharmaceuticals Terminally Sterilized by Moist Heat, Supplement, Volume 53, Number 4,
July-August 1999

Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme (PIC/S):
Guidance on Parametric Release, 2007, PI 005-3, September 25, 2007.

Sasaki, T., 2002, Parametric Release for Moist Heated Pharmaceutical Products in Japan, PDA
Journal of GMP and Validation in Japan, Volume 4, Number 1.

United States Pharmacopeia (USP) 32-NF, General Chapter <1222> Terminally Sterilized
Pharmaceutical Products-Parametric Release, 2009.

---

### Document: FDA ProcessInspection Complete (FDA)

# FDA Compliance Program Guidance Manual 7356.002A: Sterile Drug Process Inspections (2015): Sterile Drug Process Inspections — FDA CPGM 7356.002A

===== PAGE 1 =====
 Page 1 of 38
FOOD AND DRUG ADMINISTRATION
COMPLIANCE PROGRAM GUIDANCE MANUAL
PROGRAM
7356.002A

CHAPTER 56 – DRUG QUALITY ASSURANCE

SUBJECT:
STERILE DRUG PROCESS INSPECTIONS

Revision Note: Program revised 09/11/2015 to update
implementation date, completion date,
organizational/procedural changes and program
contacts.
IMPLEMENTATION DATE
September 11, 2015
COMPLETION DATE
September 11, 2016
DATA REPORTING
PRODUCT CODES
PRODUCT/ASSIGNMENT CODES
Industry codes 54, 56 and 60-66 inclusive
Domestic / Foreign Inspections:
56002A (Full Inspection)
56002I (Abbreviated Inspection)
Related PACs
56002
56002C
56002M

FIELD REPORTING REQUIREMENTS:

Establishment Inspection Reports (EIRs) are to be created and filed electronically using the specific
module in TurboEIR or replacement system that is accessible to both ORA and CDER.
For inspections of routine commercial manufacturing classified as Official Action Indicated (OAI) due to
failure to comply with 21 CFR Part 210 and 211 Current Good Manufacturing Practice (CGMP) as they
apply to sterile drug process inspections, submit advisory, administrative, or judicial action
recommendations via MARCS-CMS in accordance with the Regulatory Procedures Manual (RPM).
Districts should immediately report significant issues according to current FACTS, Panorama and CMS
procedures. This includes promptly filing and changing OAI notifications.
During an inspection, if you obtain information pertaining to inadequate adverse drug experience (ADE)
reporting, unapproved drug issues, or post-approval reporting violations (application supplements, Field
Alert Reports (FARs), etc.), report in accordance with directions provided in the applicable compliance
programs and under separate captions in the EIR. Data system information about these inspectional
activities should be reported under separate Program Assignment Codes (PACs).  Expansion of coverage
under these programs into a CGMP inspection should be reported under this compliance program.

===== PAGE 2 =====
PROGRAM
7356.002A
PAGE 2 of 38

The Districts are requested to use this compliance program for all sterile drug process inspections.

NOTE: Districts should assure that each operation performed by direction of this program circular is
entered against the correct Product Code and Program/Assignment Code (P/AC).

===== PAGE 3 =====
PROGRAM
7356.002A
PAGE 3 of 38

TABLE OF CONTENTS

PART I
BACKGROUND ................................................................................................... 4

PART II
IMPLEMENTATION ............................................................................................. 5
2.1   Objective....................................................................................................... 5
2.2   Program Management Instructions .............................................................. 5
A. Strategy ............................................................................................... 5
B. Inspection Planning............................................................................. 6
C. Profile Reporting ................................................................................. 6

PART III
INSPECTIONAL ................................................................................................... 7
3.1   Types of Sterilization .................................................................................... 7
A. Terminal sterilization ........................................................................... 7
B. Aseptic processing .............................................................................. 7
3.2   Reporting ...................................................................................................... 8
3.3   Inspection Approaches................................................................................. 9
3.4   System Inspection Coverage ..................................................................... 11
3.5   Quality System ........................................................................................... 11
3.6   Facilities and Equipment System ............................................................... 13
A. Facilities ............................................................................................ 13
B. Equipment ......................................................................................... 14
3.7   Materials System ........................................................................................ 19
3.8   Production System ..................................................................................... 21
3.9   Packaging and Labeling System ................................................................ 27
3.10 Laboratory Control System......................................................................... 27
3.11 Sampling..................................................................................................... 29

PART IV
ANALYTICAL..................................................................................................... 30

PART V
REGULATORY/ADMINISTRATIVE STRATEGY .............................................. 31

PART VI
REFERENCES, ATTACHMENTS AND PROGRAM CONTACTS ................... 33
6.1   References ................................................................................................. 33
6.2   Attachments................................................................................................ 34
6.2   Contacts ..................................................................................................... 34

PART VII
CENTER RESPONSIBILITIES .......................................................................... 36

ATTACHMENT A
.................................................................................................................A

[end Cover Page]

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PART I - BACKGROUND

This program covers the manufacture and testing of all sterile drug products, including drugs that are
sterilized by filtration or other means and aseptically processed, and drug products that are terminally
sterilized. The type of products covered by this program include sterile bulk drugs, ophthalmic drugs,
otic dosage forms, small volume parenteral (SVS) products for small molecule and licensed biological
therapeutic drug products, large volume parenteral (LVP) products, and any other drug products
required to be sterile or labeled as sterile. Center for Biologics Evaluation and Research (CBER)
regulated products and veterinary drug products are excluded from coverage under this program.

The guidance information in this program is tailored to sterile manufacturing operations and should be
used in conjunction with the Compliance Program for Drug Manufacturing Inspections (CP 7356.002).

In 2004, Food and Drug Administration (FDA) published the Guidance for Industry Sterile Drug
Products Produced by Aseptic Processing-- Current Good Manufacturing Practice, which is referred to
throughout this Compliance Program as FDA’s “2004 Aseptic Processing Guidance.” The document
represents FDA’s current thinking on Current Good Manufacturing Practices (CGMPs) for aseptically
processed drugs.

The Guidance for Industry does not establish mandatory requirements and should not be referred to as
the justification for an inspectional observation. Justification for inspectional observations originates
from the CGMP regulations, 21 CFR Parts 210 and 211.

Manufacturers who follow the 2004 Aseptic Processing Guidance are generally considered compliant
with CGMP regulations. However, alternate approaches may be used if such approaches satisfy the
requirements of 21 CFR Parts 210 and 211.

For technical questions and unusual circumstances encountered during an inspection, investigators are
encouraged to contact their District, ORA Office of Medical Products and Tobacco Operations/Division
of Medical Products and Tobacco Program Operations and/or CDER for consultation. For questions
concerning microbiological analysis, sterility and related sampling concerns, contact ORA Office of
Regulatory Science/Medical Products and Tobacco Scientific Staff.

[end Part I]

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PART II - IMPLEMENTATION

### 2.1 OBJECTIVES

The primary objective of this program is to provide guidance for conducting inspections of
manufacturers of sterile bulk1 and sterile finished dosage drug products to determine compliance with
the Food, Drug, and Cosmetic Act and the Current Good Manufacturing Practice Regulations (CGMPs),
Title 21, CFR Parts 210 and 211.

Other objectives include:
• Obtain information on operations impacting on sterility, to identify areas for improvement and
correction.
• Evaluate current good manufacturing practices in the sterile drug industry.
• Initiate appropriate action against manufacturers observed to be out of compliance.

### 2.2 PROGRAM MANAGEMENT INSTRUCTIONS

A. STRATEGY
(1) Inspection of Systems

Inspections of drug manufacturers should be made and reported using the system definitions and
organization in this compliance program. Focusing on systems will increase inspection efficiency
because the systems are often applicable to multiple profile classes. The selection of the system(s) for
coverage will be made by the District Office based on the firm’s specific operation, previous coverage,
compliance history, or other priorities determined by the District Office.

The inspection should normally result in a determination of acceptability or non-acceptability for all
profile classes. Coverage of a system should be sufficiently detailed, i.e., select an example of each
profile class, so that the conclusion about the system’s state-of-control applies to all the profiles classes.
However, the determination that a system is adequately controlled for one profile class can be extended
to another profile class(es) even if that other profile class(es) was not specifically reviewed. The lead
Investigator must consider the uniqueness of the various manufacturing situations at the plant and use
their best judgment when selecting profile classes to review.

Selecting specific areas unique functions within a system will be at the discretion of the lead
Investigator.

The options for system coverage are described in CPGM 56002. Any given inspection need not cover
every system. See  Part III - Inspectional.

Complete inspection of one system may necessitate further follow up of some items within the activities
of another system(s) to fully document the findings. Such follow up does not constitute full coverage of
the other system (and cannot be reported as such in FACTS); nor does that follow up obligate the
investigator to perform full coverage of the other system.

1 “Sterile bulk” refers to sterile active pharmaceutical ingredients (APIs).

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(2) Inspectional Scope
Inspections of sterile product drug manufacturers are performed as either Full Inspections or
Abbreviated Inspections using the systems strategy outlined in Part II –Implementation, of Compliance
Program 7356.002, Drug Manufacturing Inspections.

See Part III – Inspectional, of this program for a complete discussion of the coverage requested under
these inspection options.

B. INSPECTION PLANNING
Implement this program when sterile drug manufacturers are inspected as part of a regular statutory
inspection. CDER will identify firms for inspection based on the risk-based prioritization model on
annual performance goals, as part of the initiative to ensure risk-based prioritization of inspection
coverage.

Consider using a team approach for conducting inspections when appropriate. Utilize investigators
familiar with sterile drug manufacturing and aseptic processing and consider the participation of a
microbiologist with expertise in microbial controls. Specifically,
• All team members should be very familiar with FDA’s Guidance for Industry Sterile Drug
Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September
2004).
• Investigators or team members should be well qualified in sterile product manufacturing, and
have completed formal training courses in parenteral drug manufacture, aseptic technique,
sterilization methods, and related procedures and equipment. Microbiologists involved should
have experience in sterility, endotoxin testing, and evaluation of microbial controls in
manufacturing.

C. PROFILE REPORTING

Update all applicable profile classes in the profile screen of the FACTS coversheet based on inspection
findings. The following is a list of sterile product profile classes effective at the time this program was
implemented. Use the codes corresponding to the product and process type covered.

PROFILE
CLASS
FULL DESCRIPTION
LVP
Large Volume Parenterals are sterile injectable drugs packaged in containers labeled as
containing more than 100 mL. Most are terminally sterilized, but some can be sterilized by
filtration and aseptically processed.
SVT
Small Volume Parenterals are sterile injectable drugs packaged in containers labeled as
containing less than 100 mL that are terminally sterilized.
SVS
Small Volume Parenterals are sterilized by filtration and aseptically processed.
SVL
Small Volume Parenteral are sterilized by filtration, aseptically filled and lyophilized.
SLQ
Sterile liquid (other than suspensions and emulsions)
SON
Sterile ointment
SPW
Sterile powder
CSS
Sterile bulk drugs that are made by chemical synthesis.
CFS
Sterile crude drugs made by fermentation.
CRX
API sterile or API intermediate/NEC inorganic/mineral
[end Part II]

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PART III - INSPECTIONAL

### 3.1 TYPES OF STERILIZATION

There are two broad methods to produce a sterile drug product:

• Terminal Sterilization
• Aseptic Processing of sterilized unit components

There are basic differences between the production of sterile drug products using aseptic processing and
production using terminal sterilization. Terminal sterilization should be utilized when the product and
container/closure system are able to withstand the terminal sterilization process.

A. TERMINAL STERILZATION - The terminal sterilization process usually involves filling and
sealing product containers under high quality environmental conditions designed to minimize microbial
and particulate contamination of the product. This minimization of upstream bioburden reduces the
challenge to the subsequent sterilization process. In most cases, the product, container, and closure have
low bioburden, but are not sterile at the time of filling. The product is then subjected to a sterilization
process in its final container.

There are various methods of terminal sterilization including:

• Moist Heat Sterilization
• Irradiation
• Ethylene Oxide (typically for assembled components/kits)
Types of sterilization cycles include:

1. Overkill method:
o Generally used for heat stable materials.
o Designed to provide a significant level of sterility assurance regardless of the number and
resistance of the actual bioburden organisms in the load.
o Results in greater heat/exposure input to the product or items being sterilized.

2.  Bioburden Based cycle:
o Requires studies to determine the number and resistance of the microorganisms found in the
product and the bioburden load of the incoming components and containers/closures.
o Cycle development to destroy the microbial load, but not degrade the product.
o Routine bioburden monitoring of batches and ongoing knowledge of the heat/exposure
resistance of organisms found in product bioburden, container/closure bioburden and
environmental monitoring samples.

Reference to terminal sterilization:  PDA Technical Report No. 1 (Revised 2007) Validation of Moist
Heat Sterilization Processes: Cycle Design, Development, Qualification and Ongoing Control.

B. ASEPTIC PROCESSING  - Aseptic processing presents a higher risk of microbial contamination of
the product than terminal sterilization. In an aseptic filling process, the drug product, containers and

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closures are sterilized separately and then brought together under an extremely high quality
environmental condition designed to reduce the possibility of a non-sterile unit. Aseptic processing
involves more variables than terminal sterilization. Any manual or mechanical manipulation of the
sterilized drug, containers, or closures prior to or during aseptic filling and assembly poses the risk of
microbial contamination.

Some types of aseptic processing involve manual manipulations of sterile components, containers, and
closures in addition to routine operator interventions in the critical area. Humans are a significant source
of contamination in traditional aseptic processing, especially in production lines that require operators to
routinely enter critical areas (Class 100, ISO 5, or Grade A) of the filling line. Aseptic processing
systems based on more advanced control-based technologies, such as Restricted Access Barrier Systems
(RABS) and Blow-Fill-Seal systems, are designed to reduce human interventions in the critical areas of
the fill line while an isolator system completely separates the aseptic filling line from the external
environment and minimizes employee interaction with the critical area.

Note: More information about Isolator Technology and Blow-Fill-Seal systems is found
in FDA’s 2004 Aseptic Processing Guidance.

When conducting inspections of sterile drug manufacturers, it is important to cover systems and areas
within systems that present the greatest risk of product contamination and/or require strict control of
processing parameters. For example, if a firm has several aseptic processing lines, cover the line(s) that
require the most manual manipulations in the Class 100 (ISO 5) areas. If the firm terminally sterilizes a
number of products, review one that is sensitive to heat and requires a product specific (bioburden
based) sterilization cycle.

Note:  For terminal sterilized products that are aseptically filled prior to terminal sterilization, less
rigorous aseptic controls can be considered.

Because of the time limitations often associated with foreign inspections, careful inspection planning is
particularly important. Prioritize areas for coverage based upon their potential impact on product
quality.

### 3.2 REPORTING

Follow instructions in the current editions of the IOM (Investigations Operations Manual) and Guide to
International Inspection and Travel in preparing the inspection report.

Use Turbo EIR for all reports, both domestic and international, even if a FDA-483 was not issued or was
issued outside of Turbo EIR. The “Manufacturing / Design Operations” section of the report should be
organized by the systems described in this program that were covered during the inspection. Briefly
summarize your review of each covered system in accordance with the key elements outlined in this
Compliance Program. Add more details and supporting evidence for the systems found to be deficient.

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### 3.3 INSPECTION APPROACHES

If the sterile drug products to be inspected are radioactive drugs, then Compliance Program 7356.002C,
Radioactive Drugs, should be followed as supplementary guidance. This program should not be used for
the inspection of Positron Emission Tomography (PET) Drug. Compliance Program 7356.002P is
specific for PET drugs.

This program (CP 7356.002A) should also be used in conjunction with Compliance Program
7356.002M, Inspection of Licensed Biological Therapeutic Drug Products for the inspection of sterile
licensed biological products.

The CGMP Compliance Program 7356.002 provides general information on the system based approach
to conducting inspections of drug manufacturers. It describes the six systems (Quality, Facilities and
Equipment, Materials, Production, Packaging and Labeling, and Laboratory) and the two inspection
options (Full Inspection and Abbreviated Inspection). It also provides guidance on when each option
should be selected and discusses what “state of control” means in relation to the systems inspected.

Inspections of sterile drug manufacturers are performed as either Full or Abbreviated inspections using
the systems strategy outlined below.

Full Inspections include surveillance or compliance inspections and provide a comprehensive evaluation
of the firm’s compliance with CGMP. A Full Inspection will normally include an inspection of at least
four systems, one of which must be the Quality System. Under this program, a Full Inspection should
include the Facilities & Equipment, and Production Systems due to the critical role these systems play in
the sterility assurance of finished product.

Full Inspections (PAC 56002A) are conducted

• when initial inspection of the drug firm is to be conducted;
• when it is the first inspection conducted as a follow-up to a Warning Letter,  regulatory action,
or significant FDA 483 findings;
• when information obtained during the Abbreviated Inspection reveals significant deficiencies
with the firm’s practices and procedures in one or more system areas;
• when there have been significant changes in the firm’s operations since the last inspection; or
• for surveillance purposes at the District’s discretion because the firm has a history of recurring
violations, fluctuating in and out of compliance, or when other information (samples,
complaints, Field Alerts, recalls, etc.) calls into question the firm’s ability to produce quality
products.

Abbreviated Inspections (PAC 56002I) may be appropriate if the following two conditions are satisfied:

1. the firm has implemented a formal risk management program that assures effective design and
control (including maintenance). This includes a risk mitigating design of their processing lines
that incorporates a modern separation and automation approach (e.g., isolators, closed RABS),
and upstream bioburden controls. The responsiveness of the firm’s quality system to potential
hazards is also part of the evaluation, including whether the firm’s program provides robust

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daily assurance and effective consumer protection through a formal lifecycle quality risk
management program that proactively uncovers and corrects issues in accord with ICH Q9.

2. the firm has a record of sustained acceptable compliance history and a strong risk management
program.
o the firm produces finished drug products that are terminally sterilized using robust
sterilization methods. (Note: Terminal sterilization provides a much more robust process to
ensure sterility);  or,
o the firm has implemented robust risk management that provides daily assurance through
their overall design and control program;
o at the start of the inspection, conduct an extensive review of sterility assurance data since
the last Full Inspection. The review of media fills, sterility testing data, recalls,
defect/adverse event complaints, and reports reveals no findings of sterility failure of a
distributed batch, and
o the firm has a record of satisfactory CGMP compliance (e.g., two consecutive NAI or no
more than one VAI inspection), with no Class 1 recalls.

Microbial controls and sterility assurance should be the main focus of an abbreviated sterile drug
inspection. The following critical elements of each system (other than the Quality System) should be
covered in an Abbreviated Inspection under this program:

• Facilities and Equipment:
o cleaning and disinfection
o facility/equipment layout and air handling system for preventing viable and non-viable
contamination
o material flow
o quality control of classified areas, including air pressure balance and HEPA filtration
o trending data supporting the adequacy of clean room quality
o documented investigation into discrepancy

• Materials:
o microbial and bacterial endotoxin control of incoming materials and components
o quality of water supply, maintenance, qualification
o operation of the systems that provide the requisite water and process gases
o documented investigations into OOS, deviations, and discrepancies

• Production:
o observation of adequacy of operator behavior and aseptic techniques during manufacturing
o production line operations and interventions
o personnel training in aseptic techniques
o major production line repair or maintenance issues
o risk assessment on microbial and bacterial endotoxin controls, including hold times of
critical steps

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o validation of sterilization of equipment, container-closures and supplies
o media fills design and results
o documented investigations into, deviations, discrepancies, and OOS results

• Laboratory:
o investigations into OOS, deviations, and discrepancies
o test methods and controls, including adherence to validated methods
o training and qualifications of laboratory personnel
o trending of water system test results
o systems used for recovery, identification and trending of environmental monitoring isolates

### 3.4 SYSTEM INSPECTION COVERAGE

Compliance Program 7356.002, Drug Manufacturing Inspections, lists the areas that should be covered
when inspecting each of the six systems. This program provides additional guidance, by system, for
areas of specific concern for sterile drug products.

Attachment A is a list of questions intended to be an aid in conducting inspections and obtaining
information needed to assess a firm’s operations. The answers do not have to be reported in the EIR
unless they are relevant. The list of questions covers: moist heat sterilization; dry heat
sterilization/depyrogenation; aseptic filling; lyophilization; isolators; environmental monitoring; and
biological indicators.

### 3.5 QUALITY SYSTEM

As noted in Compliance Program 7356.002, the inspection of the quality system is two-phased. The first
phase is to evaluate whether the Quality Unit has fulfilled their responsibility regarding the review and
approval of procedures and assured their suitability for use. The second phase is to assess the data
collected by the firm to identify potential quality problems. For sterile manufacturing operations, this
latter objective involves large amounts of data that link to the other inspectional systems. The
comprehensive review of such data by the firm is an essential element in assuring that products are
produced with a high degree of sterility assurance. It is therefore important to review the firm’s system
for using the data to assess the state of control of their manufacturing operations and facility. The data
summaries and trend reports maintained by the Quality Unit should be reviewed during every
inspection. During a routine CGMP inspection, this review can help determine which option (Full or
Abbreviated) to select.

The inspection of the Quality System should include the areas listed in CP7356.002. For this program,
the inspection should include a review of all data and reports that may indicate product contamination
and sterility assurance issues.

Records pertaining to quality consist of the following:

1. Periodic product evaluations, complaints, adverse events, investigations, Field Alert Reports,
product retain evaluations, complaints, rejected lots, stability, and returned goods that indicate

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possible product contamination or risks to patients (for example, hazy or cloudy product,
foreign matter/particulates in injectable products, cracked, and leaky containers).

2. Discrepancy and failure investigations, such as:

o All initial positive sterility tests and endotoxin and media fill failures regardless of final
disposition.
o Unexpected results or trends.
o All failures that occurred during validation or revalidation of sterilization / depyrogenation
processes.
o All investigations involving media fills / process simulations.
o Environmental (microbial/viable and particle/non-viable counts) and personnel monitoring
results that exceed alert or action levels.
o Process deviations or equipment malfunctions that involve critical equipment, such as
sterilizers and lyophilizers.
o Out of Specification (OOS) results for assay, impurities, particulate matter, or reconstitution
time, if applicable.
o Product rejects (rejects determined during manufacturing and Quality Control test)

3. Trends reports/ summaries of quality indicators:

o For aseptic processing, summary of all media fills performed since last inspection.
o Environmental monitoring trend data (microbial and particle counts).
o Personnel monitoring trend data.
o Summary of water system test results.

4. Summary of change controls for critical utilities and equipment implemented since the  last
inspection, for example:

o Sterilizers, lyophilizers, depyrogenation equipment
o Aseptic processing line
o Clean steam generator, process gas system
o WFI and / or Purified Water system
o Air handling systems
o Automated building management system

Every inspection of a sterile drug manufacturer should include a review of the type of information listed
above and observation of the manufacturing operations occurring in the critical areas. The information
can be used to select other system(s) to be covered during the inspection.

In addition, the review of summary data and observation of operations can focus the inspection on
potential problem areas and provides an overview of the effectiveness of the Quality System. The
inspection of the Quality System may necessitate follow-up within another system. However, this
coverage does not constitute or require complete coverage of these systems.

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### 3.6 FACILITIES AND EQUIPMENT SYSTEM

Compliance Program 7356.002 lists the general areas to cover when inspecting the Facilities and
Equipment System. The areas are applicable to sterile drug products and should be covered if this
system is selected. The principle objective of an effective sterile drug manufacturing operation from a
facility and equipment standpoint is to provide suitable protection of product. The inspectional
evaluation of this objective is again two-part:

• Review and evaluate the firm’s rationale for, and adequacy of, the facility and equipment
design (Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance).
• Evaluate the data that provide information relevant to the state of control of the facility and
equipment.

In addition to the review of design elements and data, investigators should look for visible deficiencies in
the facility and equipment, such as cleanliness, equipment deterioration (e.g., warping, corrosion),
inaccessible and/or difficult to clean surfaces, and changes to critical equipment or systems that have not
been qualified which may impact product quality. Investigator should look for aberrant events due to
facility deterioration, a pattern of recurring and uncorrected maintenance issues, and increase or changes
in production output that exceed the capacity of the facility and equipment.

A. FACILITIES

Evaluate the design and layout of the facility (e.g., personnel/material flow, cleanroom design).

Specifications for clean room areas (layout, air filtration, appropriate air classification, pressure
differentials between rooms and areas, temperature, and humidity) should be appropriate, and based on
the risk of product contamination with particulate matter and microorganisms. Review the certification
and qualification of the clean room areas to verify the areas meet design criteria and specifications.
Certification and qualification typically includes data in support of the following: air flow pattern
studies, HEPA (High Efficiency Particulate Air) filter integrity testing, air velocity measurement, non-
viable particle, and verification of appropriate pressure differentials, temperature and humidity setpoints.
Evaluate the airflow pattern (smoke studies) conducted under dynamic conditions to verify the
unidirectional airflow and air turbulence within the critical area where sterilized drug product,
containers, and closures are exposed to environmental conditions.

• Reference: Section IV of FDA’s 2004 Aseptic Processing Guidance.
• Routine monitoring and maintenance to assure air handling systems continue to operate within
established parameters (microbiological monitoring is discussed under the Laboratory Control
System).
o Afford special attention to facilities that are performing construction in the clean areas, or at
the vicinity of cleanroom. Because microbes (e.g., fungal spores) can be liberated from the
movement of walls and other construction activities, determine if the facility is returned to
acceptable environmental control through proper measures (environmental monitoring,
media fills) before production can resume.
o Verify that environmental monitoring of non-viable particle is occurring during operations
including sites where there is the most risk to exposed product, container and closures.

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o Check if pressure differentials, temperature, and humidity are continuously monitored
during routine production.
o Determine if continuous monitoring systems are alarmed to alert operators of excursions.
o Check if excursions from acceptable ranges are investigated to determine impact on product
and that needed corrective actions are taken.
o Evaluate the program for periodic testing / recertification of the HEPA filters in critical
areas to maintain appropriate air flow. The tests typically include integrity testing of the
HEPA filters and air velocity checks.

• Sanitization / disinfection of clean room areas, processing lines, and non autoclavable
equipment, materials, and components should be reviewed. Focus on the areas where the
sterile product is exposed up to and including sealing operations. These critical areas represent
the highest risk to the product. The suitability, efficacy, and limitations of disinfecting agents
and adequacy of procedures should be reviewed, including the data that establishes the expiry
of the disinfection solution. (Reference:  Section X.A.3 of FDA’s 2004 Aseptic Processing
Guidance)
• For multi-use facilities and non-dedicated equipment, evaluate the adequacy of the changeover
procedures and cleaning to prevent cross-contamination between products.

B. EQUIPMENT

Equipment used in the manufacture of sterile drug products may include the following:

• Production Equipment
• Container/closure processing equipment (e.g. stopper washer, glassware depyrogenation
equipment)
• Support system/material system related equipment (e.g. WFI system and related equipment,
process gas related equipment)

Specific considerations include:

(1) Production Equipment

(a) Aseptic Processing Equipment. Determine that all equipment that comes in direct contact
with product (e.g., filters, transfer lines, holding tanks, stopper bowls, filling line equipment) and
sterile components (e.g., stoppers) are sterilized and protected from contamination prior to and
during use. Equipment logs or other related information may provide insight into significant
maintenance or other problems that may increase exposure of batches to contamination risk.

(b) Stopper washer. Inspectional considerations include the qualification of the equipment,
cycle validation and supporting data, equipment preventative maintenance (maintenance
requirements and frequency), quality of water used for washing, and associated water
sampling/qualification data. The appropriateness of the air supply used in any drying operations
should also be verified.

(c) Capping Equipment (vials). The vial cap provides the final closure element of a sealed vial.
The capping machine folds and crimps the cap (aluminum) over the neck of the stoppered vial.
The cap on the vial protects the stopper from external damage, while firmly holding the stopper

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in the fully seated, sealed position. Evaluate the established processing settings (crimp angles,
pressures), and preventative maintenance schedules of the capping machine. Air supply quality
to the capping units should also be evaluated.

(d) Post fill Visual Inspection/Automated Inspection Equipment. The 100% inspection of the
final filled and sealed product may occur via a manual, automated, or semi-automated inspection
process. Manual and semi-automated inspection processes involve specified viewing fields and
calibrated light sources. Semi-automated processes may use conveyor belts and rotational units
that present the filled product to an operator for visual inspection. All conveyor and rotational
speed set points should be verified against established parameters. Automated inspection systems
may inspect for one or all types of defects in a given filled product. Defect categories with
relevant action levels should be defined. The qualification of the equipment and the challenges
performed to verify equipment functionality prior to routine use should be evaluated as well as
the training program for operators performing manual visual inspections.

(e) Sterilizers. The inspection should cover the Installation and Operation Qualification of
equipment and the Performance Qualification of the process (IQ, OQ and PQ), and operation,
calibration and preventative maintenance of representative types of equipment used to sterilize
finished dosage forms, filling equipment, containers, closures, etc. Such equipment includes
autoclaves, dry heat ovens, dry heat tunnels, steam-in-place (SIP) equipment and chemical
sterilization systems (i.e., hydrogen peroxide, peracetic acid). Inspection of sterilizers should
include physical examination of the equipment. Review the engineering specifications which
may be described in the equipment’s DQ (Design Qualification). DQ is performed prior to the IQ
(Installation Qualification) and OQ (Operational Qualification), and verify that the sterilizer is
maintained, calibrated and drained properly and that it has appropriate measuring devices
(temperature sensors, pressure gauges, etc.).

Records of unplanned maintenance, as well as preventative maintenance, should be reviewed to
assure all significant changes have been evaluated and qualified as appropriate. Equipment logs
should also be reviewed. For example, repeat sterilization of loads because of cycle failures can
indicate a serious problem with a sterilizer. Impact of re-sterilization to product quality should be
evaluated. (Performance qualification is covered under the Production System).

The equipment can be computer controlled or operated in a manual mode. For computer
controlled system, programmable logic controller (PLC) or a more complex Supervisory
Controlled and Data Acquisition Management System (SCADA), may require an assessment to
determine if the computer control and/or monitoring system are Part 11 compliant.

Reference:
o PDA Technical Report No. 1 Revised 2007 Validation of Moist Heat Sterilization
Processes: Cycle Design, Development, Qualification and Ongoing Control;
o ISO 17665 Moist Heat Sterilization.

(f) Lyophilizer. Because partially sealed vials are used in the lyophilization process, sterile
product is exposed to the environment from the time of filling until the vials are fully stoppered
in the lyophilization chamber at the end of the cycle. The inspection should verify that partially

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sealed vials are transported and loaded into the lyophilizers under Class 100 (ISO 5) protection.
Investigators should observe the transport of vials and loading of lyophilizers.

Other key equipment areas to cover include: validation of the sterilization of the lyophilization
chamber between uses, current sterilization controls, leak testing of the chamber, integrity testing
of air/gas filters, and calibration of temperature and pressure controllers.

Reference: FDA’s Guide to Inspections of Lyophilization of Parenterals.

(g) Isolators. Evaluate the design and control elements that maintain the separation or isolation
of the product. Pressure differential, glove integrity, and protection of the transfer (i.e., entry,
exit) ports are key elements for the isolators. The transfer of containers, closures and supplies
(including environmental monitoring supplies) into an isolator should be carefully controlled.
Another critical element for these systems is the effectiveness of the chamber decontamination
program. Current methods (e.g., vaporized hydrogen peroxide, steam hydrogen peroxide,
peracetic acid) used to decontaminate isolator barriers are capable of surface sterilization but
lack the penetrating capabilities of steam sterilization. Investigators should be mindful of the
limitations of these surface sterilants, including their inefficiency in penetrating obstructed or
protected surfaces. Validation of the decontamination of the interior (surfaces) of an isolator
should demonstrate a 6-log reduction of the biological indicator (BI). Quantitative measuring
devices (e.g., near infrared) or chemical indicators (qualitative test) can be used to determine the
worst case location for decontamination validation using BI. Factors to be considered in
decontamination validation include the location of the BI and the type of surfaces where the BIs
are inoculated.

Utensils and equipment surfaces inside the isolator that have direct contact with sterile product
and components should be sterilized to render them free of microorganisms. The sterilization
validation should achieve a minimum of a 6-log reduction of the BI

Reference:
o Appendix 1 of FDA’s 2004 Aseptic Processing Guidance;
o PDA Technical Report 51 (2010) Biological Indicators for Gas and Vapor Phase
Decontamination Processes: Specifications, Manufacture, Control and Use provides
general principles to be considered in decontamination by BI.

(h) Restricted Access Barrier System (RABS). In general, a RABS is a fill-finish line in a rigid
wall enclosure that provides full physical separation of the filling line from operators. It is
important to note that the inside surfaces of the RABS are disinfected with a sporicidal agent2 ,
but this is not accomplished using the automated decontamination cycles employed for isolators.
This requires firms to carefully supervise disinfection procedures and assure ongoing
effectiveness of the disinfection program. Operators use glove ports, half suits or automation to
access areas within the enclosure during filling. There are 2 types of RABS, “open” and “closed”
RABS. The doors to a “closed” RABS are never opened during an operation. While an “open”
RABS is designed to operate with doors closed at all times, on rare pre-defined circumstances

2 Robust disinfection of all non-product contact surfaces within the RABS should be performed with a suitable sporicidal
agent before batch manufacture. Product contact equipment should be subject to sterilization.

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the doors of the enclosure can be opened to perform certain interventions. If doors are routinely
opened during a filling operation, the system is not considered a RABS because it no longer
restricts access to the critical areas. Typically, the cleanroom surrounding the RABS is
controlled as a Class 10,000 (ISO 7) area and operators are fully gowned.

Reference: Restricted Access Barrier Systems (RABS) for Aseptic Processing; ISPE; August 16
2005.

When inspecting a RABS:
o Determine that the gloves and gauntlets attached to the glove ports are sterile when
installed. After installation, the gloves should be disinfected or changed at appropriate
intervals to minimize the risk of contamination.
o Verify there is a well defined written procedure that describes what is done when an open-
door intervention is performed. All open-door interventions should be documented and
described in batch records, and followed by disinfection.
o RABS entry is often accompanied by an appropriate line clearance, which should be clearly
documented in batch records.
o Determine that all fluid pathways and product contact parts such as stopper bowl, feed and
placement systems are sterilized prior to the filling of each batch.
o Observe how sterile components and supplies are transferred to the RABS. Verify that the
transfer system prevents exposure of sterile surfaces to less clean environments.
o Verify that non-product contact surfaces within the RABS undergo thorough disinfection
with a sporicidal agent before each batch. The effectiveness of the overall disinfection
program should be validated and routinely evaluated by the environmental monitoring
program.

(i) Blow-fill-seal (BFS) Technology. BFS is an automated aseptic filling process in which
containers are formed, filled and sealed in a continuous operation. BFS systems can reduce the
risk of product contamination by reducing operator interventions. The systems are typically used
for filling sterile ophthalmic and respiratory care products. See Appendix 2 of FDA’s 2004
Aseptic Processing Guidance for information about BFS systems. It should be noted that the
inner surfaces of the containers can be exposed to the surrounding environment during the
formation and molding steps prior to filling. The sterile product can also be exposed to the
environment during the filling and sealing steps of the BFS process. Therefore, the air quality
should meet the microbiological level established for Class 100 (ISO 5) should be supplied to
where the sterile product or its containers are exposed during the BFS process. Some of the more
advanced BFS equipments that provide enhanced protection for the sterile product operation can
be located in a Class 100,000 (ISO 8) area. Otherwise, a Class 10,000 (ISO 7) area is
appropriate. Research has demonstrated a direct relationship between the number of
contaminated units and the level of microbial contamination in the air surrounding the machine
(see Reference #20). Typically, the product supply line and sterilizing product filters are steam
sterilized-in-place (SIP).

When inspecting BFS:

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o Verify that HEPA-filtered or sterile air is used during steps where sterile product or
materials are exposed (e.g., parison formation, container molding, and filling steps).
o Evaluate the monitoring and preventative maintenance programs to determine the integrity
of the utilities (cooling water, heating, etc.) associated with the BFS machine is routinely
checked. Leaks in the molds or utility connections at the molds can contaminate the sterile
product or containers.
o Review the SIP system used to sterilize the product line. Determine the sterilization cycle
has been validated and the condensate properly drains from the line. The line should also be
protected between sterilization and use.
o Verify that personnel who enter the classified environment surrounding the BFS machine
are properly gowned and trained.
o If possible, observe equipment setup and any difficulties that can lead to contamination
risks.

Other control procedures (media fills, environmental monitoring, disinfection of surfaces, etc.)
are the same as discussed for conventional aseptic processing line.

(j) Reactor, Centrifuge, Dryer, Mill. This type of equipment can be used to aseptically
manufacture sterile bulk Active Pharmaceutical Ingredients (APIs). The equipment and all
transfer piping must be sterilized prior to processing. This is typically done with sterilize-in-
place (SIP) systems which use clean steam or a chemical sterilant. Review the validation, cycle
controls and the routine monitoring of the SIP system. The equipment and all transfer piping
must remain integral (no fluid or air leaks) and sterile throughout the entire manufacturing
process. Determine how the firm verifies the integrity of the equipment train throughout the
process. If a piece of equipment is opened in the process (e.g. adding seed crystals), verify the
area surrounding the open operation is robustly protected from contamination risks with a Class
100 (ISO 5) air system as well as implementing a carefully designed aseptic operation.
Reference: FDA’s Guide to Inspections of Sterile Drug Substance Manufacturers.
(2) Container/Closure Processing Equipment

Depyrogenation equipment may include a dry heat oven and/or depyrogenation tunnel.
Depyrogenation of stoppers can also be accomplished by dilution via a washing process. The
final rinse of the washing process uses Water for Injection (WFI). For more information, see
FDA’s Aseptic Processing Guidance, Section VI.B, Containers/Closures.

(3) Support Utilities

(a) Water System. Specifically, review WFI generation equipment and distribution loop(s),
including tanks, water lines, isometric diagrams, vent filters, and preventive maintenance
schedules (See also Materials System). Monitoring equipment associated with the Water System
should also be evaluated.

(b)HVAC. Refer to Section IV of FDA’s 2004 Aseptic Processing Guidance on qualification
and maintenance of the HVAC system.

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(c) Process Gases. Gases that are in contact with the drug product or components in drug
manufacturing operations are referred to as process gases. Gases used in aseptic operations, or
downstream of sterilization, must be filtered through a sterilizing grade filter to maintain asepsis.
The integrity testing of these filters (typically hydrophobic) should be evaluated. The system
used in the generation of the process gas(es) should also be evaluated including preventive
maintenance (PM) schedules, monitoring (including temperature, pressure, and humidity), and
sampling. See also under Materials System.

### 3.7 MATERIALS SYSTEM

Compliance Program 7356.002 lists the areas to cover when inspecting the Materials System. The areas
are applicable to sterile drug products and should be covered if this system is selected. In sterile
operations, the quality attributes of each of the materials (ingredients, WFI, containers, closures) have a
bearing on the critical attributes of the finished product. Review the firm’s procedures for receipt,
handling, sampling, testing, approval and storage of manufacturing materials to verify their fitness for
use. Emphasis should be placed on incoming materials that are represented to be sterile and / or pyrogen
free.

Areas of special concern for sterile drug products include:

(1) Water Systems. Water for Injection (WFI) is an ingredient in many sterile drugs, including
injectable products and sterile ophthalmic products. It is also used in depyrogenation (or endotoxin
removal) of equipment and stoppers and in cleaning operations. The quality of the water, and its
endotoxin levels and controls, used in the upstream process should also be evaluated in order to ensure
the removal of bacterial endotoxin to the appropriate level downstream. Purified water can be used for
some sterile non-injectable solutions.

• Observe and understand elements of the generation and distribution systems.
• Evaluate the water system “As Built” diagrams” and inspect for leaks, pipe slopes (via the
isometric diagrams and verification of the degree of the slopes), so called “dead legs”, and
non-sanitary fittings in the distribution system.
• Evaluate how microbial alert and action levels are established.
• Evaluate sampling sites, procedures, frequencies and tests performed.
• Review procedures for preventative maintenance and calibration of critical instruments,
including scheduling and equipment update procedures.
• Review raw data to verify that all of the above is completed per established procedure.
• Review and observe routine monitoring (in-line TOC and conductivity) of water system.
• Review trend data for chemistry, microbiological and endotoxin tests.
• Review investigation of results that are at or over alert and action levels.
Reference: FDA’s Guide to Inspections of High Purity Water Systems.

(2) Process Gas. Process gas and related equipment controls may be covered in conjunction with the
Facilities and Equipment System. Specific considerations include controls over final filtration of the

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processed gas and filter integrity testing. Gas used as a component in a finished product may include the
Nitrogen gas overlay for Oxygen sensitive products.

(3) Pre-washed / Ready to Sterilize Closures. The CGMP regulation (21 CFR 211.94(c)) states that,
where indicated, containers and closures must be processed to remove pyrogenic substances. Many
manufacturers of small volume parenterals purchase stoppers that are ready-to-sterilize, (i.e., they are
pyrogen-free). No washing or depyrogenation is done by the dosage form manufacturers but these firms
are still responsible for assuring the stoppers are of acceptable quality for use in manufacturing. The
pyrogen requirements should be included in specifications for the stoppers and, if the manufacturer does
not conduct testing of each incoming lots for pyrogen/endotoxin, they should establish the reliability of
the supplier’s test results by qualification of the vendor, followed by periodic testing.

(4) Microbiological and Endotoxin Testing of Component, Container and Closure. 21 CFR
211.84(d) specifies that each lot of component, container or closure that is liable to microbial
contamination which is objectionable in view of its intended use shall be subjected to microbiological
tests before use. Evaluate the firm’s system for determining if microbiological or endotoxin testing is
required and the rationale for setting acceptance criteria. Review test data to verify that the materials
meet test criteria and, if not, verify that investigations were conducted to determine the cause and
corrective actions were implemented.

(5) Verification of Container and Closures. The physical and chemical characteristics of containers
and closures can be critical to the sterility and stability of the finished product. Many containers and
closures look alike (color and dimensions), but are made of different materials or have a different
surface treatment such as silicone on stoppers and ammonium sulfate on Type I glass. Evaluate the
firm’s procedures for assuring containers and closure consistently meet appropriate specifications.
Determine what tests and examinations are done to verify the containers and closures are made of the
correct materials with the correct dimensions (critical to ensuring continuing container-closure integrity)
and are free of critical defects.

(6) Container / Closure Integrity. The integrity of the container / closure system is critical to assuring
that all units of drug products remain sterile through shipment, storage and use. Leaking containers or
closures lead to product contamination.

Reference: FDA’s 1994 Guidance for Industry for the Submission of Sterilization Process Validation in
Applications for Human and Veterinary Drug Products.

Evaluate the tests and studies performed to demonstrate the integrity of container / closure systems for
all sterile drugs, including:

• Verify that all incoming container-closure components meet specifications, including all
appropriate dimensions.
• Determine studies adequately simulate the stress conditions of the sterilization process,
handling and storage.
• Verify that the units tested in validation are appropriate (e.g., for terminally sterilized drug
product, the units selected should be exposed to the maximum sterilization cycles using the
production process).

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• Sensitivity of the test is specified.
• Container-closure integrity is demonstrated during validation and as part of the stability
program (in lieu of sterility testing), over the shelf life of the product.

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### 3.8 PRODUCTION SYSTEM

Compliance Program 7356.002 lists areas to cover when inspecting the Production System. The listed
areas are applicable to sterile drug products and should be covered during inspections.

Production practices and conditions can have a direct and significant adverse impact on drug sterility
assurance. The Production System, as well as the Quality System, should be included in all Full
Inspections. Coverage of critical elements, which are typically defined by the firm of the Production
System, should be part of all inspections (full and abbreviated) of aseptically processed sterile drug
manufacturers.

The risk of contamination posed by an operation depends greatly on the design of the overall
manufacturing operation. Observation of manufacturing is a critical part of evaluating the adequacy of
an aseptic processing operation. The following should be carefully observed.

• adequacy of aseptic technique [See section V of FDA aseptic processing guidance]
• personnel behavior and practices in the cleanroom [See section V of FDA aseptic processing
guidance]
• movement of people and materials before and during the aseptic operation
• robustness of production process design (e.g., process performance, validation, impact of
equipment configuration on ergonomics of aseptic manipulations)  [See section IV of FDA
aseptic processing guidance]
• disinfection practices   [See section X.A.3 of FDA aseptic processing guidance]

More specifically, the inspection must include real time observation of the higher risk operations
including but not limited to (these are examples and not an all inclusive list):

• Set-up of filling lines, especially difficult to assemble lines (e.g. powder filling lines), and lines
that require multiple aseptic assemblies or do not employ SIP of the product pathway.
• Cleaning and disinfection of the line and room to ensure all difficult to access surfaces are
consistently and properly cleaned and disinfected.
• Protection of critical contact surfaces to ensure their sterility throughout operations and post
sterilizations.
• Aseptic technique and cleanroom behavior during operations, including handling of equipment
jams and stoppages.
• Personnel flow in relation to microbial control of the environment.
• Material flow (e.g., whether materials are moved from a lesser controlled area to a cleaner area
without disinfection), including number of staff and their activities in the aseptic filling room.
• Filling operations, especially personnel gowning technique, gown integrity, strict adherence to
SOPs), the nature and frequency of interventions (interventions are also performed during the
media fill simulations), and overall condition of the critical filling area.
• Atypical interventions associated with unplanned events (e.g., operator attempts to change the
filling pump during operations).

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• Extra manipulations during filling operations for assembly of sterile filtration apparatus that is
not SIP sterilized.
• Handling (transfer, storage, loading) of partially stoppered vials in lyophilization processes.
Note that for lyophilized products, vials of sterile products are stoppered but not fully sealed
until the lyophilization process is completed. The sterile product is exposed to the environment
during filling, half-stoppering, transport, loading of the lyophilizer, and the lyophilization
cycle. Complete seating of stoppers typically occurs in the chamber after the cycle is
completed. All of these manipulations must be performed under Class 100 conditions.
• Preparation of equipment for sterilization (cleaning, the type of wrapping to ensure protection
while still allowing for penetration as part of the validated sterilization cycle with defined
loading patterns).
• Environmental monitoring (while the monitoring program is considered a Laboratory System,
inspection should include observation of the actual monitoring operations and rationale for
sample site locations).
• Proper placement and sealing of stoppers on vials as applicable, and the capping (aluminum
crimp) is performed in a protected area under unidirectional flow.
• Production of sterile suspensions and sterile bulk powders (e.g., antibiotics) where sterile
filtration of the final bulk is not feasible. These are typically formulated and manufactured
under aseptic conditions. This requires the sterilization of large pieces of production equipment
(e.g., tanks, reactors, dryers and associated lines) and assurance that these pieces of equipment
retain their integrity and remain sterile.

Critical operations that should be covered during an inspection of the Production System include:

(1) Media fills or process simulations. Media fills are used to validate aseptic processing operations,
including those employing newer technologies, such as isolators, BFS or RABS systems. Media fills
representing manually intensive aseptic operations should equal or approach the size and duration of a
commercial production lot. In contrast, a process conducted in an isolator is designed to have a lower
risk of microbial contamination because of the lack of direct human intervention and can be simulated
with a lower number of units as a proportion of the overall operation. All media fills should closely
simulate manufacturing operations, incorporating, as appropriate, worst-case activities and conditions as
well as operator interventions. FDA’s current expectations for media fills are discussed in Section IX.A
of the 2004 Aseptic Processing Guidance.
• Verify Media Fills represent actual manufacturing operations by comparing observed
operations to those documented in Media Fill batch records.
• Determine if media fills are conducted semi-annually for each processing line. The activities
and interventions representative of each shift should be included in the semi-annual media fill
program. This may require more than one media fill per line every 6 months, if aseptic
processing is performed during more than one shift. With the exception of isolator operations,
at least one semi-annual media fill is performed per line per shift. Determine if the aseptic
filling of all types of containers are supported by the media fills performed. If a matrix
approach is used, evaluate the firm’s justification for selecting the worst case container /
closure configurations for each line.
• Determine accountability of all filled units (units filled vs. units incubated).

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• Verify that all units that were discarded during and after filling have a reasonable and
assignable cause for rejection (e.g., rubber stopper missing, aluminum cap missing).
• Determine that cracked and leaking units found after incubation are investigated, counted and
all rejected units properly justified (e.g., is there an assignable cause that is reasonable for the
rejection?).
• Determine how and who examines units after incubation. If the examination is not performed
by a microbiologist, determine if it is overseen by the quality unit and if the operators doing
the exam are properly trained by a microbiologist.

Reference:
• FDA’s 2004 Aseptic Processing Guidance, Section IX A.
• PDA Technical Report No. 28, revised 2006, Process Simulation Testing for Sterile Bulk
Pharmaceutical Chemicals.
• PDA Technical Report No. 22, revised 2011, Process Simulation for Aseptically Filled
Products.

(2) Sterile filtration (aseptic processing).

• Verify filters used in production are identical to those used in validation studies (i.e., those
submitted in drug applications)
• Verify that actual operating parameters and allowable extremes are covered in the validation
studies.
• Determine that validation of filter sterilization has been performed for all products. Pay special
attention to legacy products. These include older products and those for which applications
have not been submitted.
• Observe filter integrity testing to verify procedures are followed.
• Review investigations of any integrity test failures.

Reference:
• FDA’s 2004 Aseptic Processing Guidance, Section IX.B; and
• PDA Technical Report #26, 2008, Sterilizing Filtration of Liquids.

(3) Sterilization and depyrogenation of containers, closures and processing equipment.

• Review the validation or revalidation of sterilization and depyrogenation processes used for
containers, closures and, in the case of aseptic processing, equipment that comes in contact
with the sterile product or sterile components.
• Check if firm verifies that validated parameters (loading patterns, cycle parameters) are met for
each load.
• Rubber stoppers that are not purchased pre-sterilized or pre-siliconized may require
depyrogenation and siliconization prior to use. As previously noted, depyrogenation may be
achieved via a washing dilution process with the use of repeated WFI washing steps. The
validation should demonstrate a successful 3-log reduction of bacterial endotoxin. When the
firm performs its own siliconization of stoppers, silicon level after wash should be validated to
meet the predetermined acceptance criteria.

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• Stoppers are sterilized by steam sterilization. Verify that the clean steam used to provide the
sterilization is acceptable and has been assayed for endotoxin.
• Review the practices and procedures to determine if a firm needs to revalidate the sterilization
and depyrogenation process.
• Review change control procedures.
• Determine if reprocessing is performed.
• Evaluate bioburden level:  Evaluate the firm’s understanding of process bioburden (e.g., from
incoming components/container/closure) and determine if the firm has adequately validated
hold time for critical steps. It is important to note that increased bioburden can lead to the
degradation of the drug product as well as contributing impurities (including endotoxin) to the
drug product. Sampling points (location in process flow) and methods should be evaluated
based on product quality risks.

(4) Lyophilization.

• Review the validation of lyophilization cycles established for selected products.
• Verify the firm confirms all critical cycle parameters are met for each lot.
• Determine environmental monitoring is routinely performed in the areas of loading and
unloading of the product from the lyophilizer. In addition, ensure personnel monitoring is
conducted on those operators who perform the loading and unloading operations.
• Observe the transport of the partially stoppered vials and the loading of the lyophilization
chambers to verify it is done under proper environmental conditions (Class 100) and to verify
that proper aseptic techniques are used.

Reference: FDA’s Guide to Inspections of Lyophilization of Parenterals.

(5) Sealing of vials.

• A vial is not sealed until the aluminum overseal is placed over the rubber stopper and crimped
in place.
• If stoppered vials exit the aseptic processing zone prior to capping, verify proper safeguards
are in place, such as HEPA filtered air protection and qualified in-line detectors that reject
vials with improperly seated stoppers.

(6) Terminal sterilization.

• Determine what type of sterilization cycles are used (bioburden based or overkill).
• Review validation / revalidation / or periodic evaluation of terminal sterilization cycles for
representative types of products.
• For selected products, verify that the parameters and loading patterns used in production are
the same as those used in validation studies.
• Determine the minimum acceptable cycle allowed in the SOP (as opposed to the nominal or
routine cycle) and compare that to the validated cycle (using BI) to verify it has been properly
qualified.
• Determine how sterilization cycles are documented, monitored and reviewed.

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• Review deviations or atypical data from sterilization operations that indicate inconsistencies in
process performance.

(7) Parametric release of terminally sterilized drug product. This is defined as a sterility assurance
release based on demonstrated control of the sterilization process. It enables a firm to use defined
critical process control data, in lieu of the sterility test to fulfill the intent of 21 CFR 211.167(a). It is
allowed only for products that are terminally sterilized by heat and it must be identified in the
appropriate regulatory filing as the release method. Parametrically released product must have an
approved application.

• If encountered during an inspection, verify the parametric release method has been submitted
and approved in the appropriate drug application. If the drug is not the subject of an approved
application, collect pertinent information and validation data for evaluation by the Center.
• Verify that the conditions described in FDA’s Compliance Policy Guide Section 490.200,
Parametric Release – Drug Products Terminally Sterilized by Heat, are met.

(8) 100% inspection of injectable products including: cracks, visible particles and other significant
defects.

• Verify the firm has written procedures that define the defects to be removed from the lot and
actions to take if the number of critical defects exceeds a pre-determined level.
• Significant defect categories should be identified. Results of inspection of each batch should be
compared to established action levels.
• Evaluate the appropriateness of and the rationale or justification for pre-determined action
levels.
• Evaluate the firm’s investigation into the cause of rejects, including units rejected for cracks
and visible particulates (e.g., foreign matter).
• Observe the inspection process.
• Challenge visual/manual inspection rates through observation.
• Evaluate the adequacy of written procedures for visual inspection.
• Evaluate personnel qualification and requalification and equipment qualifications according to
established procedures. Evaluate personnel qualification including the use of reference samples
for qualification.
o If a manual system is used, determine if employees are trained and qualified to verify they
can recognize and remove defects under actual or simulated production conditions.
o If an automated or semi-automated system is used, determine the equipment is qualified and
the software program or equipment settings have been validated for all types of products
being inspected (e.g., clear vials, amber vials, colored solution, suspensions). If the
equipment is an automatically controlled computer based system, an assessment of the
system and validation is warranted.
• Evaluate the firm’s program for sampling and examination of inspected vials and evaluate the
effectiveness of inspection and action taken if the reject level is reached.

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• Evaluate the firm’s assessment of units rejected during filling operations (any separate
inspection prior to the 100% inspection stage), established alert/action limits, and
investigations where appropriate.

(9) Personnel (gowning, training, aseptic techniques). The type of gowns and personal protective
equipment (PPE) worn by employees should be appropriate for the areas in which they work. There
should be detailed written procedures that describe the gowning requirements for each processing area.
Evaluate the following:

• For aseptic processing, determine the gowns (which typically include face masks, hoods,
protective goggles, gloves, and boots) are sterilized and made of non-particle shedding
material. Ensure that the gowns cover all skin, hair and facial hair.
• Review how the incoming sterile gowns/garb are accepted or rejected for use.
• Evaluate the firm’s program for training, testing and qualifying and re-qualifying employees
who work in the controlled areas, especially those who set-up and operate aseptic processing
lines.
• Evaluate the aseptic techniques of employees by observing aseptic processing operations.
• For selected employees, verify the training, testing, qualifying, and re-qualifying were done as
specified in procedures.
• Verify the training is done on a continuing basis.
Reference:  FDA’s 2004 Aseptic Processing Guidance, Section V.
(10) Batch records.

• Review of environmental and personnel monitoring data, as well as other data relating to
acceptability of support systems (e.g., HEPA / HVAC, WFI, steam generator) and
manufacturing equipment. This review is considered essential to batch release decisions. The
batch record should include documentation that assures this type of holistic review is done
before the release of a lot for distribution.
• For aseptic processing, verify interventions into critical areas (Class 100/ ISO 5) are
documented so they can be reviewed and evaluated by the Quality Unit.
• Review batch records to verify they include complete information for all sterilization
processes.

Reference: FDA Aseptic Processing Guidance, Section XII.

(11) Environmental and personnel monitoring.

•
See section below under “Laboratory Control System”.

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### 3.9 PACKAGING AND LABELING SYSTEM

Compliance Program 7356.002 lists the areas to cover when inspecting the Packaging and Labeling
Control System. All of the areas that are applicable to sterile drug products and should be covered if this
system is selected for coverage. Areas of special concern for sterile products include:

• Determine that packaging and labeling operations do not introduce risk to product integrity (for
example, damage to the container or closure that could affect the integrity of the unit).
• Determine that the container, closure and packaging systems provide adequate protection
against foreseeable external factors in storage, shipment, and use that can cause contamination
or deterioration (e.g. cracked vials during shipment if not properly protected; pinhole leaks in
bags, frozen drug products, tears or holes in overwraps of sterile bulk antibiotics and large
volume parenterals; and unseating of stoppers in aluminum cans containing sterile bulk APIs
due to pressure changes during shipment by air).
• It is not unusual for filled containers of sterile products to be stored unlabeled for a period of
time. The firm must have adequate controls to assure proper identification of the unlabeled
product at all times.
• Tracking of refrigerated or temperature controlled units for room temperature exposure times
(e.g. warm up of refrigerated units prior to label application).
• Tracking and investigation (as specified and appropriate) of rejected units culled during
packaging and labeling operations.

### 3.10 LABORATORY CONTROL SYSTEM

Compliance Program 7356.002 lists general areas to cover when inspecting laboratories. Inspections of
sterile drug manufacturers should also cover microbiology laboratories. Quality control tests (sterility
and Limulus Amebocyte Lysate or LAL test) and the collection of environmental and personnel
monitoring samples should be observed to verify that acceptable techniques are used and written
procedures are followed. The inspection of microbiology laboratory should evaluate the following:

• Sterility testing, including the collection of samples that are representative of the entire lot and
processing conditions; adequate control and monitoring of the testing environment; validation
of the method for specific products; growth promotion testing of the media; and incubation
times and temperature. It is important to note that increasing the number of samples or the
number of tests does not greatly increase the probability of detecting contamination if it is
present at a very low level in a lot. Reference: FDA’s Guide to Inspections of Microbiology
Pharmaceutical Quality Control Laboratories and FDA’s 2004 Aseptic Processing Guidance,
Section XI.

• LAL testing, including product specific validation; collection of representative samples of raw
materials, components/containers, in-process, and finished product, where appropriate; and
adequate laboratory facilities for conducting the tests. Verify the rationale of sample size of
endotoxin test relative to the production batch. Reference: Bacterial endotoxins – Test
methodologies, routine monitoring, and alternatives to batch testing. ANSI/AAMI ST
72:2002/ (R) 2010, Association for the Advancement of Medical Instrumentation.
• Environmental monitoring, which includes: a well defined written program that covers all
production shifts and includes air, floors, walls, equipment surfaces, and, in aseptic process

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operations, critical surfaces that come in contact with sterile product, containers and closures;
establishment of appropriate alert and action levels, use of sampling (contact plates, swabs,
active air samplers) and testing methods (media, plate exposure times, incubation times and
temperatures) that are designed to detect environmental isolates. Evaluation of the validity of
the sampling locations and sampling methods. Reference: FDA 2004 Aseptic Processing
Guidance, Section X. Note: environmental monitoring is performed during the processing of
all types of sterile drug products, including an appropriate program for terminally sterilized
products.
• Personnel monitoring which includes: a routine program for daily/shift monitoring of operators
gloves and an appropriate schedule for monitoring gowns; establishment of limits that are
based on the contamination risk to the product; and investigations of results that exceed the
established levels or demonstrate an adverse trend. Personnel monitoring is important in all
sterile product operations, but it is especially critical in aseptic processing, and inspectional
emphasis should be risk based, focusing on those operations that require employees to enter
the critical areas of the processing line. Reference:  FDA’s 2004 Aseptic Processing Guidance,
Section V.C.
• Efficacy of disinfectants, including assessment of the suitability, efficacy and limitations of the
disinfecting agents used in the controlled area, production equipment and laboratories. The
firm’s assessment typically includes laboratory studies that test the effectiveness of agents on
different surface materials. Material coupons are usually used with surfaces types as found in
production. The studies should be done with the same disinfecting agents, contact times (which
should be clearly defined in written procedures). It is also important to understand that
disinfectants have limitations and most are not effective against every type of microorganism.
For this reason, firms should normally use more than one type of disinfectant. Reference:
FDA’s 2004 Aseptic Processing Guidance, Section X.A.3.
• Identification of microorganisms, including procedures that require identification of organisms
found in positive sterility tests, media fills, and environmental monitoring (environmental and
personnel) samples as specified by the firm. The program should assure routine identification
of microorganisms found in samples are taken in critical areas, surrounding areas and from
personnel in the production area. Review the procedures, equipment and controls used in
identification activities of the contaminants.
• Microbiological media, including the preparation, sterilization and growth promotion testing of
the media used in performing tests (sterility tests, raw material testing, pre-filtration bioburden,
environmental monitoring, media fills, etc.). Where appropriate, inactivating agents for
disinfectants or product residuals should be added to allow detection of contaminants.
• BIs and biological cultures used in sterilization validation studies should be used and stored
under appropriate conditions. Typically, the conditions are described in the literature received
with the BI, if supplied by a vendor. The microbial population should be confirmed by testing
each lot. Spore counts should be verified prior to use in validation studies. The D-value should
be determined for each lot of a BI if it is used in a way not described by the vendor. If used
specifically as directed, the D-value supplied by the vendor can be accepted if the reliability of
the Certificate of Analysis has been established, but D-value of incoming batches should be
periodically verified. Reference: 2004 FDA Aseptic Guidance.

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• Microorganisms (e.g., ATCC) are used for growth promotion tests of media. Organisms
isolated from environmental monitoring samples can also be used to perform growth
promotion test.
• Monitoring, calibration and maintenance programs for microbiology laboratory equipment,
such as incubators.
• Training of microbiologists and evaluation of microbiologists or technicians that perform
sterility, LAL and environmental monitoring tests.
• Documented investigations into out-of-specification results. Evaluate positive sterility tests and
media fill and LAL failures investigations. Also review environmental / personnel monitoring
results at alert and action levels to identify and determine the firm’s response to the significant
incidents or trends. Because of the limited sensitivity of the sterility tests to detect batch
contamination, any positive is a serious issue and should be thoroughly investigated by the
firm with quality unit oversight and approval. The investigation and followed should be
reviewed during inspections to assess the decision making process. An initial positive can be
found invalid only if there is clear documented evidence that the microbial growth was
unequivocally a laboratory error. Reference: Section XI.C of FDA’s 2004 Aseptic Processing
Guidance.

21 CFR 211.180(e) requires that records be maintained in such a manner that the data can be used to
evaluate adherence to quality standards. The evaluation of data generated by the microbiology lab plays
an integral role in establishing the sterility assurance of the finished product. The inspection should
determine if the firm generates and reviews testing data and product quality related data (e.g., trend
reports) to make timely, informed and science-based decisions to assure an ongoing state of control.

### 3.11 SAMPLING

Samples of sterile drug products should be collected to document suspected contamination, adulteration
or misbranding encountered during an inspection. The samples can be physical or documentary. In the
event of a for-cause assignment where in-process samples are being requested, collect the samples
aseptically at points where such contamination might occur. These samples should be collected by the
firm under the observation of the investigator. Great care shall be taken to prevent the possibility of
contamination and/or compromising the integrity of the sample for all physical samples of raw
materials, in-process samples or finished drug products. Consult the district management and/or Center
as well as the servicing laboratory for guidance on sample size and sampling techniques. A production
lot with an initial sterility failure result that was invalidated by the firm may be considered a good
candidate for sampling.

Physical sample analysis is not necessary to document CGMP deficiencies. Documentary samples may
be submitted when the documentation illustrates the deficiencies and to obtain evidence of interstate
shipment. Please be aware to collect the appropriate number of sample units in order to accommodate
the 702(b) section of the Act.

For finished products requiring sterility testing, collect 48 units of product. For finished products
requiring endotoxin testing, collect 20 units of product.

For additional sampling guidance, refer to Investigations Operations Manual (IOM) Chapter 4.

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[end Part III]

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PART IV - ANALYTICAL

In general, samples will be submitted to your District's designated servicing laboratory, except as
requested in a special assignment or your supervisor.

4.1 . ANALYZING LABORATORIES

For Sterility and Bacterial Endotoxin testing:

Region
Examining Laboratory
NER
NRL
SER
SRL
CER
NRL
PAR
SAN-DO
SWR
DEN-DO

For particulate matter in injectables analysis, contact the ORA/Office of Regulatory Science/Medical
Products and Tobacco Staff to determine the most appropriate laboratory for this test.

### 4.2 ANALYSIS

Sterility testing methods should be based on current editions of USP <71> Sterility Tests and the
Sterility Analytical Manual (SAM). The SAM provides supplemental information to the USP. The SAM
has the goal of standardizing the performance of testing for pharmaceutical microbiology in FDA
laboratories.

Bacterial endotoxin testing methods should be based on current editions of USP <85> Bacterial
Endotoxin Test and the Sterility Analytical Manual (SAM).

Particulate matter testing methods should be based on current editions of USP <78>.

Other microbiological examinations should be based on appropriate sections of USP and the SAM.

[end Part IV]

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PART V - REGULATORY/ADMINISTRATIVE STRATEGY

A recommendation for regulatory action should be submitted by the District Office when a judgment is
made that the firm is not operating in a state of control and management of the firm is unwilling or
unable to make adequate corrective actions in an appropriate time frame. The therapeutic use of the drug
product and the potential adverse effect of the CGMP deviations on the finished product must be
considered in determining the appropriate action needed.

When deciding the type of action to recommend, the initial decision should be based on the seriousness
of the problem and the most effective way to protect the consumer (i.e., when non-sterile parenterals are
found, injunction/seizure, recall would be the action(s) of choice). Instructions in the Regulatory
Procedures Manual (RPM) should be followed.

If the nature of the CGMP deviations is determined to pose minimal risks when considered in relation to
the intended use of the drug, the primary action should normally be voluntary corrections by the firm.
The District should require that all commitments for achieving voluntary compliance by firm
management be submitted in writing and contain a time schedule for completion. The District should
determine if the schedule is a reasonable time frame and should monitor the progress.

When voluntary action is not accomplished or when the deviations observed pose a serious risk to the
consumer, regulatory and / or administrative action should be recommended.

NOTE:  Regulatory action is independent of the collection of a violative physical
sample. The lack of a violative physical sample is not a barrier to pursuing
regulatory and/or administrative action providing the CGMP deficiencies have
been well documented. Physical samples found to be in compliance likewise
are not a barrier to pursuing action under CGMP charges.

The following list of deficiencies represents examples of practices that CDER believes could warrant
regulatory and/or administrative action (please note the following is not intended to be an inclusive list):

1.
Contamination with filth, objectionable microorganisms, toxic chemicals or other drug
chemicals; or a reasonable potential for product contamination, with demonstrated avenues of
contamination such as poor aseptic methods, contact with unclean equipment, or airborne
contamination.

2.
Failure to assure that each batch conforms to label claims or established specifications, such as
NDA, ANDA, USP monographs, and the firm’s finished product specifications.

3.
Distribution of product which does not conform to established specifications.

4.
Lack of adequate validation of critical steps in sterilization processes, including sterilization by
filtration; sterilization cycles used for drug products; and, for aseptically processed products,
sterilization processes used to sterilize components (formulation and/or its ingredients, as well as
containers and closures), or to sterilize equipment surfaces that contact sterile product or any
elements of the product.

5.
Lack of adequate validation of aseptic processing operations (media fills).

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6.
Failure to appropriately conduct and document investigations of discrepancies and failures of
drug products or any of their components to meet specifications, especially inadequate
investigations of sterility test failures, media fill failures and repeated or significant
environmental or personnel monitoring results that meet or exceed action levels.

7.
Facilities and equipment which do not provide adequate protection for aseptically processed
product while the sterile product or sterile components are exposed to the environment. This
includes both lack of robustness due to poor design, as well as failure to maintain equipment as
sterile (e.g., by providing proper barriers as well as assuring adequate sterilization frequency).

8.
Failure to assure a robust cleanroom disinfection program. This may include the failure to assure
sufficiently detailed cleaning procedures to assure repeatability in cleaning, or failure to
demonstrate the suitability and efficacy of the disinfecting agents used for the critical controlled
areas and production equipment.

9.
Failure of a WFI system to deliver water that consistently meets chemical, microbiological and
endotoxin specifications.

10.
For aseptic processing, poor employee practices that increase the risk of product contamination.

11.
Failure to provide adequate training to employees who work in critical operations, such as
operators on aseptic processing lines, operators responsible for initiating and checking
sterilization cycles and those who perform the 100% inspection of filled injectable products.

12.
Failure to perform adequate 100% inspections of injectable products for particulate matter and
other defects.

13.
Failure of batch records to include complete information related to the production and control of
each batch, including documentation that assures environmental and personnel monitoring data
and data related to the support systems, and assure quality unit review of these records prior to
approval of a lot for distribution and release. For aseptically processed product, batch
documentation includes records of purposeful operator interventions into critical (Class 100 /
ISO 5) areas of the line. Operator intervention should be minimized as much as possible to
preclude and control contamination.

14.
Use of test methodology (sterility test, endotoxin test) that is not adequate or validated.

15.
Lack of an adequate environmental monitoring program, that is, one that does not include
dynamic monitoring during all production shifts or has not established appropriate alert and
action levels and, in the case of aseptic processing, does not include representative critical
surfaces that come in contact with sterile product, containers and closures.

16.
Lack of an adequate personnel monitoring program for aseptic processing operations. For
example, the program does not include daily monitoring of operators’ gloves and periodic
monitoring of gowns; has not established appropriate limits or does not require investigations
and corrective actions when limits are exceeded.

[end Part V]

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PART VI - REFERENCES, ATTACHMENTS, AND PROGRAM CONTACTS

### 6.1 REFERENCES

All of the references listed below, with the exception of number 17 through 26, are available on FDA’s
internet website.

1.
Code of Federal Regulations, Title 210 and 211 as revised, including the preamble.

2.
Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good
Manufacturing Practice; FDA; September 2004.

3.
Guidance for Industry for the Submission Documentation for Sterilization Process Validation in
Applications for Human and Veterinary Drug Products; FDA; November 1994.

4.
Guidance for Industry Process Validation: General Principles and Practices of Process; FDA;
January 2011.

5.
Guide to Inspections of Lyophilization of Parenterals; FDA; July 1993.

6.
Guide to Inspections of Microbiology Pharmaceutical Quality Control Laboratories: FDA; July
1993.

7.
Guide to Inspections of High Purity Water Systems, FDA; July 1993.

8.
Guide to Inspections of Sterile Drug Substance Manufacturers; FDA; July 1994.

9.
Guide to Inspection of Dosage Form Drug Manufacturers; FDA; Oct. 1993.

10.
Compliance Policy Guide 7132a.13, Parametric Release – Drug Products Terminally Sterilized
by Heat; FDA.

11.
Compliance Program 7356.002, Drug Manufacturing Inspections.

12.
Compliance Program 7356.002C, Radioactive Drugs.

13.
Compliance Program 7356.002M, Inspection of Licensed Biological Therapeutic Drug Products.

14.
Investigations Operations Manual

15.
Guide to the International Inspections and Travel

16.
Regulatory Procedures Manual

17.
Restricted Access Barrier Systems (RABS) for Aseptic Processing ISPE Definition; ISPE; August
16 2005.;

18.
ISO 17665 Moist Heat Sterilization.

19.
ISO 14644 Cleanrooms and Associated Controlled Environments.

20.
ISO 14698 Cleanrooms and Associated Controlled Environments- Biocontamination Control.

21.
PDA Technical Report No. 1 (Revised 2007) Validation of Moist Heat Sterilization Processes:
Cycle Design, Development, Qualification and Ongoing Control.

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22.
PDA Journal of Pharmaceutical Science & Technology; Vol. 49, No. 6; November – December
1995 Performance of Blow/Fill/Seal Equipment under Controlled Airborne Microbial
Challenge.

23.
PDA Technical Report 51 (2010) Biological Indicators for Gas and Vapor-Phase
Decontamination Processes: Specifications, Manufacture, Control and Use.

24.
PDA Technical Report No. 22, revised 2011, Process Simulation for Aseptically Filled Products.

25.
PDA Technical Report No. 28, revised 2006, Process Simulation Testing for Sterile Bulk
Pharmaceutical Chemicals.

26.
PDA Technical Report #26, 2008, Sterilizing Filtration of Liquids.

27.
Bacterial endotoxins – Test Methodologies, Routine Monitoring, and Alternatives to Batch
Testing. ANSI/AAMI ST 72:2002/ (R) 2010, Association for the Advancement of Medical
Instrumentation.

28.
CGMP Q&As. FDA website.

29.
Sterility Analytical Manual (SAM); FDA May 2012.

### 6.2 ATTACHMENTS

A  “Inspections: Points to Consider” This attachment includes a list of questions intended to be an aid
in conducting inspections and obtaining information needed to assess a firm’s operations. This list of
questions and/or considerations is not intended to be an all inclusive or an exhaustive list of
concerns. They are intended to assist focusing of the inspection and include areas worthy of
consideration and evaluation during an inspection. The answers do not have to be reported in the
EIR unless they are relevant. The list of questions covers: Moist Heat Sterilization; Dry Heat
Sterilization / Depyrogenation; Aseptic Filling; Lyophilization; Isolators; Environmental
Monitoring; and Biological Indicators. CDER welcomes feedback and any additional questions to
this list.

### 6.3 CONTACTS

Office of Regulatory Affairs (ORA)

For technical questions concerning inspections contact:
Office of Regulatory Affairs (ORA)
Office of Medical Products and Tobacco Operations (OMPTO)
Division of Medical Products and Tobacco Program Operations (DMPTPO)
Telephone number: 301-796-0358
Email: ORAHQDrugInspectionPOC@fda.hhs.gov

For questions concerning particulate matter in injectables analysis and appropriate testing laboratory
contact:

Office of Regulatory Affairs (ORA)
Office of Regulatory Science (ORS)
Medical Products and Tobacco Scientific Staff (MPTSS)

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Bruce Harris
Telephone number: 301-796-3030
E-mail: Bruce.Harris@fda.hhs.gov

For questions concerning microbiological analysis, sterility issues and related sampling concerns
contact:

Office of Regulatory Affairs (ORA)
Office of Regulatory Science (ORS)
Medical Products and Tobacco Scientific Staff (MPTSS)
Angele Smith
Telephone number: 301-796- 4200
E-mail:   Angele.smith@fda.hhs.gov

Center for Drug Evaluation and Research (CDER)

CGMP or any Quality-Related Policy Questions
For CGMP or any quality-related policy question, technical or scientific questions or
information needs, including questions about this program, please send an email to the
following address and it will be handled as a top priority:

CDER-OPQ-Inquiries@fda.hhs.gov

Enforcement-Related Guidance or Policy
For enforcement-related guidance or policy, including evidence need and sufficiency,
citations, and case evaluation/recommendation advice, please send an email
to the following address and it will be handled as a top priority:

CDER OMQ Compliance Policy: CDEROMQCompliance@fda.hhs.gov

Labeling Requirements and Policies

Office of Unapproved Drugs and Labeling Compliance, see intranet home page for
contacts
[CDER | Office of Compliance | Office of Unapproved Drugs and Labeling Compliance]

Registration and Drug Listing Requirements
CDER Office of Compliance, see “CDER: Who’s the Lead” intranet page for contacts
[CDER | Office of Communications | CDER: Who’s the Lead]

[end Part VI]

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PART VII - CENTER RESPONSIBILITIES

A. COMPLIANCE

The CDER Office of Product Quality (OPQ), Office of Surveillance (OS) will evaluate the operations
under this Compliance Program. Reports of these evaluations will be shared with the ORA
Headquarters offices, field offices and CDER headquarters offices.

The Center reviews enforcement recommendations and provides the agency’s technical decisions in
coordination with District Offices and Office of Chief Counsel

B. DRUG SHORTAGES

If a violative conditions are identified that may result in a shortage, field staff should notify CDER drug
shortage staff at DrugShortages@CDER.fda.gov and ensure the company also contacts this staff. This
notification should occur as soon as the District becomes aware of a possible shortage or through
communication with the firm.

CGMPs are a preventive system intended to preclude to the occurrence of critical product defects and
loss of assurance of quality. A warning letter is an advisory action meant to notify a manufacturer that
significant violative conditions compromising the assurance of quality, safety, and/or efficacy were
observed and must be promptly corrected by an appropriate and timely action plan. In situations where
the firm’s corrective actions may reduce the supply of medically necessary products, the agency will
work closely with the firm to assure the medically necessary drugs remain available and the CGMP
deficiencies are corrected in a timely manner.

[end Part VII]

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ATTACHMENT A
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ATT. A
PAGE 1 of 16
TRANSMITTAL #
FORM FDA 2438g (electronic-02/2003)

Inspections: Points to Consider
Below is an extensive list of questions provided as an aid in conducting inspections and obtaining
information needed to assess a firm’s operations.
o This list of questions and/or considerations is not intended to be an all inclusive or an
exhaustive list of concerns. They are intended to assist focusing of the inspection and include
areas worthy of consideration and evaluation during an inspection.
o The answers do not have to be reported in the EIR unless they are relevant.

TOPICS:

Moist Heat Sterilization
Dry Heat Sterilization / Depyrogenation
Aseptic Filling
Lyophilization
Isolator Barrier Technology
Environmental Monitoring (Non-viable)
Environmental and Personnel Monitoring – Microbiology
Biological Indicators.

CDER welcomes feedback and any additional questions to this list.

MOIST HEAT STERILIZATION

Reference:  PDA Technical Report No. 1 Revised 2007 Validation of Moist Heat Sterilization Processes:
Cycle Design, Development, Qualification and Ongoing Control; and

General.

1. Who is the manufacturer of the steam sterilizer (autoclave)?

2. What is the model number, age, and internal volume of the autoclave?

3. What is the sterilizing agent? (e.g., steam, air over pressure, superheated water, gamma irradiation)?

4. If jacketed, what pressure/temperature is maintained in the jacket as opposed to the chamber?

5. What types of vent filters are used and how often are they integrity tested?

6. Are vent filters hydrophobic? Are the vent filter housings heated to prevent condensation?

7. Are cycles controlled manually or automatically?

8. What type of monitoring and controlling sensors are used (e.g., mercury-in-glass thermometer,
thermocouple, RTD, pressure gauge)?

9. How are these sensors calibrated? Are the standards NIST traceable (or traceable to a National
standards for foreign firms), where appropriate?

10.  Is the autoclave equipped with a steam spreader (more than one steam entry line would be
considered in this category)?

11.  If more than one autoclave is used by the firm, what is the system's capacity for steam production in
relation to all autoclaves being in operation at the same time?

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12.  What are the sterilization cycle parameters? (Compare Master Process Record / SOP specifications
against processing records completed for selected drug products)

13.  What are the firm's specifications and observed parameters for:

• Time

• Temperature

• Pressure (psi, in. Hg)

14.  Where is the cycle controller sensor located?

15.  How are each of the sterilization (#13) parameters monitored?  Are the come-up times for chamber
temperature during sterilization reproducible when compared to the come-up time achieved in
validation studies?

16.  Is the slowest to heat spot ("cold spot") in each load monitored during each autoclave cycle?

17.  Have any changes in the steam sterilization system occurred since the last EI? Have these changes
been evaluated for the need for re-validation?

18.  Is clean steam being used (control of bacterial endotoxin)?

Validation.

19.  Does the firm have written procedures for validation that include

• Design  Objectives
• Installation qualification (IQ) of equipment
• Operational qualification (OQ) of equipment
• Performance qualification (PQ) with product (maximum and minimum load submitted in the
application, and any changes after)
• Description of circumstances requiring revalidation of the system
• Procedures for revalidation

20.  Does validation documentation include the following?

A.   Empty chamber / loaded chamber heat distribution studies:
o Number of runs?
o Was cold spot determined?
o Allowable variation?
o Actual variation found?
o What is the worst-case load?

B. Heat penetration studies
o For each type of loading pattern/for each container size utilized?

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o Number of runs per pattern?
o Was the "cold spot" determined for each pattern?
o Is the established load configuration submitted in the application followed and/or
reportable changes submitted as appropriate?

21.  What type of temperature measurement system was used? Does it provide a separate printed reading
for each thermocouple?

22.  What type of temperature sensors were used, and were they calibrated before and after each run?

23.  If biological indicators were used during validation runs:

• Type of indicator (spore strip, inoculated product, ampule)
• Source of indicator
• Microorganism used, including concentration and D value
• Were BIs used in an "end point" or "count reductions" mode? If any positive BIs were found
(when not expected), what was the firm's response?

23.  In the event a heat distribution or penetration variance was disclosed during the studies, how did the
firm correct or allow for it?

24.  Has the firm determined lag times for all container sizes/mass, product viscosities, etc. and adjusted
their cycles accordingly?

DRY HEAT STERILIZATION / DEPYROGENATION

Dry heat sterilizers are used, primarily, to sterilize and depyrogenate glass containers for injectable drug
products. Both dry heat ovens and dry heat tunnels are used. An oven is a batch process and, at the end
of the cycle, the sterile vials are manually removed from the oven, transported and then manually loaded
onto the filling line. A dry heat tunnel uses a continuous, integrated process. In a tunnel, the vials move
on a belt from the wash processing through a heating zone where the vials are sterilized and
depyrogenated to a cooling zone and then directly into the Class 100 area of a filling line. Typically,
firms validate the depyrogenation of the glassware rather than the sterilization cycle. This is based on
the fact that it is generally more difficult to remove or denature pyrogenic substances than
microorganisms. Components that have undergone heat depyrogenation are rendered sterile.

General.

25.  Determine what types of dry heat sterilizers are used (ovens, tunnels)?

26.  Determine the location of the heat source. The heating element/device that generates the
depyrogenation temperature can affect the HEPA filters and their ability to provide the desired
filtration for non-viable particles. For example, the high temperatures create expansion and
contraction of the HEPA filters and filter housing, which can compromise the integrity and
functionality of the HEPA filters.

27.  How is the heat distributed in the oven or tunnel (fan or convection)?

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28.  Where are the HEPA filters located in the oven or tunnel?  What zones in a tunnel are supplied with
HEPA filtered air (supply, heating, cooling zones)?  Does the cool down section of the tunnel
provide a Class 100 conditions to ensure the sterility of the containers are maintained? What zones
are controlled as Class 100 areas?

29.  Due to thermal dynamics (high temperature of >360 degree C leads to the expansion and contraction
of the filter housing), the HEPA filter normally undergoes integrity testing every 6 months.
However, depending on the amount of usage of the depyrogenation tunnel and data obtained from
particle monitoring in the vicinity outside the heat tunnel, integrity testings may need to be
conducted on a more frequent basis. How does the firm assure integrity of the HEPA filters? How
often are HEPA filters changed?

30.  Are non-viable particle counts taken in hot air tunnel? Non-viable particle measurement for the
Class 100/ ISO-5 zone of the depyrogenation tunnel are not done during routine operation because
of high temperature. However, periodic measurement of non-viable in ISO 5 area should be verified
and they are normally measured prior to and subsequent to the manufacture of a batch/campaign
and at ambient temperature.

31.  Are the sterilization / depyrogenation cycles controlled manual or automatically?

32.  What type of monitoring and controlling sensors are used (e.g., thermocouple, RTD, pressure
gauge, belt speed indicators)? How often are they calibrated?

Parameters.

33.  What are the sterilization / depyrogenation cycle parameters or equipment settings?  Compare
master production record / SOP specifications and processing records for specific representative
products.

34.  What are the firm's specifications for time, temperature, belt speed, and pressures if applicable?

35.  What are the critical parameters? How were they established? How does the firm assure the critical
parameters are met for each lot or cycle?

36.  Where are the sensors for the cycle controllers located?

37.  How are each of the above parameters monitored? Are any of the parameters not monitored?  Are
the critical parameters alarmed in continuous systems, such as those used in tunnels?   What is done
when there is an alarm?

38.  How does the firm assure that all critical parameters are met for each cycle in an oven or for the
continuous run of the tunnel?

39.  Do dry heat tunnels have alarms to alert operators if critical parameters (heat, belt speed, pressure)
are not met?  Are the alarms documented?  Did the conditions that caused the alarm require the
implementation of change controls and did they impact the validated process?

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40.  Have any changes in the dry heat sterilization / depyrogenation system occurred since the last
inspection?  Have these changes been evaluated for the need for revalidation?

Validation.

41.  Does the firm have written procedures for qualifying the dry heat sterilizers that include:

• Design Objectives
• Installation qualification of equipment
• Operational qualification of equipment
• Performance qualification with product
• Description of circumstances requiring re-validation and procedures

42.  Does validation documentation include heat distribution / penetration studies?

• What is the firm's allowable temperature variation and the actual variation found in
production?
• What type of temperature measurement system was used?
• Was calibration performed before and after the validation?
• If dry heat sterilizer is an oven, was the slowest to heat area determined?

43.  How was the depyrogenation cycle validated?

• Was a known amount of endotoxin added to vials?
• Was the endotoxin allowed to dry on the vials?
• Was validation conducted with recovery tests to assure the spiked endotoxin can be recovered?
Were the vials challenged with enough endotoxin to allow calculation of a 3-log reduction?
• What cycle or equipment settings were used in the validation runs?
• Was a 3 log reduction of endotoxin achieved?

44.  Are the depyrogenation cycles for all vials validated or does the firm use a matrix approach?  If a
matrix approach (vial sizes/mass) is used, what criteria are used to select the worst case challenges
to the system? Are all vials types and sizes bracketed?

45.  Have the dry heat sterilizer cycles or equipment settings changed since the validation studies were
completed?   Compare validation studies, current SOPs and processing records for recent batches.

ASEPTIC FILLING

46.  When observing personnel during production, do operators practice proper cleanroom behaviors as
specified in established cleanroom SOPs?

47.  Can you observe the aseptic filling processes without going into the clean room (i.e., through
window or TV monitor)?

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A.   If yes, watch / observe the aseptic filling processes from preparation of bulk liquid product
to filling and sealing of final dosage form, including the environmental monitoring
performed in critical areas during actual production.

B. If not, consider observing the aseptic filling inside the clean room, for example, via a Class
10,000 (ISO-7) area. Prior to entry, consult the District.
o Do personnel enter and perform interventions at the critical Class 100 (ISO 5) areas of
the filling lines?  If so, how are such entries recorded?

o How is this done (full body entry, hands only)?

o Why?

o Is this done routinely or infrequently?

o Are proper aseptic techniques used?  [Reference: FDA 2004 Aseptic Processing
Guidance, Section V.A.]

o Do hands or arms go over open vials for sterile components?  If yes, are the vials
discarded?

48.  Does the firm have written procedures describing aseptic filling of drug products?  Does it include
discussions of proper aseptic techniques and acceptable techniques for performing interventions
into the Class 100 areas?

49.  Review trend reports of the non-viable, viable and personnel monitoring data.

• Have any trends been identified by the firm? If yes, what is done?

• Are investigations done of out of limit results?

Aseptic Filling Validation.

Reference:  FDA’s 2004 Aseptic Processing Guidance, Section IX

50.  How does the process used for media fill compare to the aseptic filling of commercial drug
products?  Does the firm accurately evaluate the production operation on a routine basis (changes
over time) against the media fill design?  Does the firm have detailed procedures that describe the
media fill process, including frequency, challenge conditions, personnel participation, container /
closures, interventions, duration of fill, reconciliation of vials, acceptance criteria, incubation,
examination after incubation, actions to take if positive growth is found, etc?

51.  Request a summary of all media fills conducted since last inspection, including lot identification,
fill dates, production lines, number of units filled, number of units incubated, number of vials with
no growth, number of vials with positive growth, microbial identification for any containers with
growth, disposition of media fill units, etc.

• Have media fills been done at the frequency described in the procedure?

• Have any media fills showed positive growth?

• Have any media fills failed to meet acceptance criteria?

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52.  Are procedures followed when positive growth is found in media filled vials? Are investigations
conducted of all positive growth found in media filled vials?  What is done when a media fill fails
to meet acceptance criteria? Review investigations of any positive growth.

53.  Are media fills performed on all shifts (e.g., representative of shift operations in a campaign)?  Do
media fills include shift changes and breaks that occur during routine production?

54.  When can media fills be aborted or units not incubated?  Would production lots be rejected if the
same conditions existed during filling?

55.  Are all personnel included in the media fill program?  Does this include set up personnel and
mechanics who work on the aseptic filling lines?  What system does the firm have for assuring all
personnel are included?

56.  If end-line filters are used in actual manufacture, are they also used during media fills?

57.  What size vials or ampules are used for media fills?  Evaluate justification for selecting worst case
challenge if firm does not perform media fills using all the container / closure configurations filled
on the line.

58.  Are vials inverted before incubation to assure media touches all inner surfaces?

59.  How does the firm conduct media fills for products that are filled into amber or opaque containers?

60.  How does the firm assure that all integral vials are incubated?  How does the firm handle filled vials
removed during the run because of interventions?

61.  Do media fills include interventions that occur during routine production?  Are there written
procedures specifying removal of media fill units (type of intervention and number of units
removed) corresponding to the practice of a routine production run?  Did you observe any
interventions during the filling of routine production lots that are not included in media fills?

62.  Does the duration of a media fill approximate the duration of a routine production lot?  If not,
evaluate firm’s justification for running shorter media fills?

63.  What is the microbial growth medium?

64.  Are growth promotion studies performed on each type of medium used?

65.  Are growth promotion studies conducted every time a media fill is done?

66.  When are the growth promotion studies performed (before/after filling; after incubation; etc.)?

67.  What organisms are used to perform the growth promotion tests?  Are any environmental organisms
used?

68.  What temperatures and incubation times are used to incubate media filled vials?

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69.  Are microorganisms from positive vials identified to genus and species? Are such microorganisms
correlated to those found during environmental monitoring?

70.  Is an investigation done when cracked vials are found after incubation begins?

71.  When and where are the media filled vials examined?

72.  Who performs the examination of media filled vials?  If production employees perform the
examination, have they been trained to recognize all types of microbial growth. Is a microbiologist
present when the examination is done?

73.  What incubators are used to incubate media filled vials?  How is the temperature controlled and
monitored?  Have tests been done to determine if the temperature is uniform throughout the
incubator?

LYOPHILIZATION (FREEZE-DRYING)

Reference: Guide to Inspections of Lyophilization of Parenterals; FDA; July 1993

General.

74.  Who is the manufacturer of the lyophilizer?

75.  Describe the heating and cooling systems used in the lyophilizer; the vacuum system; gas that is
used to break the vacuum and whether it is sterile; and the temperature controlling system.

76.  How are the vials transported from the filling line to the lyophilizer?  How are Class 100 (ISO 5)
conditions maintained during transport, loading, and unloading of the lyophilizer?

77.  Are the loading and unloading of the vials automated or manual?

78.  How is the sealing of vials (final seating of stoppers) performed?

79.  If the stoppering is performed automatically in the chamber at the end of the cycle, is it under
vacuum? If not under vacuum, what gas is used and how is it sterilized?

80.  If the vials are stoppered outside of the chamber, how is the lyophilized product protected from
contamination during transport to the stoppering station and during the stoppering operation?

81.  Describe the chamber clean-up procedures between batches of the same product and between
different products (including sterilant / cleaning agents used, monitoring for sterilant residue where
appropriate, and exposure cycle).

82.  Past history has shown that the lyophilizer condenser can be a source of contamination and an
assessment of the lyophilization process should include an inspection of the condenser. How is
lyophilization cycle monitored/ documented and reviewed?

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Lyophilization Validation – Sterilization of Chamber.

81.  How is the lyophilization chamber sterilized?  How are all surfaces, such as all surfaces of moving
shelves, exposed to steam?

82.  When is the lyophilization chamber sterilized? What is explanation / justification if it is not done
between each batch?

83.  How are sterilization cycles controlled (manual, programmed)?  How are cycles monitored during
production?

84.  Has the sterilization of the lyophilization chamber been validated? Have the slowest to heat surfaces
in the chamber been determined and challenged in the validation runs?

85.  Review current procedures and sterilization records for production lots. Are the cycle parameters
the same as those used during validation?  Do production cycles meet the validated cycle
parameters?

Lyophilization Validation – Aseptic Handling.

86.  Is the aseptic handling of lyophilized products validated by media fills?

87.  In the aseptic process, is lyophilization simulation performed during media fill?

88.  Is the maximum amount of time the vials are held prior to lyophilization simulated during media
fills? If vials are not sealed in lyophilization chamber, is the maximum hold time prior to stoppering
simulated in media fills?

89.  During validation, what level of vacuum is pulled on the lyophilization chamber?

90.  How long do media fill vials remain in the lyophilization chamber under vacuum? How does this
compare to commercial lots?

91.  Does the process simulation result in freezing of the media? Note that this process simulation
should not include freezing of the media.

92.  Is environmental monitoring performed during loading of the lyophilizer both during production
and as well as during validation?

93.  Does the firm have data on growth promotion of the media?  Are growth promotion tests done on
vials after incubation is completed?

94.  Is environmental monitoring performed during unloading of the chamber during production as well
as during media fill validation?

95.  What is used to break the vacuum during media fills (nitrogen, air, other gas)?

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Lyophilization Validation – Process.

98.  Has the firm validated the lyophilization cycle (e.g., time, rate of heat input, temperatures, eutectic
melting point) for each product? Review validation records for selected drug products with different
physical and chemical characteristics.

99.  Review lyophilization production records for the same products. Are the cycle parameters and
observed results within the validated cycles?

100.  What are the firm’s criteria for acceptable vs. unacceptable runs, including general appearance,
cake appearance, meltback, reconstitution time, moisture, etc.?

101.  Has the firm performed equipment qualification, preventative maintenance, critical instrument
calibration, and cleaning validation?

Lyophilization of sterile API: The aseptic process may include either a manual or automated transferring
process, or a combination of both, to transfer the lyophilized API out of the lyophilizer and into an SIP
holding vessel or transfer tank. It is equally important to observe and assess the manual operations of the
aseptic lyophilization process and assure that similar operations are performed during the media fill
processing steps for the API.

ISOLATOR BARRIER TECHNOLOGY

Reference: Appendix 1 of FDA’s 2004 Aseptic Processing Guidance

NOTE: Methods (e.g., hydrogen peroxide, peracetic acid) used to decontaminate isolator
barriers are capable of rendering surfaces free of viable organisms, but lack the
capabilities of steam sterilization. While these agents do not effectively penetrate
obstructed or protected surfaces, validated systems are highly effective at assuring
contamination-free internal isolator surfaces.

102.  Determine:

•  Model of isolator or barrier, and materials of construction

•  Type of isolator (open or closed)?

•  Airflow (turbulent, unidirectional)?

•  Classification of surrounding room environment

•  Number and location of gloves or half-suits

•  Attire worn by operators (e.g., are sterile gloves worn under isolator gloves?)

•  Operating parameters (pressures, air velocities, temperature, humidity)

103.  Is a written maintenance program in place which requires routine documented checks or tests of
gloves, half-suits, door seals, etc. for integrity?  What type of tests/checks are done and how
frequently?

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104.  Do written procedures specify glove replacement frequency? If so, what is the frequency and is
the SOP followed?

105.  Does the isolator maintain continuous positive pressure and at sufficient levels?

106.  How are materials transferred into and out of the isolator?  How robust are the transfer
mechanisms?

107.  Are the equipment and surfaces that have direct contact with sterile products and components
sterilized by heat. Does it achieve a minimum of a six-log reduction of the BI spores?

108.  What method is used to decontaminate the inner surface of the isolator barrier (e.g., vapor
hydrogen peroxide, steam hydrogen peroxide, chlorine dioxide, etc.)?  Determine decontamination
parameters.

109.  Did the surface decontamination validation study sufficiently address the ability of the sterilant to
disperse throughout the chamber and reach all surfaces?  Did the decontamination process include
the use of Chemical Indicators (CI) to determine the presence or absence of the VHP on the work
surfaces and/or the worst case locations to decontaminate?  The CI can assists in the evaluation
process by providing useful qualitative data. Were replicate BIs placed throughout the isolator,
including the most difficult to reach locations (e.g., underneath any items remaining in isolator
during sterilization). Are the most difficult to sterilize materials evaluated?

110.  What is the isolator decontamination frequency and is it justified by validation data?

111.  Is a decontamination cycle performed after a power failure or pressure reversal or other
unanticipated breach of system integrity?

112.  How often is the isolator decontamination cycle revalidated?

113.  Does the written environmental monitoring program include routine tests for nonviable particles,
as well as an appropriate number of microbial tests (e.g., active air and surface samples; gloves
samples) during each campaign?  Evaluate the tests performed and the testing frequencies.

Testing Isolators (Sterility test).

114.  Have any false positives been identified in the laboratory isolator barrier (this should be an
exceedingly rare occurrence)?  Were the false positive investigated to determine and correct the
cause.

ENVIRONMENTAL MONITORING – Non-viable

Reference: FDA’s 2004 Aseptic Processing Guidance, Section IV.

115.  Is the air supplied to critical areas (exposed product / filling areas) filtered through HEPA filters
under positive pressure?

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116.  Is the air flow in critical areas unidirectional when delivered to the point of use? At what velocity?
Is velocity determined at the critical work height and at the filter face? Air flow pattern
evaluations (smoke studies) under dynamic conditions are performed to visualize and demonstrate
unidirectional air flow within a designated area/room [e.g., Class 100 & 10,000 (ISO5 & ISO7)].
The smoke studies may also reveal air turbulences and air eddies that could be a vector assisting
the dissemination of microbial and/or non-viable contamination within critical manufacturing
areas.

117.  How is the air filtered that is supplied to critical areas (where unsterilized product, in-process
materials, and container/closures are prepared)?

118.  What are the firm's air quality classifications for the following areas:

•  Compounding
•  Equipment preparation
•  Any area where product or sterilized components are exposed
•  Areas where aseptic connections are made
•  Filling lines
•  Room surrounding filling lines
•  Capping (crimping) area

119.  How often are HEPA filters integrity tested? What test method is used? What is done if leaks are
found?  If done by an outside firm, are results reviewed by on-site personnel including the quality
unit?

120.  How often are air flow velocities checked for each HEPA filter?  What are the air velocity
specifications?  What is done if velocity readings are out of specification?

121.  Does the firm have a written monitoring program for classified areas that includes scientifically
sound sampling schedules; descriptions of sampling locations and frequency of sampling?   How
were the locations selected?

122.  What type of instrument is used to check non-viable particle counts in the classified areas?  Is the
air sampled continuously? If continuous, is there an alarm when counts exceed pre-set limits or
detects cleanroom doors open for an extended time?  What is done in response to the alarms?  Is
there an alarm log? Are permanently installed sensors used or portable units that are taken into
and out of the critical areas?  What is done if counts meet or exceed alert and action limits?

123.  What are the pressure differential requirements in the sterile core area?  Does this assure an air
cascade from most clean area to least clean air (by air classification)?

124.  How are pressure differentials monitored?  Is a continuous monitoring system used? If yes, does it
include alarms so operators are aware of excursions?  Are alarm conditions documented (alarm
log)? What is done in response to an alarm?  How long must a condition exist before an alarm
sounded?

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125.  How are temperature and humidity monitored?  What is the acceptable range?  What is done if the
reading is outside of the range?

126.  How are environmental excursions (readings that meet or exceed alert and action levels) handled?
Are the excursions investigated to determine impact on product, root cause and needed corrective
actions?

ENVIRONMENTAL AND PERSONNEL MONITORING – Microbiology

Reference:  FDA’s 2004 Aseptic Processing Guidance, Sections V and X.A

Air.

127.  Does the firm have an effective Environmental Monitoring (EM) Program in place?  What is the
purpose and scope of the EM Program? Are EM sampling locations strategic, based on product
contamination risk of the process and operation? Are the microbial alert and action levels based on
the historical EM data derived from the manufacturing operations, support utilities and personnel
practices performed at the manufacturing site?  What is the frequency of microbiological sampling
of air using "active" samplers (systems that sample a known volume of air) in various locations,
such as:
• Areas where product or sterile components are exposed to the environment
• Filling areas
• Loading areas for lypohilizers
• Surrounding areas

128.  What are the established microbial alert and action levels or limits for quantitative air samples?
What is the length of the sampling period? Is sampling done during production or at rest?

129.  What type of active air sampling equipment is used (centrifugal, impaction, membrane)?  Is the
sampling equipment calibrated? What is the efficiency of the active air sampler?

130.  Does the firm have data on the ability of these samplers to recover organisms without deleterious
effect on survivability such as through impact or desiccation of the media?

131.  What is the actual volume of air sampled per location?

132.  Are settling plates used?  What is the length of exposure period?  Sampling frequency? Locations
(including proximity to critical operations)?  Microbial limits?

Surfaces.

133.  Are there written procedures that describe the monitoring of surfaces in the clean rooms?  Does it
describe locations, frequency and sampling techniques?

134.  What surfaces are sampled in the critical (Class 100 / ISO 5) areas?  Are critical surfaces included
(those that touch the sterile product or sterile components)?

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135.  When are surface samples taken?  Are critical surfaces only sampled at the end of the operation?

136.  What is the frequency of sampling surfaces?

137.  What types of samples are collected at each location (RODAC plate, swab samples)?

138.  What are the alert and action levels / limits for the microbial sampling of critical surfaces, surfaces
in Class 100 areas and surfaces in other classified areas?  How were the levels / limits established?
What is done when the samples meet or exceed alert and action levels?

Personnel.

139.  Are there specific programs for training personnel who work in classified and aseptic processing
areas?  Does the program include microbiological testing or qualifying employees before they are
allowed to work in these areas?  Does the program include prequalification requirements?

140.  How often is monitoring performed on filling room personnel?   Is it done at least upon existing
the cleanroom (e.g., per shift)?  How often are gloves (hands) sampled?  How often are gowns
sampled?  Is any sampling done after interventions are performed?

141.  Who performs the sampling of personnel?  Is it self-sampling? Is the sampling performed by
another production employee, a microbiologist, technician or other quality control employee?

142.  What are the firm's alert and action levels / limits for personnel monitoring?  How were the levels
/ limits established?  What is done if the sample results reach or exceed the alert and action limits?

143.  Do employees spray their hands with sanitizer or disinfectant before the sample is taken?

General.

144.  What are the microbiological growth media used for environmental and personnel monitoring
samples?

145.  Are the media used in the viable monitoring program shown to be capable of detecting molds and
yeasts as well as bacteria by means of growth promotion tests?

146.  Is anaerobic monitoring ever performed?  When?

147.  Are inactivators used for antibiotics or other bactericidal / bacteriostatic substances? Has the firm
shown that these are effective?  Are records available?

148.  When are recovered microorganisms identified? To what level (genus, species)?

149.  What are the incubation times and temperatures?

150.  How are environmental and personnel monitoring data trended?  How often are trend reports
prepared?  How often are they reviewed?  Who reviews the trend reports?  What type of action is
taken based on review of trend reports?

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151.  Are environmental and personnel monitoring samples that exceed action levels investigated to
determine product impact, cause and needed corrective actions?  What is done when an alert level
is exceeded?

Review and assess the EM trending data, which will provide a good indication if the viable and non-
viable particles are maintained within the established levels or drifting out of control. What are the
causes of the aberrant events? Were corrective actions and preventive measures taken to preclude the
reoccurrence of the viable and non-viable particle anomalies?

BIOLOGICAL INDICATORS (BIs)

In sterile drug manufacturing, BIs are typically used to validate the cycles used for terminal sterilization,
sterilization of equipment and components. BIs are also used to validate SIP systems used to sterilize
lyophilizers, processing tanks, sterilizing filters, and product lines and systems used to decontaminate
surfaces in isolators.

152.  What type of indicator is used (e.g., inoculated carrier, inoculated product, inoculated simulated
product, etc.)?  Are BIs inoculated into the components (i.e., stoppers) used whenever possible?
What are their corresponding D values?  Is the sterilization cycle adequate corresponding to the D
value of the BI?

153.  If the source of the indicator is commercial, what is the brand name and manufacturer?  What
labeling is received with the BI?  If the BI is prepared in-house, determine the supplier of the
organism, how the BI is propagated and stored, and the method of preparation?

154.  What organism is used (Genus, species)? Is it the appropriate microorganism used for
sterilization?

155.  What is the challenge level of the biological indicator prior to exposure to sterilant?

156.  Does the firm verify viable spore count on each lot of BIs before use in validation?

157.  Does the firm or the BI labeling claim to meet USP performance criteria for steam or ETO
biological indicators?

158.  Does the firm perform USP testing on each lot of BIs received?

159.  What is the approximate D-value of the biological indicator?  Is this verified prior to validation?

160.  How many BIs are used per sterilizer load?

161.  What procedure is used to assay the indicators after exposure? What growth media is used? What
are the optimal and actual incubation time and temperature for the BI (compare to COA received
with the BI)?

162.  How are the BIs prepared for sterilization?

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163.  Are biological indicators located in the most difficult to sterilize product sites (explain)? How are
these locations determined?

164.  Is there a diagram of the distribution of biological indicators in the loading pattern(s) used?

165.  What is the elapsed time (hrs.) between removing indicators from the sterilizer and testing? Are
there time limits established for this period? What happens if they are exceeded?

166.  What is done if positive BIs are found after sterilization?

167.  Describe biological indicator storage conditions:

A.   Type of room, cabinet, etc. (if stored in freezer or refrigerator, state if frost-free)
B. Temperature
C. Relative humidity (if known)

D.   Compare to literature received with BI or written procedures

168.  Does the firm use chemical process monitor(s) to indicate cycle exposure or to measure one or
more cycle parameters?

---

### Document: FDA ProcessVal Complete (FDA)

# FDA Guidance for Industry: Process Validation: General Principles and Practices (January 2011)

[PAGE 4]

Guidance for Industry1

Process Validation: General Principles and Practices

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic.  It
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.

I.
INTRODUCTION

This guidance outlines the general principles and approaches that FDA considers appropriate
elements of process validation for the manufacture of human and animal drug and biological
products, including active pharmaceutical ingredients (APIs or drug substances), collectively
referred to in this guidance as drugs or products.  This guidance incorporates principles and
approaches that all manufacturers can use to validate manufacturing processes.

This guidance aligns process validation activities with a product lifecycle concept and with
existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH)
guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and
Q10 Pharmaceutical Quality System.2  Although this guidance does not repeat the concepts and
principles explained in those guidances, FDA encourages the use of modern pharmaceutical
development concepts, quality risk management, and quality systems at all stages of the
manufacturing process lifecycle.

1 This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug
Evaluation and Research (CDER), in cooperation with CDER’s Office of Pharmaceutical Sciences, the Center for
Biologics Evaluation and Research (CBER), the Office of Regulatory Affairs (ORA) and the Center for Veterinary
Medicine (CVM) at the Food and Drug Administration.

2 To make sure you have the most recent version of a guidance, check the CDER guidance page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, the CBER guidance
page at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or
the CVM guidance page at
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
.

[PAGE 5]

Contains Nonbinding Recommendations

The lifecycle concept links product and process development, qualification of the commercial
manufacturing process,3  and maintenance of the process in a state of control during routine
commercial production.  This guidance supports process improvement and innovation through
sound science.

This guidance covers the following categories of drugs:
• Human drugs
• Veterinary drugs
• Biological and biotechnology products
• Finished products and active pharmaceutical ingredients (APIs or drug substances)4
• The drug constituent of a combination (drug and medical device) product

This guidance does not cover the following types of products:
• Type A medicated articles and medicated feed
• Medical devices5
• Dietary supplements
• Human tissues intended for transplantation regulated under section 361 of the Public Health
Service Act6

This guidance does not specify what information should be included as part of a regulatory submission.
Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining
the type of information to include in a submission.

This guidance also does not specifically discuss the validation of automated process control systems
(i.e., computer hardware and software interfaces), which are commonly integrated into modern drug
manufacturing equipment.  This guidance is relevant, however, to the validation of processes that
include automated equipment in processing.

3 In this guidance, the term commercial manufacturing process refers to the manufacturing process resulting in
commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold).  For the purposes of
this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material.

4 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug
substances) and intermediates have not published as of the date of this guidance, but these components are subject to
the  statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)
(21 U.S.C. 351(a)(2)(B)).  Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7 Good
Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7), available on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  Section XII of ICH
Q7 describes in detail the principles for validating API processes.

5 Guidance on process validation for medical devices is provided in a separate document, Quality Management
Systems – Process Validation, edition 2,   See infra note 6.

6 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for
Transplantation, available on the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities.  Instead, guidances describe the Agency’s current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited.  The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.

II.
BACKGROUND

In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the
availability of a guidance entitled Guideline on General Principles of Process Validation (the
1987 guidance).7  Since then, we have obtained additional experience through our regulatory
oversight that allows us to update our recommendations to industry on this topic.  This revised
guidance conveys FDA’s current thinking on process validation and is consistent with basic
principles first introduced in the 1987 guidance.  The revised guidance also provides
recommendations that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical
CGMPs for the 21st Century ― A Risk-Based Approach,” particularly with regard to the use of
technological advances in pharmaceutical manufacturing, as well as implementation of modern
risk management and quality system tools and concepts.8  This revised guidance replaces the
1987 guidance.

FDA has the authority and responsibility to inspect and evaluate process validation performed by
manufacturers.  The CGMP regulations for validating pharmaceutical (drug) manufacturing
require that drug products be produced with a high degree of assurance of meeting all the
attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).

A.
Process Validation and Drug Quality

Effective process validation contributes significantly to assuring drug quality.  The basic
principle of quality assurance is that a drug should be produced that is fit for its intended use.
This principle incorporates the understanding that the following conditions exist:

• Quality, safety, and efficacy are designed or built into the product.

• Quality cannot be adequately assured merely by in-process and finished-product
inspection or testing.

7 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and
Radiological Health (CDRH).  Since that time, CDRH elected to reference a process validation guidance prepared in
cooperation with the Global Harmonization Task Force (GHTF).  The principles and recommendations in that
document, Quality Management Systems – Process Validation, edition 2 (available on the Internet at
http://www.ghtf.org/sg3/sg3-final.html) are also useful to consider for drug manufacturing processes.

8 See “Pharmaceutical cGMPS for the 21st Century — A Risk-Based Approach: Second Progress Report and
Implementation Plan,” available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan
ufacturingPracticescGMPforDrugs/ucm071836.htm.

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• Each step of a manufacturing process is controlled to assure that the finished product
meets all quality attributes including specifications.

B.
Approach to Process Validation

For purposes of this guidance, process validation is defined as the collection and evaluation of
data, from the process design stage through commercial production, which establishes scientific
evidence that a process is capable of consistently delivering quality product.  Process validation
involves a series of activities taking place over the lifecycle of the product and process. This
guidance describes process validation activities in three stages.

• Stage 1 – Process Design:  The commercial manufacturing process is defined during this
stage based on knowledge gained through development and scale-up activities.

• Stage 2 – Process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing.

• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine
production that the process remains in a state of control.

This guidance describes activities typical of each stage, but in practice, some activities might
occur in multiple stages.

Before any batch from the process is commercially distributed for use by consumers, a
manufacturer should have gained a high degree of assurance in the performance of the
manufacturing process such that it will consistently produce APIs and drug products meeting
those attributes relating to identity, strength, quality, purity, and potency.  The assurance should
be obtained from objective information and data from laboratory-, pilot-, and/or commercial-
scale studies.  Information and data should demonstrate that the commercial manufacturing
process is capable of consistently producing acceptable quality products within commercial
manufacturing conditions.

A successful validation program depends upon information and knowledge from product and
process development.  This knowledge and understanding is the basis for establishing an
approach to control of the manufacturing process that results in products with the desired quality
attributes.   Manufacturers should:

• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process
and product

Each manufacturer should judge whether it has gained sufficient understanding to provide a high
degree of assurance in its manufacturing process to justify commercial distribution of the

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product.  Focusing exclusively on qualification efforts without also understanding the
manufacturing process and associated variations may not lead to adequate assurance of quality.
After establishing and confirming the process, manufacturers must maintain the process in a state
of control over the life of the process, even as materials, equipment, production environment,
personnel, and manufacturing procedures change.9

Manufacturers should use ongoing programs to collect and analyze product and process data to
evaluate the state of control of the process.  These programs may identify process or product
problems or opportunities for process improvements that can be evaluated and implemented
through some of the activities described in Stages 1 and 2.

Manufacturers of legacy products can take advantage of the knowledge gained from the original
process development and qualification work as well as manufacturing experience to continually
improve their processes.  Implementation of the recommendations in this guidance for legacy
products and processes would likely begin with the activities described in Stage 3.

III.
STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS
VALIDATION

Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable
requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the
following:

A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do not
conform to or are not operated or administered in conformity with current good
manufacturing practice to assure that such drug meets the requirements of this Act as to
safety and has the identity and strength, and meets the quality and purity characteristics,
which it purports or is represented to possess.

FDA regulations describing current good manufacturing practice (CGMP) for finished
pharmaceuticals are provided in 21 CFR parts 210 and 211.

The CGMP regulations require that manufacturing processes be designed and controlled to
assure that in-process materials and the finished product meet predetermined quality
requirements and do so consistently and reliably.  Process validation is required, in both general
and specific terms, by the CGMP regulations in parts 210 and 211.  The foundation for process
validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for
production and process control designed to assure that the drug products have the identity,
strength, quality, and purity they purport or are represented to possess...” (emphasis added).  This
regulation requires manufacturers to design a process, including operations and controls, which
results in a product meeting these attributes.

9 The statute and regulations described in section III of this guidance explain the requirement that the methods and
facilities used for the manufacturing of drugs be operated and administered under control sufficient to assure that the
identity, strength, purity, and quality of a drug are as they purport or are represented to possess.

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Other CGMP regulations define the various aspects of validation.  For example, § 211.110(a),
Sampling and testing of in-process materials and drug products, requires that control procedures
“. . . be established to monitor the output and to validate the performance of those manufacturing
processes that may be responsible for causing variability in the characteristics of in-process
material and the drug product” (emphasis added).  Under this regulation, even well-designed
processes must include in-process control procedures to assure final product quality.  In addition,
the CGMP regulations regarding sampling set forth a number of requirements for validation:
samples must represent the batch under analysis (§ 211.160(b)(3)); the sampling plan must result
in statistical confidence (§ 211.165(c) and (d)); and the batch must meet its predetermined
specifications (§ 211.165(a)).

In addition to sampling requirements, the CGMP regulations also provide norms for establishing
in-process specifications as an aspect of process validation.  Section 211.110(b) establishes two
principles to follow when establishing in-process specifications.  The first principle is that “. . .
in-process specifications for such characteristics [of in-process material and the drug product]
shall be consistent with drug product final specifications . . . .”  Accordingly, in-process material
should be controlled to assure that the final drug product will meet its quality requirements.  The
second principle in this regulation further requires that in-process specifications “. . . shall be
derived from previous acceptable process average and process variability estimates where
possible and determined by the application of suitable statistical procedures where appropriate.”
This requirement, in part, establishes the need for manufacturers to analyze process performance
and control batch-to-batch variability.10

The CGMP regulations also describe and define activities connected with process design,
development, and maintenance.  Section 211.180(e) requires that information and data about
product quality and manufacturing experience be periodically reviewed to determine whether
any changes to the established process are warranted.  Ongoing feedback about product quality
and process performance is an essential feature of process maintenance.

In addition, the CGMP regulations require that facilities in which drugs are manufactured be of
suitable size, construction, and location to facilitate proper operations (§ 211.42).  Equipment
must be of appropriate design, adequate size, and suitably located to facilitate operations for its
intended use (§ 211.63).  Automated, mechanical, and electronic equipment must be calibrated,
inspected, or checked according to a written program designed to assure proper performance
(§ 211.68).

In summary, the CGMP regulations require that manufacturing processes be designed and
controlled to assure that in-process materials and the finished product meet predetermined
quality requirements and do so consistently and reliably.

10 The Agency further explains this principle in the preamble to the final rule on “Current Good Manufacturing
Practice in Manufacture, Processing, Packing, or Holding”  (43 FR 45013 at 45052, September 29, 1978) (available
on the Internet at http://www.fda.gov/cder/dmpq/preamble.txt).

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IV.
RECOMMENDATIONS

In the following sections, we describe general considerations for process validation, the
recommended stages of process validation, and specific activities for each stage in the product
lifecycle.

A.
General Considerations for Process Validation

In all stages of the product lifecycle, good project management and good archiving that capture
scientific knowledge will make the process validation program more effective and efficient.  The
following practices should ensure uniform collection and assessment of information about the
process and enhance the accessibility of such information later in the product lifecycle.
• We recommend an integrated team approach11 to process validation that includes
expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy,
analytical chemistry, microbiology, statistics, manufacturing, and quality assurance).
Project plans, along with the full support of senior management, are essential elements
for success.
• Throughout the product lifecycle, various studies can be initiated to discover, observe,
correlate, or confirm information about the product and process.  All studies should be
planned and conducted according to sound scientific principles, appropriately
documented, and approved in accordance with the established procedure appropriate for
the stage of the lifecycle.
• The terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process,
operating, and equipment) are not categorized with respect to criticality in this guidance.
With a lifecycle approach to process validation that employs risk based decision making
throughout that lifecycle, the perception of criticality as a continuum rather than a binary
state is more useful. All attributes and parameters should be evaluated in terms of their
roles in the process and impact on the product or in-process material, and reevaluated as
new information becomes available.  The degree of control over those attributes or
parameters should be commensurate with their risk to the process and process output.  In
other words, a higher degree of control is appropriate for attributes or parameters that
pose a higher risk.  The Agency recognizes that terminology usage can vary and expects
that each manufacturer will communicate the meaning and intent of its terminology and
categorization to the Agency.
• Many products are single-source or involve complicated manufacturing processes.
Homogeneity within a batch and consistency between batches are goals of process
validation activities.  Validation offers assurance that a process is reasonably protected
against sources of variability that could affect production output, cause supply problems,
and negatively affect public health.

11 This concept is discussed in more detail in FDA’s guidance for industry, Quality Systems Approach to
Pharmaceutical Current Good Manufacturing Practice Regulations, available at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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B.
Stage 1 ― Process Design

Process design is the activity of defining the commercial manufacturing process that will be
reflected in planned master production and control records.  The goal of this stage is to design a
process suitable for routine commercial manufacturing that can consistently deliver a product
that meets its quality attributes.

1.
Building and Capturing Process Knowledge and Understanding

Generally, early process design experiments do not need to be performed under the CGMP
conditions required for drugs intended for commercial distribution that are manufactured during
Stage 2 (process qualification) and Stage 3 (continued process verification).  They should,
however, be conducted in accordance with sound scientific methods and principles, including
good documentation practices.  This recommendation is consistent with ICH Q10
Pharmaceutical Quality System.12   Decisions and justification of the controls should be
sufficiently documented and internally reviewed to verify and preserve their value for use or
adaptation later in the lifecycle of the process and product.

Although often performed at small-scale laboratories, most viral inactivation and impurity
clearance studies cannot be considered early process design experiments.  Viral and impurity
clearance studies intended to evaluate and estimate product quality at commercial scale should
have a level of quality unit oversight that will ensure that the studies follow sound scientific
methods and principles and the conclusions are supported by the data.

Product development activities provide key inputs to the process design stage, such as the
intended dosage form, the quality attributes, and a general manufacturing pathway.  Process
information available from product development activities can be leveraged in the process design
stage.  The functionality and limitations of commercial manufacturing equipment should be
considered in the process design, as well as predicted contributions to variability posed by
different component lots, production operators, environmental conditions, and measurement
systems in the production setting.  However, the full spectrum of input variability typical of
commercial production is not generally known at this stage.  Laboratory or pilot-scale models
designed to be representative of the commercial process can be used to estimate variability.

Designing an efficient process with an effective process control approach is dependent on the
process knowledge and understanding obtained.  Design of Experiment (DOE) studies can help
develop process knowledge by revealing relationships, including multivariate interactions,
between the variable inputs (e.g., component characteristics 13 or process parameters) and the
resulting outputs (e.g., in-process material, intermediates, or the final product).  Risk analysis
tools can be used to screen potential variables for DOE studies to minimize the total number of
experiments conducted while maximizing knowledge gained.  The results of DOE studies can
provide justification for establishing ranges of incoming component quality, equipment

12 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

13 “Component means any ingredient [raw material] intended for use in the manufacture of a drug product, including
those that may not appear in such drug product” (§ 210.3(b)(3)).

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parameters, and in-process material quality attributes.  FDA does not generally expect
manufacturers to develop and test the process until it fails.

Other activities, such as experiments or demonstrations at laboratory or pilot scale, also assist in
evaluation of certain conditions and prediction of performance of the commercial process.  These
activities also provide information that can be used to model or simulate the commercial process.
Computer-based or virtual simulations of certain unit operations or dynamics can provide
process understanding and help avoid problems at commercial scale.  It is important to
understand the degree to which models represent the commercial process, including any
differences that might exist, as this may have an impact on the relevance of information derived
from the models.

It is essential that activities and studies resulting in process understanding be documented.
Documentation should reflect the basis for decisions made about the process.  For example,
manufacturers should document the variables studied for a unit operation and the rationale for
those variables identified as significant.  This information is useful during the process
qualification and continued process verification stages, including when the design is revised or
the strategy for control is refined or changed.

2.
Establishing a Strategy for Process Control

Process knowledge and understanding is the basis for establishing an approach to process control
for each unit operation and the process overall.  Strategies for process control can be designed to
reduce input variation, adjust for input variation during manufacturing (and so reduce its impact
on the output), or combine both approaches.

Process controls address variability to assure quality of the product.  Controls can consist of
material analysis and equipment monitoring at significant processing points (§ 211.110(c)).
Decisions regarding the type and extent of process controls can be aided by earlier risk
assessments, then enhanced and improved as process experience is gained.

FDA expects controls to include both examination of material quality and equipment monitoring.
Special attention to control the process through operational limits and in-process monitoring is
essential in two possible scenarios:

1. When the product attribute is not readily measurable due to limitations of sampling or
detectability (e.g., viral clearance or microbial contamination) or
2. When intermediates and products cannot be highly characterized and well-defined quality
attributes cannot be identified.

These controls are established in the master production and control records (see § 211.186(a) and
(b)(9)).

More advanced strategies, which may involve the use of process analytical technology (PAT),
can include timely analysis and control loops to adjust the processing conditions so that the
output remains constant.  Manufacturing systems of this type can provide a higher degree of

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process control than non-PAT systems.  In the case of a strategy using PAT, the approach to
process qualification will differ from that used in other process designs.  Further information on
PAT processes can be found in FDA’s guidance for industry on PAT ― A Framework for
Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.14

The planned commercial production and control records, which contain the operational limits
and overall strategy for process control, should be carried forward to the next stage for
confirmation.

C.
Stage 2 ― Process Qualification

During the process qualification (PQ) stage of process validation, the process design is evaluated
to determine if it is capable of reproducible commercial manufacture.  This stage has two
elements: (1) design of the facility and qualification of the equipment and utilities and (2)
process performance qualification (PPQ).  During Stage 2, CGMP-compliant procedures must be
followed.  Successful completion of Stage 2 is necessary before commercial distribution.15
Products manufactured during this stage, if acceptable, can be released for distribution.

1.
Design of a Facility and Qualification of Utilities and Equipment

Proper design of a manufacturing facility is required under part 211, subpart C, of the CGMP
regulations on Buildings and Facilities.  It is essential that activities performed to assure proper
facility design and commissioning precede PPQ.  Here, the term qualification refers to activities
undertaken to demonstrate that utilities and equipment are suitable for their intended use and
perform properly.  These activities necessarily precede manufacturing products at the
commercial scale.

Qualification of utilities and equipment generally includes the following activities:

• Selecting utilities and equipment construction materials, operating principles, and
performance characteristics based on whether they are appropriate for their specific uses.

• Verifying that utility systems and equipment are built and installed in compliance with
the design specifications (e.g., built as designed with proper materials, capacity, and
functions, and properly connected and calibrated).

• Verifying that utility systems and equipment operate in accordance with the process
requirements in all anticipated operating ranges.  This should include challenging the
equipment or system functions while under load comparable to that expected during

14  Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
Other references that may be useful include ASTM E2474-06 “Standard Practice for Pharmaceutical Process Design
Utilizing Process Analytical Technology” and ASTM E2476-09 “Standard Guide for Risk Assessment and Risk
Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture.”

15 As discussed in section III of this guidance, process validation (including process qualification) is legally
enforceable under section 501(a)(2)(B) of the Act.  FDA regulations require that process validation procedures be
established and followed (§ 211.100) before a batch can be distributed (§§ 211.22 and 211.165).

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routine production.  It should also include the performance of interventions, stoppage,
and start-up as is expected during routine production.  Operating ranges should be shown
capable of being held as long as would be necessary during routine production.

Qualification of utilities and equipment can be covered under individual plans or as part of an
overall project plan.  The plan should consider the requirements of use and can incorporate risk
management to prioritize certain activities and to identify a level of effort in both the
performance and documentation of qualification activities.  The plan should identify the
following items:
1. the studies or tests to use,
2. the criteria appropriate to assess outcomes,
3. the timing of qualification activities,
4. the responsibilities of relevant departments and the quality unit, and
5. the procedures for documenting and approving the qualification.
The project plan should also include the firm’s requirements for the evaluation of changes.
Qualification activities should be documented and summarized in a report with conclusions that
address criteria in the plan.  The quality control unit must review and approve the qualification
plan and report (§ 211.22).

2.
Process Performance Qualification

The process performance qualification (PPQ) is the second element of Stage 2, process
qualification.  The PPQ combines the actual facility, utilities, equipment (each now qualified),
and the trained personnel with the commercial manufacturing process, control procedures, and
components to produce commercial batches.  A successful PPQ will confirm the process design
and demonstrate that the commercial manufacturing process performs as expected.

Success at this stage signals an important milestone in the product lifecycle.  A manufacturer
must successfully complete PPQ before commencing commercial distribution of the drug
product.16  The decision to begin commercial distribution should be supported by data from
commercial-scale batches.  Data from laboratory and pilot studies can provide additional
assurance that the commercial manufacturing process performs as expected.

The approach to PPQ should be based on sound science and the manufacturer’s overall level of
product and process understanding and demonstrable control.  The cumulative data from all
relevant studies (e.g., designed experiments; laboratory, pilot, and commercial batches) should
be used to establish the manufacturing conditions in the PPQ.  To understand the commercial
process sufficiently, the manufacturer will need to consider the effects of scale.   However, it is
not typically necessary to explore the entire operating range at commercial scale if assurance can
be provided by process design data.  Previous credible experience with sufficiently similar
products and processes can also be helpful.  In addition, we strongly recommend firms employ

16 See section III of this guidance, Statutory and Regulatory Requirements for Process Validation.

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objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve
adequate assurance.

In most cases, PPQ will have a higher level of sampling, additional testing, and greater scrutiny
of process performance than would be typical of routine commercial production.  The level of
monitoring and testing should be sufficient to confirm uniform product quality throughout the
batch.  The increased level of scrutiny, testing, and sampling should continue through the process
verification stage as appropriate, to establish levels and frequency of routine sampling and
monitoring for the particular product and process.  Considerations for the duration of the
heightened sampling and monitoring period could include, but are not limited to, volume of
production, process complexity, level of process understanding, and experience with similar
products and processes.

The extent to which some materials, such as column resins or molecular filtration media, can be
re-used without adversely affecting product quality can be assessed in relevant laboratory
studies.  The usable lifetimes of such materials should be confirmed by an ongoing PPQ protocol
during commercial manufacture.

A manufacturing process that uses PAT may warrant a different PPQ approach.  PAT processes
are designed to measure in real time the attributes of an in-process material and then adjust the
process in a timely control loop so the process maintains the desired quality of the output
material.  The process design stage and the process qualification stage should focus on the
measurement system and control loop for the measured attribute.  Regardless, the goal of
validating any manufacturing process is the same:  to establish scientific evidence that the
process is reproducible and will consistently deliver quality products.

3.
PPQ Protocol

A written protocol that specifies the manufacturing conditions, controls, testing, and expected
outcomes is essential for this stage of process validation.  We recommend that the protocol
discuss the following elements:

• The manufacturing conditions, including operating parameters, processing limits, and
component (raw material) inputs.

• The data to be collected and when and how it will be evaluated.

• Tests to be performed (in-process, release, characterization) and acceptance criteria
for each significant processing step.

• The sampling plan, including sampling points, number of samples, and the frequency
of sampling for each unit operation and attribute.  The number of samples should be
adequate to provide sufficient statistical confidence of quality both within a batch and
between batches.   The confidence level selected can be based on risk analysis as it
relates to the particular attribute under examination.  Sampling during this stage
should be more extensive than is typical during routine production.

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• Criteria and process performance indicators that allow for a science- and risk-based
decision about the ability of the process to consistently produce quality products.  The
criteria should include:

— A description of the statistical methods to be used in analyzing all collected data
(e.g., statistical metrics defining both intra-batch and inter-batch variability).

— Provision for addressing deviations from expected conditions and handling of
nonconforming data.  Data should not be excluded from further consideration in
terms of PPQ without a documented, science-based justification.17

• Design of facilities and the qualification of utilities and equipment, personnel training
and qualification, and verification of material sources (components and
container/closures), if not previously accomplished.

• Status of the validation of analytical methods used in measuring the process, in-
process materials, and the product.

• Review and approval of the protocol by appropriate departments and the quality unit.

4.
PPQ Protocol Execution and Report

Execution of the PPQ protocol should not begin until the protocol has been reviewed and
approved by all appropriate departments, including the quality unit.  Any departures from the
protocol must be made according to established procedure or provisions in the protocol.  Such
departures must be justified and approved by all appropriate departments and the quality unit
before implementation (§ 211.100).

The commercial manufacturing process and routine procedures must be followed during PPQ
protocol execution (§§ 211.100(b) and 211.110(a)).  The PPQ lots should be manufactured under
normal conditions by the personnel routinely expected to perform each step of each unit
operation in the process.  Normal operating conditions should include the utility systems (e.g., air
handling and water purification), material, personnel, environment, and manufacturing
procedures.

A report documenting and assessing adherence to the written PPQ protocol should be prepared in
a timely manner after the completion of the protocol.  This report should:

• Discuss and cross-reference all aspects of the protocol.

• Summarize data collected and analyze the data, as specified by the protocol.

17 For additional guidance regarding out-of-specification results, see FDA’s Guidance for Industry, Investigating
Out-of-Specification (OOS)Test Results for Pharmaceutical Production, available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070287.pdf.

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• Evaluate any unexpected observations and additional data not specified in the
protocol.

• Summarize and discuss all manufacturing nonconformances such as deviations,
aberrant test results, or other information that has bearing on the validity of the
process.

• Describe in sufficient detail any corrective actions or changes that should be made to
existing procedures and controls.

• State a clear conclusion as to whether the data indicates the process met the
conditions established in the protocol and whether the process is considered to be in a
state of control.  If not, the report should state what should be accomplished before
such a conclusion can be reached.  This conclusion should be based on a documented
justification for the approval of the process, and release of lots produced by it to the
market in consideration of the entire compilation of knowledge and information
gained from the design stage through the process qualification stage.

• Include all appropriate department and quality unit review and approvals.

D.
Stage 3 ― Continued Process Verification

The goal of the third validation stage is continual assurance that the process remains in a state of
control (the validated state) during commercial manufacture.  A system or systems for detecting
unplanned departures from the process as designed is essential to accomplish this goal.
Adherence to the CGMP requirements, specifically, the collection and evaluation of information
and data about the performance of the process, will allow detection of undesired process
variability.  Evaluating the performance of the process identifies problems and determines
whether action must be taken to correct, anticipate, and prevent problems so that the process
remains in control (§ 211.180(e)).

An ongoing program to collect and analyze product and process data that relate to product
quality must be established (§ 211.180(e)).  The data collected should include relevant process
trends and quality of incoming materials or components, in-process material, and finished
products.  The data should be statistically trended and reviewed by trained personnel.  The
information collected should verify that the quality attributes are being appropriately controlled
throughout the process.

We recommend that a statistician or person with adequate training in statistical process control
techniques develop the data collection plan and statistical methods and procedures used in
measuring and evaluating process stability and process capability.18  Procedures should describe

18 Some references that may be useful include the following: ASTM E2281-03 “Standard Practice for Process and
Measurement Capability Indices,” ASTM E2500-07 “Standard Guide for Specification, Design, and Verification of
Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment,” and ASTM E2709-09 “Standard
Practice for Demonstrating Capability to Comply with a Lot Acceptance Procedure.”   This is not a complete list of
all useful references on this topic.  Many industry standards, books, and guides on these topics are available.

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how trending and calculations are to be performed and should guard against overreaction to
individual events as well as against failure to detect unintended process variability.  Production
data should be collected to evaluate process stability and capability.  The quality unit should
review this information.  If properly carried out, these efforts can identify variability in the
process and/or signal potential process improvements.

Good process design and development should anticipate significant sources of variability and
establish appropriate detection, control, and/or mitigation strategies, as well as appropriate alert
and action limits.  However, a process is likely to encounter sources of variation that were not
previously detected or to which the process was not previously exposed.  Many tools and
techniques, some statistical and others more qualitative, can be used to detect variation,
characterize it, and determine the root cause.  We recommend that the manufacturer use
quantitative, statistical methods whenever appropriate and feasible.  Scrutiny of intra-batch as
well as inter-batch variation is part of a comprehensive continued process verification program
under § 211.180(e).

We recommend continued monitoring and sampling of process parameters and quality attributes
at the level established during the process qualification stage until sufficient data are available to
generate significant variability estimates.  These estimates can provide the basis for establishing
levels and frequency of routine sampling and monitoring for the particular product and process.
Monitoring can then be adjusted to a statistically appropriate and representative level.  Process
variability should be periodically assessed and monitoring adjusted accordingly.

Variation can also be detected by the timely assessment of defect complaints, out-of-
specification findings, process deviation reports, process yield variations, batch records,
incoming raw material records, and adverse event reports.  Production line operators and quality
unit staff should be encouraged to provide feedback on process performance.  We recommend
that the quality unit meet periodically with production staff to evaluate data, discuss possible
trends or undesirable process variation, and coordinate any correction or follow-up actions by
production.

Data gathered during this stage might suggest ways to improve and/or optimize the process by
altering some aspect of the process or product, such as the operating conditions (ranges and set-
points), process controls, component, or in-process material characteristics.  A description of the
planned change, a well-justified rationale for the change, an implementation plan, and quality
unit approval before implementation must be documented (§ 211.100).  Depending on how the
proposed change might affect product quality, additional process design and process
qualification activities could be warranted.19

Maintenance of the facility, utilities, and equipment is another important aspect of ensuring that a
process remains in control.  Once established, qualification status must be maintained through
routine monitoring, maintenance, and calibration procedures and schedules (21 CFR part 211,

19  Certain manufacturing changes may call for formal notification to the Agency before implementation, as directed
by existing regulations (see, e.g., 21 CFR 314.70 and 601.12).

[PAGE 19]

Contains Nonbinding Recommendations

subparts C and D).  The equipment and facility qualification data should be assessed periodically
to determine whether re-qualification should be performed and the extent of that re-qualification.
Maintenance and calibration frequency should be adjusted based on feedback from these
activities.

V.
CONCURRENT RELEASE OF PPQ BATCHES

In most cases, the PPQ study needs to be completed successfully and a high degree of assurance
in the process achieved before commercial distribution of a product.  In special situations, the
PPQ protocol can be designed to release a PPQ batch for distribution before complete execution
of the protocol steps and activities, i.e., concurrent release.  FDA expects that concurrent release
will be used rarely.

Concurrent release might be appropriate for processes used infrequently for various reasons,
such as to manufacture drugs for which there is limited demand (e.g., orphan drugs, minor use
and minor species veterinary drugs) or which have short half lives (e.g., radiopharmaceuticals,
including positron emission tomography drugs).  Concurrent release might also be appropriate
for drugs that are medically necessary and are being manufactured in coordination with the
Agency to alleviate a short supply.

Conclusions about a commercial manufacturing process can only be made after the PPQ protocol
is fully executed and the data are fully evaluated.  If Stage 2 qualification is not successful (i.e.,
does not demonstrate that the process as designed is capable of reproducible performance at
commercial scale), then additional design studies and qualification may be necessary.  The new
product and process understanding obtained from the unsuccessful qualification study(ies) can
have negative implications if any lot was already distributed.  Full execution of Stages 1 and 2 of
process validation is intended to preclude or minimize that outcome.

Circumstances and rationale for concurrent release should be fully described in the PPQ
protocol.  Even when process performance assessment based on the PPQ protocol is still
outstanding, any lot released concurrently must comply with all CGMPs, regulatory approval
requirements, and PPQ protocol lot release criteria.  Lot release under a PPQ protocol is based
upon meeting confidence levels appropriate for each quality attribute of the drug.

When warranted and used, concurrent release should be accompanied by a system for careful
oversight of the distributed batch to facilitate rapid customer feedback.  For example, customer
complaints and defect reports should be rapidly assessed to determine root cause and whether the
process should be improved or changed.  Concurrently released lots must also be assessed in
light of any negative PPQ study finding or conclusions and appropriate corrective action must be
taken (§§ 211.100(a), 211.180(e), and 211.192).  We recommend that each batch in a concurrent
release program be evaluated for inclusion in the stability program.  It is important that stability
test data be promptly evaluated to ensure rapid detection and correction of any problems.

[PAGE 20]

Contains Nonbinding Recommendations

VI.
DOCUMENTATION

Documentation at each stage of the process validation lifecycle is essential for effective
communication in complex, lengthy, and multidisciplinary projects.  Documentation is important
so that knowledge gained about a product and process is accessible and comprehensible to others
involved in each stage of the lifecycle.   Information transparency and accessibility are
fundamental tenets of the scientific method.  They are also essential to enabling organizational
units responsible and accountable for the process to make informed, science-based decisions that
ultimately support the release of a product to commerce.

The degree and type of documentation required by CGMP vary during the validation lifecycle.
Documentation requirements are greatest during Stage 2, process qualification, and Stage 3,
continued process verification.   Studies during these stages must conform to CGMPs and must
be approved by the quality unit in accordance with the regulations (see §§ 211.22 and 211.100).
Viral and impurity clearance studies, even when performed at small scale, also require quality
unit oversight.

CGMP documents for commercial manufacturing (i.e., the initial commercial master batch
production and control record (§ 211.186) and supporting procedures) are key outputs of Stage 1,
process design.  We recommend that firms diagram the process flow for the full-scale process.
Process flow diagrams should describe each unit operation, its placement in the overall process,
monitoring and control points, and the component, as well as other processing material inputs
(e.g., processing aids) and expected outputs (i.e., in-process materials and finished product).  It is
also useful to generate and preserve process flow diagrams of the various scales as the process
design progresses to facilitate comparison and decision making about their comparability.

VII.
ANALYTICAL METHODOLOGY

Process knowledge depends on accurate and precise measuring techniques used to test and
examine the quality of drug components, in-process materials, and finished products.  Validated
analytical methods are not necessarily required during product- and process-development
activities or when used in characterization studies.  Nevertheless, analytical methods should be
scientifically sound (e.g., specific, sensitive, and accurate) and provide results that are reliable.
There should be assurance of proper equipment function for laboratory experiments.  Procedures
for analytical method and equipment maintenance, documentation practices, and calibration
practices supporting process-development efforts should be documented or described.  New
analytical technology and modifications to existing technology are continually being developed
and can be used to characterize the process or the product.  Use of these methods is particularly
appropriate when they reduce risk by providing greater understanding or control of product
quality. However, analytical methods supporting commercial batch release must follow CGMPs
in parts 210 and 211.  Clinical supply production should follow the CGMPs appropriate for the
particular phase of clinical studies.

[PAGE 21]

Contains Nonbinding Recommendations

GLOSSARY

Capability of a process:  Ability of a process to produce a product that will fulfill the
requirements of that product. The concept of process capability can also be defined in statistical
terms. (ISO 9000:2005)

Commercial manufacturing process:  The manufacturing process resulting in commercial
product (i.e., drug that is marketed, distributed, and sold or intended to be sold).  For the
purposes of this guidance, the term commercial manufacturing process does not include clinical
trial or treatment IND material.

Concurrent release:  Releasing for distribution a lot of finished product, manufactured
following a qualification protocol, that meets the lot release criteria established in the protocol,
but before the entire study protocol has been executed.

Continued process verification:  Assuring that during routine production the process remains in
a state of control.

Performance indicators:  Measurable values used to quantify quality objectives to reflect the
performance of an organization, process or system, also known as performance metrics in some
regions. (ICH Q10)

Process design:  Defining the commercial manufacturing process based on knowledge gained
through development and scale-up activities.

Process qualification:  Confirming that the manufacturing process as designed is capable of
reproducible commercial manufacturing.

Process validation:  The collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that a process is capable of
consistently delivering quality products.

Quality:  The degree to which a set of inherent properties of a product, system, or process fulfils
requirements. (ICH Q9)

State of control:  A condition in which the set of controls consistently provides assurance of
continued process performance and product quality. (ICH Q10)

[PAGE 22]

Contains Nonbinding Recommendations

REFERENCES

FDA, (CBER), Validation of Procedures for Processing of Human Tissues Intended for
Transplantation, guidance for industry, May 2002.

FDA, (CDER), Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical
Production, guidance for industry, October 2006.

FDA, (CDER, CVM, and ORA), PAT — A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance, guidance for industry, September
2004.

FDA, (CDER, CBER, CVM, and ORA), Quality Systems Approach to Pharmaceutical Current
Good Manufacturing Practice Regulations, guidance for industry, September 2006.

FDA/Global Harmonization Task Force (GHTF; medical devices), Quality Management Systems
– Process Validation, edition 2, guidance, January 2004.

FDA/ICH, (CDER and CBER), Q7 Good Manufacturing Practice for Active Pharmaceutical
Ingredients, guidance for industry, August 2001.

FDA/ICH, (CDER and CBER), Q8(R2) Pharmaceutical Development, guidance for industry,
November 2009.

FDA/ICH, (CDER and CBER), Q9 Quality Risk Management, guidance for industry, June 2006.

FDA/ICH (CDER and CBER) Q10 Pharmaceutical Quality System, guidance for industry, April
2009.

ASTM E2474-06 Standard Practice for Pharmaceutical Process Design Utilizing Process
Analytical Technology.

ASTM E2476-09 Standard Guide for Risk Assessment and Risk Control as it Impacts the
Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture.

ASTM E2281-03 Standard Practice for Process and Measurement Capability Indices.

ASTM E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems and Equipment.

ASTM E2709-10 Standard Practice for Demonstrating Capability to Comply with a Lot
Acceptance Procedure.

---

### Document: ICH Q10 Complete (ICH)

# ICH Q10 Pharmaceutical Quality System: Guideline for Pharmaceutical Quality System

=== PAGE 1 ===

INTERNATIONAL
CONFERENCE
ON
HARMONISATION
OF
TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED TRIPARTITE GUIDELINE

PHARMACEUTICAL QUALITY SYSTEM
Q10

Current Step 4 version
dated 4 June 2008

This Guideline has been developed by the appropriate ICH Expert Working Group
and has been subject to consultation by the regulatory parties, in accordance with the
ICH Process.  At Step 4 of the Process the final draft is recommended for adoption to
the regulatory bodies of the European Union, Japan and USA.

=== PAGE 2 ===
Pharmaceutical Quality System

Q10
Document History

Code
History
Date
Q10
Approval by the Steering Committee under Step 2 and release
for public consultation.
9 May
2007
Current Step 4 version
Q10
Approval by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH regulatory
bodies.
4 June
2008

=== PAGE 3 ===

i
PHARMACEUTICAL QUALITY SYSTEM
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
on 4 June 2008, this guideline is recommended for
adoption to the three regulatory parties to ICH

TABLE OF CONTENTS
1.
PHARMACEUTICAL QUALITY SYSTEM ........................................................ 1
1.1
Introduction ............................................................................................................. 1
1.2
Scope ........................................................................................................................ 1

### 1.3 Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards and

ICH Q7 ..................................................................................................................... 2
1.4 Relationship of ICH Q10 to Regulatory Approaches .............................................. 2
1.5
ICH Q10 Objectives ................................................................................................. 2
1.5.1 Achieve Product Realisation ........................................................................ 2
1.5.2  Establish and Maintain a State of Control ................................................. 3
1.5.3 Facilitate Continual Improvement ............................................................... 3
1.6 Enablers: Knowledge Management and Quality Risk Management ..................... 3
1.6.1 Knowledge Management .............................................................................. 3
1.6.2 Quality Risk Management ........................................................................... 3
1.7
Design and Content Considerations ....................................................................... 3
1.8
Quality Manual ....................................................................................................... 4
2.
MANAGEMENT RESPONSIBILITY .................................................................. 4
2.1
Management Commitment...................................................................................... 4
2.2
Quality Policy .......................................................................................................... 5
2.3
Quality Planning ..................................................................................................... 5
2.4
Resource Management ............................................................................................ 5
2.5
Internal Communication ......................................................................................... 6
2.6
Management Review ............................................................................................... 6
2.7 Management of Outsourced Activities and Purchased Materials .......................... 6
2.8 Management of Change in Product Ownership ...................................................... 6

=== PAGE 4 ===
Pharmaceutical Quality System

ii
3.
CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND
PRODUCT QUALITY ........................................................................................... 7
3.1
Lifecycle Stage Goals ............................................................................................... 7
3.1.1 Pharmaceutical Development....................................................................... 7
3.1.2 Technology Transfer ..................................................................................... 7
3.1.3 Commercial Manufacturing ......................................................................... 7
3.1.4 Product Discontinuation .............................................................................. 7
3.2
Pharmaceutical Quality System Elements ............................................................. 7
3.2.1 Process Performance and Product Quality Monitoring System .................. 8
3.2.2  Corrective Action and Preventive Action (CAPA) System ............................ 9
3.2.3  Change Management System ..................................................................... 10
3.2.4  Management Review of Process Performance and Product Quality ......... 11
4.
CONTINUAL IMPROVEMENT OF THE PHARMACEUTICAL QUALITY
SYSTEM ................................................................................................................ 11
4.1 Management Review of the Pharmaceutical Quality System .............................. 11

### 4.2 Monitoring of Internal and External Factors Impacting the Pharmaceutical

Quality System ...................................................................................................... 12
4.3 Outcomes of Management Review and Monitoring .............................................. 12
5.
GLOSSARY .......................................................................................................... 13
Annex 1:Potential Opportunities to Enhance Science and Risk Based Regulatory
 Approaches ........................................................................................................... 16
Annex 2:Diagram of the ICH Q10 Pharmaceutical Quality System Model ...................... 17

=== PAGE 5 ===

PHARMACEUTICAL QUALITY SYSTEM

1.
PHARMACEUTICAL QUALITY SYSTEM

### 1.1 Introduction

This document establishes a new ICH tripartite guideline describing a model for an
effective quality management system for the pharmaceutical industry, referred to as
the Pharmaceutical Quality System. Throughout this guideline, the term
“pharmaceutical quality system” refers to the ICH Q10 model.
ICH Q10 describes one comprehensive model for an effective pharmaceutical quality
system that is based on International Standards Organisation (ISO) quality concepts,
includes applicable Good Manufacturing Practice (GMP) regulations and complements
ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management”. ICH
Q10 is a model for a pharmaceutical quality system that can be implemented
throughout the different stages of a product lifecycle. Much of the content of ICH Q10
applicable to manufacturing sites is currently specified by regional GMP
requirements. ICH Q10 is not intended to create any new expectations beyond current
regulatory requirements. Consequently, the content of ICH Q10 that is additional to
current regional GMP requirements is optional.
ICH Q10 demonstrates industry and regulatory authorities’ support of an effective
pharmaceutical quality system to enhance the quality and availability of medicines
around the world in the interest of public health. Implementation of ICH Q10
throughout the product lifecycle should facilitate innovation and continual
improvement and strengthen the link between pharmaceutical development and
manufacturing activities.

### 1.2 Scope

This guideline applies to the systems supporting the development and manufacture of
pharmaceutical drug substances (i.e., API) and drug products, including biotechnology
and biological products, throughout the product lifecycle.
The elements of ICH Q10 should be applied in a manner that is appropriate and
proportionate to each of the product lifecycle stages, recognising the differences
among, and the different goals of each stage (see Section 3).
For the purposes of this guideline, the product lifecycle includes the following
technical activities for new and existing products:
•
Pharmaceutical Development:
o Drug substance development;
o Formulation development (including container/closure system);
o Manufacture of investigational products;
o Delivery system development (where relevant);
o Manufacturing process development and scale-up;
o Analytical method development.
•
Technology Transfer:
o New product transfers during Development through Manufacturing;
o Transfers within or between manufacturing and testing sites for
marketed products.

=== PAGE 6 ===
Pharmaceutical Quality System

•
Commercial Manufacturing:
o Acquisition and control of materials;
o Provision of facilities, utilities, and equipment;
o Production (including packaging and labelling);
o Quality control and assurance;
o Release;
o Storage;
o Distribution (excluding wholesaler activities).
•
Product Discontinuation:
o Retention of documentation;
o Sample retention;
o Continued product assessment and reporting.

### 1.3 Relationship of ICH Q10 to Regional GMP Requirements, ISO

Standards and ICH Q7
Regional GMP requirements, the ICH Q7 Guideline, “Good Manufacturing Practice
Guide for Active Pharmaceutical Ingredients”, and ISO quality management system
guidelines form the foundation for ICH Q10. To meet the objectives described below,
ICH Q10 augments GMPs by describing specific quality system elements and
management responsibilities. ICH Q10 provides a harmonised model for a
pharmaceutical quality system throughout the lifecycle of a product and is intended to
be used together with regional GMP requirements.
The regional GMPs do not explicitly address all stages of the product lifecycle (e.g.,
Development). The quality system elements and management responsibilities
described in this guideline are intended to encourage the use of science and risk based
approaches at each lifecycle stage, thereby promoting continual improvement across
the entire product lifecycle.

### 1.4 Relationship of ICH Q10 to Regulatory Approaches

Regulatory approaches for a specific product or manufacturing facility should be
commensurate with the level of product and process understanding, the results of
quality risk management, and the effectiveness of the pharmaceutical quality system.
When implemented, the effectiveness of the pharmaceutical quality system can
normally be evaluated during a regulatory inspection at the manufacturing site.
Potential opportunities to enhance science and risk based regulatory approaches are
identified in Annex 1. Regulatory processes will be determined by region.

### 1.5 ICH Q10 Objectives

Implementation of the Q10 model should result in achievement of three main
objectives which complement or enhance regional GMP requirements.

#### 1.5.1 Achieve Product Realisation

To establish, implement and maintain a system that allows the delivery of products
with the quality attributes appropriate to meet the needs of patients, health care
professionals, regulatory authorities (including compliance with approved regulatory
filings) and other internal and external customers.

=== PAGE 7 ===
Pharmaceutical Quality System

#### 1.5.2 Establish and Maintain a State of Control

To develop and use effective monitoring and control systems for process performance
and product quality, thereby providing assurance of continued suitability and
capability of processes. Quality risk management can be useful in identifying the
monitoring and control systems.

#### 1.5.3 Facilitate Continual Improvement

To identify and implement appropriate product quality improvements, process
improvements, variability reduction, innovations and pharmaceutical quality system
enhancements, thereby increasing the ability to fulfil quality needs consistently.
Quality risk management can be useful for identifying and prioritising areas for
continual improvement.

### 1.6 Enablers: Knowledge Management and Quality Risk Management

Use of knowledge management and quality risk management will enable a company to
implement ICH Q10 effectively and successfully. These enablers will facilitate
achievement of the objectives described in Section 1.5 above by providing the means
for science and risk based decisions related to product quality.

#### 1.6.1 Knowledge Management

Product and process knowledge should be managed from development through the
commercial life of the product up to and including product discontinuation. For
example, development activities using scientific approaches provide knowledge for
product and process understanding. Knowledge management is a systematic approach
to acquiring, analysing, storing and disseminating information related to products,
manufacturing processes and components. Sources of knowledge include, but are not
limited to prior knowledge (public domain or internally documented); pharmaceutical
development studies; technology transfer activities; process validation studies over
the product lifecycle; manufacturing experience; innovation; continual improvement;
and change management activities.

#### 1.6.2 Quality Risk Management

Quality risk management is integral to an effective pharmaceutical quality system.  It
can provide a proactive approach to identifying, scientifically evaluating and
controlling potential risks to quality.  It facilitates continual improvement of process
performance and product quality throughout the product lifecycle. ICH Q9 provides
principles and examples of tools for quality risk management that can be applied to
different aspects of pharmaceutical quality.

### 1.7 Design and Content Considerations

(a) The design, organisation and documentation of the pharmaceutical quality
system should be well structured and clear to facilitate common understanding
and consistent application.
(b) The elements of ICH Q10 should be applied in a manner that is appropriate
and proportionate to each of the product lifecycle stages, recognising the
different goals and knowledge available for each stage.
(c) The size and complexity of the company’s activities should be taken into
consideration when developing a new pharmaceutical quality system or

=== PAGE 8 ===
Pharmaceutical Quality System

modifying an existing one. The design of the pharmaceutical quality system
should incorporate appropriate risk management principles. While some
aspects of the pharmaceutical quality system can be company-wide and others
site-specific, the effectiveness of the pharmaceutical quality system is normally
demonstrated at the site level.
(d) The pharmaceutical quality system should include appropriate processes,
resources and responsibilities to provide assurance of the quality of outsourced
activities and purchased materials as described in Section 2.7.
(e) Management responsibilities, as described in Section 2, should be identified
within the pharmaceutical quality system.
(f) The pharmaceutical quality system should include the following elements, as
described in Section 3: process performance and product quality monitoring,
corrective and preventive action, change management and management review.
(g) Performance indicators, as described in Section 4, should be identified and
used to monitor the effectiveness of processes within the pharmaceutical
quality system.

### 1.8 Quality Manual

A Quality Manual or equivalent documentation approach should be established and
should contain the description of the pharmaceutical quality system. The description
should include:
(a) The quality policy (see Section 2);
(b) The scope of the pharmaceutical quality system;
(c) Identification of the pharmaceutical quality system processes, as well as their
sequences, linkages and interdependencies. Process maps and flow charts can
be useful tools to facilitate depicting pharmaceutical quality system processes
in a visual manner;
(d) Management responsibilities within the pharmaceutical quality system (see
Section 2).
2.
MANAGEMENT RESPONSIBILITY
Leadership is essential to establish and maintain a company-wide commitment to
quality and for the performance of the pharmaceutical quality system.

### 2.1 Management Commitment

(a) Senior management has the ultimate responsibility to ensure an effective
pharmaceutical quality system is in place to achieve the quality objectives, and
that roles, responsibilities, and authorities are defined, communicated and
implemented throughout the company.
(b) Management should:
(1) Participate in the design, implementation, monitoring and maintenance
of an effective pharmaceutical quality system;
(2) Demonstrate strong and visible support for the pharmaceutical quality

=== PAGE 9 ===
Pharmaceutical Quality System

system and ensure its implementation throughout their organisation;
(3) Ensure a timely and effective communication and escalation process
exists to raise quality issues to the appropriate levels of management;
(4) Define individual and collective roles, responsibilities, authorities and
inter-relationships
of
all
organisational
units
related
to
the
pharmaceutical
quality
system.
Ensure
these
interactions
are
communicated and understood at all levels of the organisation. An
independent quality unit/structure with authority to fulfil certain
pharmaceutical quality system responsibilities is required by regional
regulations;
(5) Conduct management reviews of process performance and product
quality and of the pharmaceutical quality system;
(6) Advocate continual improvement;
(7) Commit appropriate resources.

### 2.2 Quality Policy

(a) Senior management should establish a quality policy that describes the overall
intentions and direction of the company related to quality.
(b) The quality policy should include an expectation to comply with applicable
regulatory requirements and should facilitate continual improvement of the
pharmaceutical quality system.
(c) The quality policy should be communicated to and understood by personnel at
all levels in the company.
(d) The quality policy should be reviewed periodically for continuing effectiveness.

### 2.3 Quality Planning

(a) Senior management should ensure the quality objectives needed to implement
the quality policy are defined and communicated.
(b) Quality objectives should be supported by all relevant levels of the company.
(c) Quality objectives should align with the company’s strategies and be consistent
with the quality policy.
(d) Management should provide the appropriate resources and training to achieve
the quality objectives.
(e) Performance indicators that measure progress against quality objectives
should be established, monitored, communicated regularly and acted upon as
appropriate as described in Section 4.1 of this document.

### 2.4 Resource Management

(a) Management should determine and provide adequate and appropriate
resources (human, financial, materials, facilities and equipment) to implement
and maintain the pharmaceutical quality system and continually improve its
effectiveness.
(b) Management should ensure that resources are appropriately applied to a

=== PAGE 10 ===
Pharmaceutical Quality System

specific product, process or site.

### 2.5 Internal Communication

(a) Management should ensure appropriate communication processes are
established and implemented within the organisation.
(b) Communications processes should ensure the flow of appropriate information
between all levels of the company.
(c) Communication processes should ensure the appropriate and timely escalation
of certain product quality and pharmaceutical quality system issues.

### 2.6 Management Review

(a) Senior management should be responsible for pharmaceutical quality system
governance through management review to ensure its continuing suitability
and effectiveness.
(b) Management should assess the conclusions of periodic reviews of process
performance and product quality and of the pharmaceutical quality system, as
described in Sections 3 and 4.

### 2.7 Management of Outsourced Activities and Purchased Materials

The pharmaceutical quality system, including the management responsibilities
described in this section, extends to the control and review of any outsourced activities
and quality of purchased materials. The pharmaceutical company is ultimately
responsible to ensure processes are in place to assure the control of outsourced
activities and quality of purchased materials. These processes should incorporate
quality risk management and include:
(a) Assessing prior to outsourcing operations or selecting material suppliers, the
suitability and competence of the other party to carry out the activity or
provide the material using a defined supply chain (e.g., audits, material
evaluations, qualification);
(b) Defining the responsibilities and communication processes for quality-related
activities of the involved parties. For outsourced activities, this should be
included in a written agreement between the contract giver and contract
acceptor;
(c) Monitoring and review of the performance of the contract acceptor or the
quality of the material from the provider, and the identification and
implementation of any needed improvements;
(d) Monitoring incoming ingredients and materials to ensure they are from
approved sources using the agreed supply chain.

### 2.8 Management of Change in Product Ownership

When product ownership changes, (e.g., through acquisitions) management should
consider the complexity of this and ensure:
(a) The ongoing responsibilities are defined for each company involved;

=== PAGE 11 ===
Pharmaceutical Quality System

(b) The necessary information is transferred.
3.
CONTINUAL IMPROVEMENT OF PROCESS PERFORMANCE AND
PRODUCT QUALITY
This section describes the lifecycle stage goals and the four specific pharmaceutical
quality system elements that augment regional requirements to achieve the ICH Q10
objectives, as defined in Section 1.5. It does not restate all regional GMP
requirements.

### 3.1 Lifecycle Stage Goals

The goals of each product lifecycle stage are described below.

#### 3.1.1 Pharmaceutical Development

The goal of pharmaceutical development activities is to design a product and its
manufacturing process to consistently deliver the intended performance and meet the
needs of patients and healthcare professionals, and regulatory authorities and
internal customers’ requirements. Approaches to pharmaceutical development are
described in ICH Q8. The results of exploratory and clinical development studies,
while outside the scope of this guidance, are inputs to pharmaceutical development.

#### 3.1.2 Technology Transfer

The goal of technology transfer activities is to transfer product and process knowledge
between development and manufacturing, and within or between manufacturing sites
to achieve product realisation. This knowledge forms the basis for the manufacturing
process, control strategy, process validation approach and ongoing continual
improvement.

#### 3.1.3 Commercial Manufacturing

The goals of manufacturing activities include achieving product realisation,
establishing and maintaining a state of control and facilitating continual
improvement. The pharmaceutical quality system should assure that the desired
product quality is routinely met, suitable process performance is achieved, the set of
controls are appropriate, improvement opportunities are identified and evaluated, and
the body of knowledge is continually expanded.

#### 3.1.4 Product Discontinuation

The goal of product discontinuation activities is to manage the terminal stage of the
product lifecycle effectively. For product discontinuation, a pre-defined approach
should be used to manage activities such as retention of documentation and samples
and continued product assessment (e.g., complaint handling and stability) and
reporting in accordance with regulatory requirements.

### 3.2 Pharmaceutical Quality System Elements

The elements described below might be, required in part under regional GMP
regulations. However, the Q10 model’s intent is to enhance these elements in order to
promote the lifecycle approach to product quality. These four elements are:
•
Process performance and product quality monitoring system;
•
Corrective action and preventive action (CAPA) system;
•
Change management system;

=== PAGE 12 ===
Pharmaceutical Quality System

•
Management review of process performance and product quality.
These elements should be applied in a manner that is appropriate and proportionate
to each of the product lifecycle stages, recognising the differences among, and the
different goals of, each stage. Throughout the product lifecycle, companies are
encouraged to evaluate opportunities for innovative approaches to improve product
quality.
Each element is followed by a table of example applications of the element to the
stages of the pharmaceutical lifecycle.

#### 3.2.1 Process Performance and Product Quality Monitoring System

Pharmaceutical companies should plan and execute a system for the monitoring of
process performance and product quality to ensure a state of control is maintained. An
effective monitoring system provides assurance of the continued capability of
processes and controls to produce a product of desired quality and to identify areas for
continual improvement. The process performance and product quality monitoring
system should:
(a) Use quality risk management to establish the control strategy. This can
include parameters and attributes related to drug substance and drug product
materials and components, facility and equipment operating conditions, in-
process controls, finished product specifications, and the associated methods
and frequency of monitoring and control. The control strategy should facilitate
timely feedback / feedforward and appropriate corrective action and preventive
action;
(b) Provide the tools for measurement and analysis of parameters and attributes
identified in the control strategy (e.g., data management and statistical tools);
(c) Analyse parameters and attributes identified in the control strategy to verify
continued operation within a state of control;
(d) Identify sources of variation affecting process performance and product quality
for potential continual improvement activities to reduce or control variation;
(e) Include feedback on product quality from both internal and external sources,
e.g., complaints, product rejections, non-conformances, recalls, deviations,
audits and regulatory inspections and findings;
(f) Provide knowledge to enhance process understanding, enrich the design space
(where established), and enable innovative approaches to process validation.

=== PAGE 13 ===
Pharmaceutical Quality System

Table I: Application
of
Process
Performance
and
Product
Quality
Monitoring System throughout the Product Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Process and product
knowledge generated
and process and
product monitoring
conducted throughout
development can be
used to establish a
control strategy for
manufacturing.
Monitoring during
scale-up activities can
provide a preliminary
indication of process
performance and the
successful integration
into manufacturing.
Knowledge obtained
during transfer and
scale up activities can
be useful in further
developing the control
strategy.
A well-defined system
for process
performance and
product quality
monitoring should be
applied to assure
performance within a
state of control and to
identify improvement
areas.
Once manufacturing
ceases, monitoring
such as stability
testing should
continue to
completion of the
studies. Appropriate
action on marketed
product should
continue to be
executed according to
regional regulations.

#### 3.2.2 Corrective Action and Preventive Action (CAPA) System

The pharmaceutical company should have a system for implementing corrective
actions and preventive actions resulting from the investigation of complaints, product
rejections, non-conformances, recalls, deviations, audits, regulatory inspections and
findings, and trends from process performance and product quality monitoring. A
structured approach to the investigation process should be used with the objective of
determining the root cause. The level of effort, formality, and documentation of the
investigation should be commensurate with the level of risk, in line with ICH Q9.
CAPA methodology should result in product and process improvements and enhanced
product and process understanding.
Table II: Application of Corrective Action and Preventive Action System
throughout the Product Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Product or process
variability is explored.
CAPA methodology is
useful where corrective
actions and preventive
actions are
incorporated into the
iterative design and
development process.
CAPA can be used as
an effective system
for feedback,
feedforward and
continual
improvement.
CAPA should be used
and the effectiveness
of the actions should
be evaluated.
CAPA should continue
after the product is
discontinued. The
impact on product
remaining on the
market should be
considered as well as
other products which
might be impacted.

=== PAGE 14 ===
Pharmaceutical Quality System

#### 3.2.3 Change Management System

Innovation, continual improvement, the outputs of process performance and product
quality monitoring and CAPA drive change. In order to evaluate, approve and
implement these changes properly, a company should have an effective change
management system. There is generally a difference in formality of change
management processes prior to the initial regulatory submission and after
submission, where changes to the regulatory filing might be required under regional
requirements.
The change management system ensures continual improvement is undertaken in a
timely and effective manner. It should provide a high degree of assurance there are no
unintended consequences of the change.
The change management system should include the following, as appropriate for the
stage of the lifecycle:
(a) Quality risk management should be utilised to evaluate proposed changes. The
level of effort and formality of the evaluation should be commensurate with the
level of risk;
(b) Proposed changes should be evaluated relative to the marketing authorisation,
including design space, where established, and/or current product and process
understanding. There should be an assessment to determine whether a change
to the regulatory filing is required under regional requirements.  As stated in
ICH Q8, working within the design space is not considered a change (from a
regulatory filing perspective). However, from a pharmaceutical quality system
standpoint, all changes should be evaluated by a company’s change
management system;
(c) Proposed changes should be evaluated by expert teams contributing the
appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical
Development, Manufacturing, Quality, Regulatory Affairs and Medical), to
ensure the change is technically justified. Prospective evaluation criteria for a
proposed change should be set;
(d) After implementation, an evaluation of the change should be undertaken to
confirm the change objectives were achieved and that there was no deleterious
impact on product quality.
Table III: Application of Change Management System throughout the
Product Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Change is an inherent
part of the development
process and should be
documented; the
formality of the change
management process
should be consistent
with the stage of
pharmaceutical
development.
The change
management system
should provide
management and
documentation of
adjustments made to
the process during
technology transfer
activities.
A formal change
management system
should be in place for
commercial
manufacturing.
Oversight by the
quality unit should
provide assurance of
appropriate science
and risk based
assessments.
Any changes after
product
discontinuation should
go through an
appropriate change
management system.

=== PAGE 15 ===
Pharmaceutical Quality System

#### 3.2.4 Management Review of Process Performance and Product Quality

Management review should provide assurance that process performance and product
quality are managed over the lifecycle. Depending on the size and complexity of the
company, management review can be a series of reviews at various levels of
management and should include a timely and effective communication and escalation
process to raise appropriate quality issues to senior levels of management for review.
(a) The management review system should include:
(1) The results of regulatory inspections and findings, audits and other
assessments, and commitments made to regulatory authorities;
(2) Periodic quality reviews, that can include:
(i) Measures of customer satisfaction such as product quality
complaints and recalls;
(ii) Conclusions
of
process
performance
and
product
quality
monitoring;
(iii)The effectiveness of process and product changes including those
arising from corrective action and preventive actions.
(3) Any follow-up actions from previous management reviews.
(b) The management review system should identify appropriate actions, such as:
(1) Improvements to manufacturing processes and products;
(2) Provision, training and/or realignment of resources;
(3) Capture and dissemination of knowledge.
Table IV:  Application of Management Review of Process Performance and
Product Quality throughout the Product Lifecycle
Pharmaceutical
Development
Technology
Transfer
Commercial
Manufacturing
Product
Discontinuation
Aspects of
management review
can be performed to
ensure adequacy of
the product and
process design.
Aspects of
management review
should be performed
to ensure the
developed product and
process can be
manufactured at
commercial scale.
Management review
should be a structured
system, as described
above, and should
support continual
improvement.
Management review
should include such
items as product
stability and product
quality complaints.
4.
CONTINUAL IMPROVEMENT OF THE PHARMACEUTICAL QUALITY
SYSTEM
This section describes activities that should be conducted to manage and continually
improve the pharmaceutical quality system.

### 4.1 Management Review of the Pharmaceutical Quality System

Management should have a formal process for reviewing the pharmaceutical quality
system on a periodic basis. The review should include:
(a) Measurement of achievement of pharmaceutical quality system objectives;
(b) Assessment of performance indicators that can be used to monitor the

=== PAGE 16 ===
Pharmaceutical Quality System

effectiveness of processes within the pharmaceutical quality system, such as:
(1) Complaint, deviation, CAPA and change management processes;
(2) Feedback on outsourced activities;
(3) Self-assessment processes including risk assessments, trending, and
audits;
(4) External assessments such as regulatory inspections and findings and
customer audits.

### 4.2 Monitoring

of
Internal
and
External
Factors
Impacting
the
Pharmaceutical Quality System
Factors monitored by management can include:
(a) Emerging regulations, guidance and quality issues that can impact the
Pharmaceutical Quality System;
(b) Innovations that might enhance the pharmaceutical quality system;
(c) Changes in business environment and objectives;
(d) Changes in product ownership.

### 4.3 Outcomes of Management Review and Monitoring

The outcome of management review of the pharmaceutical quality system and
monitoring of internal and external factors can include:
(e) Improvements to the pharmaceutical quality system and related processes;
(f) Allocation or reallocation of resources and/or personnel training;
(g) Revisions to quality policy and quality objectives;
(h) Documentation and timely and effective communication of the results of the
management review and actions, including escalation of appropriate issues to
senior management.

=== PAGE 17 ===
Pharmaceutical Quality System

5.
GLOSSARY
ICH and ISO definitions are used in ICH Q10 where they exist. For the purpose of
ICH Q10, where the words “requirement”, “requirements” or “necessary” appear in an
ISO definition, they do not necessarily reflect a regulatory requirement. The source of
the definition is identified in parentheses after the definition. Where no appropriate
ICH or ISO definition was available, an ICH Q10 definition was developed.
Capability of a Process:
Ability of a process to realise a product that will fulfil the requirements of that
product. The concept of process capability can also be defined in statistical terms. (ISO
9000:2005)
Change Management:
A systematic approach to proposing, evaluating, approving, implementing and
reviewing changes. (ICH Q10)
Continual Improvement:
Recurring activity to increase the ability to fulfil requirements. (ISO 9000:2005)
Control Strategy:
A planned set of controls, derived from current product and process understanding,
that assures process performance and product quality. The controls can include
parameters and attributes related to drug substance and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of monitoring and
control. (ICH Q10)
Corrective Action:
Action to eliminate the cause of a detected non-conformity or other undesirable
situation. NOTE: Corrective action is taken to prevent recurrence whereas preventive
action is taken to prevent occurrence. (ISO 9000:2005)
Design Space:
The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance
of quality. (ICH Q8)
Enabler:
A tool or process which provides the means to achieve an objective. (ICH Q10)
Feedback / Feedforward:
Feedback: The modification or control of a process or system by its results or effects.
Feedforward: The modification or control of a process using its anticipated results or
effects. (Oxford Dictionary of English. Oxford University Press; 2003)
Feedback/ feedforward can be applied technically in process control strategies and
conceptually in quality management. (ICH Q10)
Innovation:
The introduction of new technologies or methodologies. (ICH Q10)

=== PAGE 18 ===
Pharmaceutical Quality System

Knowledge Management:
Systematic approach to acquiring, analysing, storing, and disseminating information
related to products, manufacturing processes and components. (ICH Q10)
Outsourced Activities:
Activities conducted by a contract acceptor under a written agreement with a contract
giver. (ICH Q10)
Performance Indicators:
Measurable values used to quantify quality objectives to reflect the performance of an
organisation, process or system, also known as “performance metrics” in some regions.
(ICH Q10)
Pharmaceutical Quality System (PQS):
Management system to direct and control a pharmaceutical company with regard to
quality. (ICH Q10 based upon ISO 9000:2005)
Preventive Action:
Action to eliminate the cause of a potential non-conformity or other undesirable
potential situation. NOTE: Preventive action is taken to prevent occurrence whereas
corrective action is taken to prevent recurrence. (ISO 9000:2005)
Product Realisation:
Achievement of a product with the quality attributes appropriate to meet the needs of
patients, health care professionals, and regulatory authorities (including compliance
with marketing authorisation) and internal customers requirements. (ICH Q10)
Quality:
The degree to which a set of inherent properties of a product, system or process fulfils
requirements. (ICH Q9)
Quality Manual:
Document specifying the quality management system of an organisation. (ISO
9000:2005)
Quality Objectives:
A means to translate the quality policy and strategies into measurable activities. (ICH
Q10)
Quality Planning:
Part of quality management focused on setting quality objectives and specifying
necessary operational processes and related resources to fulfil the quality objectives.
(ISO 9000:2005)
Quality Policy:
Overall intentions and direction of an organisation related to quality as formally
expressed by senior management. (ISO 9000:2005)
Quality Risk Management:
A systematic process for the assessment, control, communication and review of risks
to the quality of the drug (medicinal) product across the product lifecycle. (ICH Q9)

=== PAGE 19 ===
Pharmaceutical Quality System

Senior Management:
Person(s) who direct and control a company or site at the highest levels with the
authority and responsibility to mobilise resources within the company or site. (ICH
Q10 based in part on ISO 9000:2005)
State of Control:
A condition in which the set of controls consistently provides assurance of continued
process performance and product quality. (ICH Q10)

=== PAGE 20 ===
Pharmaceutical Quality System

Annex 1
Potential Opportunities to Enhance Science and Risk Based Regulatory
Approaches *
*Note: This annex reflects potential opportunities to enhance regulatory approaches.
The actual regulatory process will be determined by region.

Scenario
Potential Opportunity
1. Comply with GMPs
Compliance – status quo
2.  Demonstrate effective
pharmaceutical quality system,
including effective use of quality
risk management principles (e.g.,
ICH Q9 and ICH Q10).
Opportunity to:
•
increase use of risk based
approaches for regulatory
inspections.
3.  Demonstrate product and process
understanding, including effective
use of quality risk management
principles (e.g., ICH Q8 and ICH
Q9).
Opportunity to:
•
facilitate science based
pharmaceutical quality
assessment;
•
enable innovative approaches to
process validation;
•
establish real-time release
mechanisms.
4.  Demonstrate effective
pharmaceutical quality system
and product and process
understanding, including the use
of quality risk management
principles (e.g., ICH Q8, ICH Q9
and ICH Q10).
Opportunity to:
•
increase use of risk based
approaches for regulatory
inspections;
•
facilitate science based
pharmaceutical quality
assessment;
•
optimise science and risk based
post-approval change processes to
maximise benefits from innovation
and continual improvement;
•
enable innovative approaches to
process validation;
•
establish real-time release
mechanisms.

=== PAGE 21 ===
Pharmaceutical Quality System

Annex 2
Diagram of the ICH Q10 Pharmaceutical Quality System Model

This diagram illustrates the major features of the ICH Q10 Pharmaceutical Quality
System (PQS) model. The PQS covers the entire lifecycle of a product including
pharmaceutical development, technology transfer, commercial manufacturing, and
product discontinuation as illustrated by the upper portion of the diagram. The PQS
augments regional GMPs as illustrated in the diagram. The diagram also illustrates
that regional GMPs apply to the manufacture of investigational products.
The next horizontal bar illustrates the importance of management responsibilities
explained in Section 2 to all stages of the product lifecycle.  The following horizontal
bar lists the PQS elements which serve as the major pillars under the PQS model.
These elements should be applied appropriately and proportionally to each lifecycle
stage recognising opportunities to identify areas for continual improvement.
The bottom set of horizontal bars illustrates the enablers: knowledge management
and quality risk management, which are applicable throughout the lifecycle stages.
These enablers support the PQS goals of achieving product realisation, establishing
and maintaining a state of control, and facilitating continual improvement.

---

### Document: ICH Q12 Complete (ICH)

# ICH Harmonised Guideline Q12 (2019): Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management

## 1.0 INTERNATIONAL COUNCIL FOR HARMONISATION OF

TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR
HUMAN USE

ICH HARMONISED GUIDELINE

TECHNICAL AND REGULATORY CONSIDERATIONS FOR
PHARMACEUTICAL PRODUCT LIFECYCLE MANAGEMENT
Q12

Final version
Adopted on 20 November 2019

This Guideline has been developed by the appropriate ICH Expert Working Group and
has been subject to consultation by the regulatory parties, in accordance with the ICH
Process.  At Step 4 of the Process the final draft is recommended for adoption to the
regulatory bodies of ICH regions.

ICH Q12 Guideline

Q12
Document History

Code
History
Date
Q12
Adopted by the Regulatory Members of the ICH
Assembly under Step 4 (document dated 19
November 2019).
20 November
2019
Q12
Endorsement by the ICH Assembly under Step 2
and release for public consultation.
16 November
2017

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ICH Q12 Guideline

ICH Q12 Guideline

ICH HARMONISED GUIDELINE

TECHNICAL AND REGULATORY CONSIDERATIONS FOR
PHARMACEUTICAL PRODUCT LIFECYCLE MANAGEMENT
Q12
ICH Consensus Guideline

TABLE OF CONTENTS

INTRODUCTION ............................................................................................................ 6
1.1
Objectives ............................................................................................................ 6
1.2
Scope ................................................................................................................... 7
1.3
ICH Q12 Regulatory Tools and Enablers ............................................................ 7
CATEGORISATION OF POST-APPROVAL CMC CHANGES .................................. 9
ESTABLISHED CONDITIONS (ECS) ......................................................................... 10
3.1
Introduction ....................................................................................................... 10
3.2
ECs in the Regulatory Submission .................................................................... 10
3.2.1
ECs Definition .................................................................................. 10
3.2.2 ECs in a Regulatory Dossier ............................................................. 10
3.2.3 Identification of ECs ......................................................................... 11

##### 3.2.3.1 Identification of ECs for the Manufacturing Processes 11

3.2.3.2 Identification of ECs for Analytical Procedures ........... 13
3.2.4 Revision of ECs ................................................................................ 14
3.3
Roles and Responsibilities ................................................................................. 14
POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP) ................. 15
4.1
Definition of a PACMP ..................................................................................... 15
4.2
Application of a PACMP ................................................................................... 15
4.3
Elements of a PACMP ....................................................................................... 16
4.4 Modification to an Approved PACMP .............................................................. 17
4.5
Types of PACMPs ............................................................................................. 17
PRODUCT LIFECYCLE MANAGEMENT (PLCM) DOCUMENT ........................... 18
5.1
PLCM Document:  Scope .................................................................................. 18
5.2
Submitting the PLCM Document ...................................................................... 18
5.3 Maintenance of the PLCM Document ............................................................... 18
5.4 Format and Location of PLCM Document ........................................................ 18
PHARMACEUTICAL QUALITY SYSTEM (PQS) AND CHANGE
MANAGEMENT ........................................................................................................... 19
6.1
PQS General Considerations ............................................................................. 19
6.2 Change Management Across the Supply Chain and Product Lifecycle ............ 20
RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND INSPECTION 20
STRUCTURED APPROACHES FOR FREQUENT CMC POST-APPROVAL
CHANGES ..................................................................................................................... 21
ICH Q12 Guideline

STABILITY DATA APPROACHES TO SUPPORT THE EVALUATION OF CMC
CHANGES ..................................................................................................................... 21
10 GLOSSARY ................................................................................................................... 22
11 REFERENCES ............................................................................................................... 23
APPENDIX 1:  CTD SECTIONS THAT CONTAIN ECS ................................................... 24
APPENDIX 2:  PRINCIPLES OF CHANGE MANAGEMENT .......................................... 30

ICH Q12 Guideline

INTRODUCTION

### 1.1 Objectives

This guideline provides a framework to facilitate the management of post-approval
CMC changes in a more predictable and efficient manner.  A harmonised approach
regarding technical and regulatory considerations for lifecycle management will benefit
patients, industry, and regulatory authorities by promoting innovation and continual
improvement in the pharmaceutical sector, strengthening quality assurance and
improving supply of medicinal products.
The concepts outlined in prior ICH Quality Guidelines (ICH Q8(R2), Q9, Q10 and Q11)
provide opportunities for science- and risk-based approaches for use in drug
development and regulatory decisions.  These guidelines are valuable in the assessment
of Chemistry, Manufacturing and Controls (CMC) changes across the product lifecycle.
ICH Q8(R2) and Q11 guidelines focus mostly on early stage aspects of the product
lifecycle (i.e., product development, registration and launch).  This guideline addresses
the commercial phase of the product lifecycle (as described in ICH Q10); and it both
complements and adds to the flexible regulatory approaches to post-approval CMC
changes described in ICH Q8(R2) and Q10 Annex 1.
This guideline is also intended to demonstrate how increased product and process
knowledge can contribute to a more precise and accurate understanding of which post-
approval changes require a regulatory submission as well as the definition of the level
of reporting categories for such changes (i.e., a better understanding of risk to product
quality).  Increased knowledge and effective implementation of the tools and enablers
described in this guideline should enhance industry’s ability to manage many CMC
changes effectively under the company’s Pharmaceutical Quality System (PQS) with
less need for extensive regulatory oversight prior to implementation.  This approach
can incentivize continual improvement by providing an opportunity for greater
flexibility in making post-approval changes.  It could also result in fewer associated
post-approval submissions to the Marketing Authorisation Application (MAA), and
less associated regulatory burden.  The extent of this operational and regulatory
flexibility and its adequate implementation is subject to the regulatory framework in
place, as well as product and process understanding (ICH Q8(R2) and Q11), application
of quality risk management principles (ICH Q9), and an effective pharmaceutical
quality system (ICH Q10).
Regulatory Members of ICH are encouraged to provide publicly available information,
preferably on their website, about the implementation of ICH Q12 in their region,
especially with regard to regulatory considerations.
ICH Q12 Guideline

### 1.2 Scope

This guideline applies to pharmaceutical drug substances1 and products (both chemical
and biological) that require a marketing authorization; and to drug-device combination
products that meet the definition of a pharmaceutical or biological product.  Changes
needed to comply with new or revised pharmacopoeial monographs are not within the
scope of this guideline.

### 1.3 ICH Q12 Regulatory Tools and Enablers

Use of the following harmonised regulatory tools and enablers with associated guiding
principles, as described in this guideline, will enhance the management of post-approval
changes, and transparency between industry and regulatory authorities, supporting
innovation and continual improvement.
• Categorisation of Post-Approval CMC Changes (Chapter 2)
Categorisation of Post-Approval CMC Changes describes a framework that
encompasses a risk-based categorisation for the type of communication
expected of the Marketing Authorisation Holder (MAH) with the regulatory
authority regarding CMC changes.
• Established Conditions (ECs) (Chapter 3)
The concept of ECs provides a clear understanding between the MAH and
regulatory authorities regarding the elements to assure product quality and that
involve a regulatory communication, if changed.  This guideline describes how
ECs are identified as well as what information can be designated as supportive
information that would not involve a regulatory communication, if changed.  In
addition, guidance is included for managing revisions of the ECs.
• Post-Approval Change Management Protocol (PACMP) (Chapter 4)

The PACMP is a regulatory tool that provides predictability regarding the
information required to support a CMC change and the type of regulatory
submission based on prior agreement between the MAH and regulatory
authority.  Such a mechanism enables planning and implementation of future
changes to ECs in an efficient and predictable manner.
• Product Lifecycle Management (PLCM) Document (Chapter 5)
The PLCM document serves as a central repository for the ECs and the
associated reporting category for changes made to ECs.  The document also
captures how a product will be managed during the commercial phase of the
lifecycle including relevant post-approval CMC commitments and PACMPs.

1  For drug substance information incorporated by reference (e.g., a Master File) in an MAA, the holder
of the referenced information may use Q12 tools where applicable. Use of Q12 tools is not intended
to change the responsibilities for the holder of the referenced information, the MAH or the regulatory
authority.  For example, the holder of the referenced information has a responsibility to report relevant
drug substance changes to the MAH referencing their submission, so that the MAH can assess the
impact of the change and report any related changes to the approved MAA, as necessary and per
regional requirements.
ICH Q12 Guideline

• Pharmaceutical Quality System (PQS) and Change Management (Chapter 6)
An effective PQS as described in ICH Q10 and compliance with regional GMPs
are necessary to gain full benefit from this guideline.  In particular, management
of manufacturing changes across the supply chain is an essential part of an
effective
change
management
system.

This
guideline
provides
recommendations for robust change management across single or multiple
entities involved in the manufacture of a pharmaceutical product.
• Relationship Between Regulatory Assessment and Inspection (Chapter 7)
This guideline outlines the complementary roles of regulatory assessment and
inspection in the oversight of post-approval changes; and how communication
between assessors and inspectors facilitates the use of the tools included herein.
• Structured Approaches for Frequent CMC Post-Approval Changes (Chapter 8)
In addition to the other tools described above, this guideline describes a strategy
for a structured approach applicable to frequent CMC changes, and a discussion
of data expectations, to enable the use of immediate or other post-
implementation notification.
• Stability Data Approaches to Support the Evaluation of CMC Changes (Chapter
9)
This guideline provides additional science- and risk-based approaches that are
relevant to strategies for confirmatory stability studies to enable more timely
implementation of CMC changes.
Tools and enablers described above are complementary and are intended to link
different phases of the product lifecycle.  Pharmaceutical development activities result
in an appropriate control strategy, elements of which are considered to be Established
Conditions.  All CMC changes to an approved product are managed through a
company’s Pharmaceutical Quality System; changes to ECs must also be reported to
the regulatory authority.  Where the regulatory system provides for Categorisation of
Post-approval CMC Changes for reporting according to risk, the MAH may propose
reporting categories for changes to ECs based on risk and knowledge gained through
enhanced pharmaceutical development.  A system with risk-based reporting categories
also facilitates the use of Post-Approval Change Management Protocols, which
provide predictability regarding planning for future changes to ECs.  The Product
Lifecycle Management Document is a summary that transparently conveys to the
regulatory authority how the MAH plans to manage post-approval CMC changes.  The
tools and enablers in this guideline do not change the Relationship Between
Regulatory Assessment and Inspection; however, collaboration and communication
between assessors and inspectors are necessary for the implementation of this guideline
by regulators.  This guideline provides Structured Approaches for Frequent CMC
Post-Approval Changes to enable the implementation of certain CMC changes for
authorised products without the need for prior regulatory review and approval.  Finally,
this guideline provides Stability Data Approaches to Support the Evaluation of
CMC Changes; i.e., where the stability study is undertaken to confirm previously
approved storage conditions and shelf-life.
ICH Q12 Guideline

CATEGORISATION OF POST-APPROVAL CMC CHANGES
Regulatory mechanisms that allow the timely and efficient introduction of CMC
changes are important for drug quality, safety, and availability.  There is a range of
potential CMC changes for which communication between a company and the
regulatory authority is required.  CMC changes vary from low to high potential risk
with respect to product quality, safety, and efficacy.  A well-characterised, risk-based
categorisation of regulatory communication requirements is important to the efficient
use of industry and regulatory resources.
In such a regulatory system, the types of CMC changes that occur during the
commercial phase of the pharmaceutical product lifecycle that invoke communication
with regulatory authorities are classified with regard to the potential to have an adverse
effect on product quality of the drug product.  The regulatory communication category,
supporting information/documentation requirements, and associated time frame for
evaluation are commensurate with that potential risk.  Based on potential risk, an
inspection may be needed.
Regulatory authorities are encouraged to utilise a system that incorporates risk-based
regulatory processes for (a) requesting prior approval from the regulatory authority, (b)
notifying the regulatory authority, or (c) simply recording CMC changes, with
associated information requirements and, where applicable, timeframes for decision.
Such a system would include the following categories for regulatory communications
with one or more levels in each case:
• Prior approval:  Certain changes are considered to have sufficient risk to
require regulatory authority review and approval prior to implementation and
are requested by the MAH in a suitably detailed regulatory submission.
• Notification:  Certain moderate- to low-risk changes are judged to not require
prior approval and generally require less information to support the change.
These changes are communicated to the regulatory authority as a formal
notification that takes place within a defined period of time before or after
implementation, according to regional requirements.  A mechanism for
immediate notification is useful when prior approval is not required, but timely
awareness of the change by the regulator is considered necessary.
In addition, the changes that are not required to be reported to regulators are only
managed and documented within the PQS, but may be verified during routine or other
inspection.
Harmonisation or convergence toward a system of risk-based categorisation of post-
approval changes is encouraged as an important step toward achieving the objectives
of this guideline.  Such a system provides inherent, valuable flexibility in regulatory
approach and a framework that can support additional regulatory opportunities such as:
-
Facilitating the use of tools and enablers described in this guideline by providing
a range of request and notification categories available as a target for a lowering
of regulatory submission requirements.
-
The use of a lower category for request/notification if certain criteria/conditions
are met and the relevant supporting documentation is provided as described in
ICH Q12 Guideline

regional regulatory guidance; the need for regulatory inspection associated with
the change may preclude the ability to use a lower category.
-
Providing options for converging to the same or similar reporting category as
that in other jurisdictions.
A risk-based categorisation system may be accomplished by having the principles
captured in regulations with further details in guidance, which can provide additional
flexibility to modify expectations as science and technology evolve.  For examples of
risk-based categorisation systems, refer to existing regulations and guidance of ICH
members, and WHO guidelines and guidance on changes to authorised products.
ESTABLISHED CONDITIONS (ECS)

### 3.1 Introduction

This guideline establishes a harmonised approach to defining which elements in an
application are considered necessary to assure product quality and therefore would
require a regulatory submission if changed post-approval.  These elements are being
defined in this guideline as “Established Conditions for Manufacturing and Control”
(referred to as ECs throughout this guideline).

### 3.2 ECs in the Regulatory Submission

#### 3.2.1 ECs Definition

ECs are legally binding information considered necessary to assure product quality.  As
a consequence, any change to ECs necessitates a submission to the regulatory authority.

#### 3.2.2 ECs in a Regulatory Dossier

This chapter describes scientific risk-based approaches which can be used when
defining ECs and their reporting categories.  Regional legal frameworks, supplemented
through regulation and guidance, may define ECs with their reporting categories and/or
may allow the scientific risk-based approaches described in this chapter to be
considered.
All regulatory dossiers contain a combination of ECs and supportive information.
Supportive information is not considered to be ECs but is provided to share with
regulators the development and manufacturing information at an appropriate level of
detail.   Knowledge gained throughout the product lifecycle (including pharmaceutical
development and characterisation of chemical and biological drug substance and drug
product) is the basis for identifying the elements of CMC that are ECs and those
elements which are supportive information.
An MAH should clearly identify the elements of CMC which they consider to be an EC
and those which they consider to be supportive information.  The rationales for the ECs
are provided in the appropriate CTD modules.
Similarly, the rationales for the associated reporting categories for changes to the ECs
should be provided in the appropriate CTD modules.  The regulator assesses the ECs
with respect to established scientific guidelines.  Where appropriate, regulators approve
the EC and associated reporting category in line with the principles outlined in Chapter
2.
ICH Q12 Guideline

See Appendix 1 for more information regarding sections of the dossier that contain ECs
and supportive information.  Unless otherwise specified by regulatory requirement
identifying ECs for a given product is not mandatory.
ECs should not be confused with CMC regulatory commitments (e.g., stability, post-
approval CMC commitment and other commitments) made by a MAH to provide data
or information to the regulatory agency in a MAA.  Such information, in the context of
this guideline, is considered supportive information.  Changes to CMC regulatory
commitments are managed according to existing regional regulations and guidance.

#### 3.2.3 Identification of ECs

This chapter outlines approaches to define ECs for manufacturing processes and
analytical procedures.  A similar approach can be used to define other types of ECs
(e.g., performance of the container closure system, device elements of drug-device
combination products) and should be justified by the applicant and approved by the
regulatory agency.
The extent of ECs may vary based on the company’s development approach, product
and process understanding, and the potential risk to product quality.  Appropriate
justification should be provided in support of the identification of ECs, the proposed
reporting categories for ECs, and those aspects that are not ECs.

##### 3.2.3.1 Identification of ECs for the Manufacturing Processes

A control strategy is designed to ensure that a product of required quality will be
produced consistently (ICH Q8(R2)).  It is a planned set of controls, derived from
current product and process understanding, that assures process performance and
product quality.  The controls can include parameters and attributes related to drug
substance and drug product materials and components, facility and equipment operating
conditions, in-process controls, finished product specifications, and the associated
methods and frequency of monitoring and control (ICH Q10).

The ECs for a manufacturing process should be defined, based on product and process
understanding, taking into account all the relevant elements of the control strategy.  In
addition to the unit operation and the sequence of steps, and in considering the overall
control strategy, ECs proposed and justified in a manufacturing process description
should be those inputs (e.g., process parameters, material attributes) and outputs (that
may include in-process controls) that are necessary to assure product quality.

Process parameters that need to be controlled to ensure that a product of required quality
will be produced should be considered ECs.  These ECs are identified through an initial
risk assessment and application of knowledge gained from executed studies, prior
knowledge, and a criticality assessment that determines the level of impact that a
process parameter could have on product quality.  The criticality assessment should
account for severity of harm and whether the ranges studied sufficiently account for the
expected variability in the EC. CPPs and other process parameters where an impact on
product quality cannot be reasonably excluded should be identified as ECs.

Once ECs are identified, an updated assessment of the potential risk to product quality
associated with changing the EC, taking into account the overall control strategy
informs the reporting category for the EC.  The assessment of potential risk is derived
from risk management activities as described in ICH Q9. The output of the risk
assessment can include changes to manufacturing process ECs that range from high to
ICH Q12 Guideline

low risk to product quality.  The reporting category should be defined based on level of
risk. A justification of the potential risk for changing ECs and corresponding reporting
categories should be provided.

A decision tree which illustrates the above step-wise approach to identifying ECs and
reporting categories for process parameters is shown in Figure 1.  The principles in the
decision tree can be applied to identify ECs for other parts of the manufacturing process
and control strategy (e.g., relevant elements of input material attributes, equipment, and
in-process controls) and associated reporting categories.

*[Figure 1: Decision Tree for Identification of ECs and Associated Reporting Categories]*

for Manufacturing Process Parameters

The details of ECs and the associated reporting category will depend on the extent to
which the company can apply knowledge from product and process understanding (i.e.,
development and experience accumulated throughout the product lifecycle) to manage
the risks to product quality.  Different approaches can be used alone, or in combination,
to identify ECs for manufacturing processes; these include, but are not limited to the
following:

• Parameter-based approaches, including:
o A minimal2 approach, with a limited understanding of the relationship
between inputs and resulting quality attributes, will include a large
number of inputs (e.g., process parameters and material attributes) along
with outputs (including in-process tests).

2 Also referred to as “traditional” in ICH Q11.
ICH Q12 Guideline

o An enhanced approach with increased understanding of interaction
between inputs and product quality attributes together with a
corresponding control strategy can lead to identification of ECs that are
focused on the most important input parameters along with outputs, as
appropriate.
• In a performance-based approach, ECs could be primarily focused on control
of process outputs (e.g., attributes, measurements, responses) rather than
process inputs (e.g., process parameters and material attributes).  This is enabled
by knowledge gained from an enhanced approach, a data-rich environment, and
an enhanced control strategy (e.g., models, Process Analytical Technology
(PAT)).  For example, a performance-based approach could be considered for
manufacturing process steps with in-line monitoring of relevant attributes or
with feedback controls or optimisation algorithms to achieve the relevant targets
for that process step.  When considering this approach, it is important to ensure
that all relevant parameters and material attributes that have a potential to
impact product quality are monitored and equipment used remains qualified in
order to assure a stable process It should be noted that not all elements of the
decision tree in Figure 1 apply because the enhanced control strategy used may
remove the need for certain process parameters to be ECs.
Use of this guideline should not lead to providing a less detailed manufacturing process
description in the MAA.  A suitably detailed description of the manufacturing process
in Module 3 is expected to provide a clear understanding regardless of the approach
used to identify ECs for manufacturing process parameters.  Manufacturing process
descriptions include supportive information as well as identified ECs.  Information
regarding product-specific post-approval change activities, such as post-change
monitoring, may be provided as supporting information to aid in the determination of
ECs and associated reporting categories.  Criticality and risk should be periodically
reviewed (as expected by ICH Q10) during the lifecycle of the product and the ECs and
reporting categories should be updated based on acquired knowledge.
When implementing the change, and consistent with Appendix 2, an MAH should
consider the impact of the planned change, whether concurrent changes are planned,
and if the originally proposed reporting category should be revised.
This guidance does not impose additional regulatory filing expectations for process ECs
due to non-conformance during routine operations.  Non-conformance to process-
related ECs should be handled in accordance with GMP regulations (i.e., deviation/non-
conformance handling process).

##### 3.2.3.2 Identification of ECs for Analytical Procedures

Similar to the principles described for manufacturing process, ECs related to analytical
procedures should include elements which assure performance of the procedure.  The
extent of ECs and their reporting categories could vary based on the degree of the
understanding of the relationship between method parameters and method performance,
the method complexity, and control strategy.  A justification to support the
identification of ECs and corresponding reporting categories for changes to ECs based
on risk management should be provided.
Different approaches can be used to identify ECs for analytical procedures, for example
as analytical technology and development approaches advance; these approaches
include, but are not limited to the following:
ICH Q12 Guideline

• When more limited development studies have been conducted this may result
in a narrow operating window to ensure method performance.  In such cases
ECs may be more extensive with fixed and/or tight conditions.
• Enhanced understanding can lead to a wider operating window that ensures
method performance, where ECs can be reduced and focused on method
performance (e.g., method parameters acceptable ranges rather than set points,
performance criteria).
Use of this guideline should not lead to providing a less detailed description of
analytical procedures in the MAA.  A suitably detailed description of the analytical
procedures in Module 3 is expected to provide a clear understanding regardless of the
approach used to identify ECs for analytical procedures.  Description of analytical
procedures includes supportive information as well as identified ECs.

#### 3.2.4 Revision of ECs

It may be necessary to change approved ECs as a result of knowledge gained during
the product lifecycle (e.g., manufacturing experience, introduction of new technologies
or changes in the control strategy).
Options available for the MAH to change approved ECs, and to revise the associated
reporting category for approved ECs include:
• Submission of an appropriate post-approval regulatory submission describing
and justifying the proposed revision to the approved ECs.  Justification may
include information such as validation data and batch analyses.
• Submission of a PACMP, in the original MAA or as part of a post-approval
submission, describing a revision to ECs or reporting categories, and how the
change will be justified and reported.
• Use of an approved post-approval regulatory commitment, as appropriate.

### 3.3 Roles and Responsibilities

The management of all changes to, and maintenance of, the approved marketing
authorisation is the responsibility of the MAH.  There is a joint responsibility to share
and utilise information between the MAH and any manufacturing organisations to
assure the marketing authorisation is maintained, reflects current operations, and that
changes are implemented appropriately across relevant sites.  Maintenance of the
marketing authorisation should follow regional expectations.  See Chapter 6 for
information related to interactions between an MAH and any manufacturing
organisations.
For any referenced submission (e.g., Type II Drug Master File, Active Substance
Master File) in an MAA, the holder of the referenced submission has a responsibility
to communicate changes to their ECs to the MAH referencing their submission, so that
the MAH can assess the impact of the change and report any related change to the ECs
found in the approved MAA, as necessary and per regional requirements.
The approval of ECs and subsequent changes to ECs is the responsibility of the
regulatory authorities.
ICH Q12 Guideline

POST-APPROVAL CHANGE MANAGEMENT PROTOCOL (PACMP)

### 4.1 Definition of a PACMP

A PACMP is a regulatory tool that provides predictability and transparency in terms of
the requirements and studies needed to implement a change as the approved protocol
provides an agreement between the MAH and the regulatory authority.  A protocol
describes the CMC change an MAH intends to implement during the commercial phase
of a product lifecycle, how the change would be prepared and verified, including
assessment of the impact of the proposed change, and the suggested reporting category
in line with regional regulations and guidance, i.e., a lower reporting category and/or
shortened review period as compared to similar change procedure without an approved
PACMP.  The PACMP also identifies specific conditions and acceptance criteria to be
met.  A PACMP can address one or more changes for a single product, or may address
one or more changes to be applied to multiple products (see section 4.5).  The PACMP
may be submitted with the original MAA or subsequently as a standalone submission
and can be proposed independent of any prior identification of ECs.  The PACMP
requires approval by the regulatory authority, and the conditions and acceptance criteria
outlined in the protocol must be met and results communicated to the regulatory
authority in the manner previously agreed, in order to implement the change(s).
A PACMP should describe changes with a level of detail commensurate with the
complexity of the change.  Once approved, there is an expectation that the validity of
the proposed approach and control strategy is confirmed prior to implementation of the
change(s).  For example, if new information becomes available following approval of
the protocol, the risk assessment provided in the initial PACMP submission should be
reviewed by the MAH before implementing the change(s), to ensure that the outcomes
of that risk assessment as they pertain to the planned change(s) are still valid.  If the
review of the initial risk assessment indicates an increased level of risk associated with
execution of the change, the previously approved reporting category should no longer
be considered appropriate; instead, existing regional regulation or guidance should be
followed or the relevant regulatory authority consulted.
The MAH is responsible for ensuring that whenever a CMC change is to be introduced
under a PACMP, the facility meets the regulatory requirements of the regulatory
jurisdiction where the PACMP was approved with respect to GMP compliance, and
inspection or licensing status.

### 4.2 Application of a PACMP

The application of a PACMP process typically involves the following two steps:
Step 1: Submission of a written protocol that describes the proposed change(s), its
rationale(s), risk management activities, proposed studies and acceptance criteria to
assess the impact of the change(s), other conditions to be met (e.g., confirmation that
there is no change to the approved specification), the proposed reporting category for
the change(s), and any other supportive information (see also below).  The
PACMP document can be located in CTD Module 3.2.R.3  This protocol is reviewed
and approved by the regulatory authority in advance of execution of the protocol.

3 In some regions, the PACMP may be included in other modules.
ICH Q12 Guideline

Step 2: The tests and studies outlined in the protocol are performed.  If the results/data
generated meet the acceptance criteria in the protocol and any other conditions are met,
the MAH submits this information to the regulatory authority according to the
categorisation (classification) in the approved protocol for review by the regulatory
authority as appropriate.  Depending on the reporting category, approval by the
regulatory authority may or may not be required prior to implementation of the change.
If the acceptance criteria and/or other conditions in the protocol (see step 1) are not met,
the change cannot be implemented using this approach and should instead follow
existing regulation or guidance and associated reporting category.
Significant changes to the manufacturing process or controls that were not anticipated
in the PACMP step 1 (e.g., change of order of unit operations) cannot be implemented
as part of step 2 and should be the subject of a regulatory submission as governed by
regional regulation or guidance.  However, minor unanticipated modifications of the
process or controls related to the intended change and not affecting the technical
principles of the protocol are normally considered within scope, if appropriately
justified.
No change outlined in a PACMP should introduce any additional risks to patient safety,
product quality or efficacy.  A CMC change that would require supportive efficacy,
safety (clinical or non-clinical), or human PK/PD data to evaluate the effect of the
change (e.g., certain formulation changes, clinical or non-clinical studies to evaluate
new impurities, assessment of immunogenicity/antigenicity) is not suitable for
inclusion in a PACMP.

### 4.3 Elements of a PACMP

The development of the PACMP is informed by the application of process and product
understanding gained from product development and/or manufacturing experience.  A
PACMP would typically include the following, e.g.:
• A detailed description of the proposed change(s), including a rationale.  The
differences before and after the proposed change(s) should be clearly
highlighted (e.g., in a tabular format).

• Based on an initial risk assessment, a list of specific tests and studies to be
performed to evaluate the potential impact of the proposed change(s), such as:
characterisation, batch release, stability (as appropriate, see Chapter 9), in-
process controls.  The PACMP should include an appropriate description of the
analytical procedures and proposed acceptance criteria for each test or study.
• Discussion regarding the suitability of the approved control strategy or any
changes needed to the control strategy associated with the planned change(s).
• Any other conditions to be met, such as confirmation that certain process
qualification steps will be completed before implementation.
• Where applicable, supportive data from previous experience with the same or
similar products related to: development, manufacturing, characterisation, batch
release, and stability to allow for risk mitigation.
• Proposed reporting category for step 2 of the PACMP.
ICH Q12 Guideline

• Confirmation, as appropriate, that ongoing verification will be performed under
the PQS to continue to evaluate and ensure that there is no adverse effect of the
change(s) on product quality.  In cases where monitoring of the impact on
product quality following implementation of the change(s) is required, a
summary of the quality risk management activities should be provided to
support the proposed PACMP.  If multiple changes are to be implemented, these
activities should address the potential risk from the cumulative effect of
multiple changes and how they are linked.
The MAH should demonstrate in the PACMP suitable scientific knowledge and
understanding of aspects impacted by the proposed change in order to conduct an
appropriate risk assessment of the proposed change(s).  Typically, more complex
changes would require enhanced product/process understanding.

### 4.4 Modification to an Approved PACMP

A modification to an already approved PACMP, such as replacement or revision of a
test, study or acceptance criterion, should provide the same or greater capability to
assess the effect of the proposed change on the product quality and would normally
involve a notification type of communication with the regulatory authority.  A
modification that more significantly alters the content of the protocol may require either
prior approval of a protocol amendment or submission of a new protocol, as agreed
upon with the regulatory authority.

### 4.5 Types of PACMPs

There are different types of PACMPs:
• One or more change(s) associated with a single product – see above and
Annexes ID and 1E, for content and implementation.  A PACMP can also be
designed to be used repeatedly to make a specified type of CMC change over
the lifecycle of a product, applying the same principles.
If the protocol describes several changes for a particular product, a justification
should be added showing how the changes are related and that inclusion in a
single protocol is appropriate.
• Broader protocols – the general principles outlined above apply.  The risk of the
proposed change(s) should be similar across products; additional considerations
should be taken into account depending on the approach, for example:
a. One or more changes to be implemented across multiple products (e.g.,
change in stopper across multiple products that use the same container
closure system): the same risk mitigation strategy should be applicable
across all impacted products;
b. One or more changes to be implemented across multiple products and at
multiple sites (e.g., change in analytical method across multiple sites,
change in manufacturing site(s) across multiple products): the same risk
mitigation strategy should be applicable across all impacted products
and/or sites (see Annex IE).
ICH Q12 Guideline

PRODUCT LIFECYCLE MANAGEMENT (PLCM) DOCUMENT
The PLCM document outlines the specific plan for product lifecycle management that
includes the ECs, reporting categories for changes to ECs, PACMPs (if used) and any
post-approval CMC commitments.  Its purpose is to encourage prospective lifecycle
management planning by the MAH and to facilitate regulatory assessment and
inspection.  The PLCM document should be updated throughout the product lifecycle
as needed.

### 5.1 PLCM Document:  Scope

The PLCM document serves as a central repository in the MAA for ECs and reporting
categories for making changes to ECs. It includes the key elements described below
and references to the related information located elsewhere in the MAA (see Annex IF).
Submission of the PLCM document is critical when the MAH proposes ECs in line
with the risk-based approaches in Chapter 3.

The elements of the PLCM document are summarised below:
• ECs (refer to Chapter 3):  The ECs for the product should be listed in the PLCM
document.  The identification and justification of ECs are located in the relevant
sections of the CTD.

• Reporting category for making changes to approved ECs (refer to Chapter
3):  The reporting categories when making a change to an EC should be listed
in the PLCM document.  The detailed justification of the reporting categories is
located in the relevant sections of the CTD.
• PACMPs (refer to Chapter 4): PACMPs that are submitted to prospectively
manage and implement one or more post-approval changes should be listed.
• Post-approval CMC commitments: specified CMC development activities,
agreed between the MAH and regulatory authority at the time of approval (e.g.,
specific process monitoring, additional testing) that will be performed during
the commercial phase should be listed in the PLCM document.

### 5.2 Submitting the PLCM Document

The PLCM document is submitted in the original MAA or in a supplement/variation
for marketed products when defining ECs (Chapter 3).

### 5.3 Maintenance of the PLCM Document

An updated PLCM document should be included in post-approval submissions for
CMC changes.  The updated PLCM document will capture the change in ECs and other
associated elements (reporting category, commitments, PACMP).  The MAH should
follow regional expectations for maintaining a revision history for the PLCM
document.

### 5.4 Format and Location of PLCM Document

A tabular format is recommended to capture certain elements of PLCM described
in section 5.1, but other appropriate formats can be used. See Annex IF for an example
PLCM table.
ICH Q12 Guideline

The PLCM document can be located in CTD Module 3.2.R.4
PHARMACEUTICAL QUALITY SYSTEM (PQS) AND CHANGE MANAGEMENT

### 6.1 PQS General Considerations

An effective PQS as described in ICH Q10 and in compliance with regional GMP
requirements where the application is filed, is necessary across the entire supply chain
and product lifecycle to support use of the tools described in this guideline.  It includes
appropriate change management, enabled by knowledge management, and
management review.  The principles are further elaborated in Appendix 2.  The
relationship between knowledge management, change management, and the regulatory
process for ECs are illustrated in Figure 2.

*[Figure 2: Connection Between Knowledge Management and Change]*

Management Process

Maintaining an effective PQS is the responsibility of a company (manufacturing sites
and MAH where relevant). It is not the intent of this guideline to require a specific
inspection assessing the state of the PQS before the company can use the principles in
this guideline.   The conduct of inspections in connection with submitted MAAs and
surveillance will nevertheless continue as foreseen by regional regulatory requirements.
It is understood that a manufacturing site can be considered to be in general GMP
compliance while resolving deficiencies that do not require regulatory action.  In the
event that such deficiencies have an impact on the effectiveness of change management

4 In some regions, the PLCM may be included in Module 1.
ICH Q12 Guideline

in the PQS, it may result in restrictions on the ability to utilise flexibility in this
guideline.

### 6.2 Change Management Across the Supply Chain and Product Lifecycle

Supply chains involve multiple stakeholders (e.g., MAHs, R&D organisations,
manufacturers, Contract Manufacturing Organisations, suppliers).  It is important that
these stakeholders interact to effectively utilise knowledge and manage changes during
the product lifecycle.
A company has to manage communication of information and interactions of PQSs
across multiple entities (internal and external).  Therefore, the implementation of robust
change management across multiple sites (outsourced or not) is necessary.  In
conjunction with change control principles in Appendix 2, the following change
management activities should be considered to support the approaches defined in this
guideline:
• Changes to ECs should be communicated in a timely fashion between the MAH
and the regulators, and between the MAH and the manufacturing chain (and
vice versa).
• The timeliness of communication is driven by the impact of any change related
to ECs and should be targeted to those entities in the chain that need to be aware
of or to implement the change over the lifecycle of the product.
• Process knowledge and continual improvement are drivers for change. For
example, a CMO may be in a position to propose process improvements which
significantly improve control and product consistency.  These data can be
utilised to revise the ECs and associated PLCM document.  The organisation
responsible for batch release should be aware of all relevant changes and where
applicable, be involved in the decision making.
• The communication mechanisms regarding MAA changes and GMP issues
should be defined in relevant documentation, including contracts with CMOs.
• A critical failure in a PQS anywhere in the supply chain may impact the ability
to use the tools in this guideline; therefore, the company should communicate
such failures to affected regulatory authorities.
RELATIONSHIP BETWEEN REGULATORY ASSESSMENT AND INSPECTION
Regulatory assessment and inspection are complementary activities and their
fundamental roles remain unchanged by this guideline.  Nevertheless, effective
communication between assessors and inspectors can facilitate regulatory oversight of
product lifecycle management.

Appropriate mechanisms to share knowledge and information obtained through
inspection or assessment activities can facilitate access to necessary information and
mitigate increased submission burden on the MAH.  For example, the conclusions from
inspections should be available to assessors to support ongoing oversight of product
lifecycle management and the most recent PLCM document, when applicable, should
be available to inspectors so they are aware of the currently approved status of the
PLCM elements.
ICH Q12 Guideline

Communication is encouraged between regulators across regions, in accordance with
appropriate bilateral/multilateral arrangements; for example, to communicate about
critical failures in aspects of a company’s PQS that may impact the use of tools
described in this guideline.
STRUCTURED APPROACHES FOR FREQUENT CMC POST-APPROVAL CHANGES
In addition to the other tools described in this guideline, a simplified approach to
accomplish certain CMC changes is needed for products whose marketing authorization
did not involve identification of ECs with associated reporting categories.  This chapter
describes a strategy for a structured approach for frequent CMC changes and includes
a discussion of the data requirements for CMC changes (e.g., stability).
The strategy described for structured approaches to frequent CMC changes is
exemplified with a description of an approach for analytical procedure changes in
Annex II.  Similar structured approaches could be developed and applied for other
frequent CMC changes such as scale, packaging, etc.  These approaches may be applied
when the following conditions exist:
• The company’s PQS change management process is effective and in compliance
as described in Chapter 6 and incorporates an appropriate risk management
system.
• A structured approach can be found in Annex II and describes the scope and the
steps to be followed, including, where appropriate, data to be generated and
criteria to be met.  Compliance with the requirements of relevant
internationally-agreed Standards and/or regulatory guidelines may be specified
as part of the structured approach.
If the approach is followed and all criteria are met, the change can be made with
immediate or other post-implementation notification, as appropriate, to the relevant
regulatory authorities.  The flexibility provided in Annex II may not be available in all
regions and in all situations; some specific changes may require prior approval as
defined in regional guidance.
STABILITY DATA APPROACHES TO SUPPORT THE EVALUATION OF CMC CHANGES
The data needed for submission to the regulatory authority in support of a post-approval
change is established by regional regulations and guidance.  This guideline provides
additional science- and risk-based approaches that can be used to develop strategies for
confirmatory stability studies supporting post-approval changes to enable more timely
filing, approval, and implementation of the changes.  Such approaches could be
included in a PACMP (see Annexes ID and IE).
Unlike the formal stability studies recommended in ICH Q1A(R2), whose objective is
to establish a useful shelf-life and storage conditions for a new, yet-to-be-marketed drug
substance/drug product, the purpose of stability studies, if needed, to support a post-
approval CMC change is to confirm the previously approved shelf-life and storage
conditions.  The scope and design of such stability studies are informed by the
knowledge and experience of the drug product and drug substance acquired since
authorisation.  Approaches to the design of such studies should be appropriately
justified and may include:
ICH Q12 Guideline

• Identifying the stability-related quality attributes and shelf-life-limiting
attributes relative to the intended CMC changes, based on risk assessments and
previously generated data
• Use of appropriate tools to evaluate the impact of the intended change. These
may include:
o Drug substance and/or drug product accelerated and/or stress studies on
representative material (which may be pilot or laboratory scale rather
than full scale)
o Pre-and post-change comparability studies on representative material
o Statistical evaluation of relevant data including existing stability studies
o Predictive degradation and other empirical or first-principles kinetic
models
o Utilisation of prior knowledge including relevant company knowledge
and the scientific literature
• Use of confirmatory stability studies post-change instead of submission of data
as part of a regulatory change submission
Where applicable, a commitment to initiate or complete ongoing, long-term stability
testing on post-change batches can assure that the approved shelf life and storage
conditions continue to be applicable after implementing the CMC change.
10 GLOSSARY
Term
Definition
CAPA
Corrective Action and Preventive Action –
System that focuses on investigating,
understanding, and correcting discrepancies
while attempting to prevent their occurrence
CMO
Contract Manufacturing Organisation
CPP
Critical Process Parameter – process parameter
whose variability has an impact on a critical
quality attribute and therefore should be
monitored or controlled to assure the process
produces the desired product quality. (Q8(R2))
CQA
Critical Quality Attribute – a physical,
chemical, biological or microbiological
property or characteristic that should be within
an appropriate limit, range, or distribution to
assure the desired product quality. (Q8(R2))
CTD
Common Technical Document
Company
Manufacturing sites and MAH where relevant
EC
Established Condition
MAA
Marketing Authorisation Application
ICH Q12 Guideline

Term
Definition
MAH
Marketing Authorisation Holder
Notification
A change to an approved established condition
that does not require approval prior to
implementation.
PACMP
Post-Approval Change Management Protocol
PLCM
Product Lifecycle Management
Post-approval CMC commitment
Commitment by the MAH to undertake
specific CMC activities to be implemented
during the commercial phase.
Prior approval
Change to an approved established condition
that requires regulatory review and approval
prior to implementation
PQR
Product Quality Review – regular periodic
review of API or drug products with the
objective to verify process consistency, to
highlight any trends and to identify product
and process improvements
PQS
Pharmaceutical Quality System
QRM
Quality Risk Management
Submission
Communication to a regulatory authority
regarding a change to an established condition
that could be prior approval or notification.

11 REFERENCES
ICH M4: The CTD -- Quality
ICH Q1A(R2) Stability Testing of New Drug Substances and Products
ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology
ICH Q5E Comparability of Biotechnological/Biological Products Subject to Changes
in Their Manufacturing Process
ICH Q8(R2) Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
ICH Q11 Development and Manufacture of Drug Substances
ICH Q8, Q9, and Q10 Questions and Answers
ICH Q8, Q9, & Q10 Questions and Answers -- Appendix: Q&As from Training Sessions
(Q8, Q9, & Q10 Points to Consider)

## APPENDIX 1: CTD SECTIONS THAT CONTAIN ECS

Notes:
•
This table does not contain a complete list of ECs for a product.  The intention of the table is to provide general guidance about the
elements of manufacture and control that constitute ECs and their location within the CTD structure.
•
White rows indicate CTD sections where ECs are generally located.  Grey rows indicate CTD sections where supportive information
is generally located.
•
CTD sections containing ECs may also contain elements of supportive information.
•
For information related to the drug delivery system for a drug-device combination product, the location or the relevant content within
the CTD structure may vary depending on the design of the particular product and region.
CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

3.2.S
DRUG SUBSTANCE
3.2.S.1
General Information

3.2.S.1.1
Nomenclature

Drug Substance Name, Structure.

3.2.S.1.2
Structure
3.2.S.1.3
General properties
Supportive information

3.2.S.2
Manufacture
3.2.S.2.1
Manufacturer(s)
Drug Substance Manufacturing Site(s) (including testing)

3.2.S.2.2
Description of manufacturing
process and process controls
Individual unit operations and their sequence in the manufacturing process

For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations,
reference is made to Chapter 3, section 3.2.3.1 – Identification of ECs for the Manufacturing Processes
3.2.S.2.3
Control of Materials
Starting material specifications (test, elements of analytical procedure and acceptance criteria)
Raw material/reagent/solvent critical controls

ICH Q12 Guideline

CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

Source of materials (e.g., cell and seed source, raw materials) and control of critical materials of biological origin
Generation and control of Master - Working Cell Bank / Master - Working Seed Lot, etc. (Applicable to
biotechnological/biological products)
3.2.S.2.4
Control of critical steps and
intermediates
Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates which
may include storage conditions of critical intermediates

3.2.S.2.5
Process validation and/or
evaluation

Supportive information

3.2.S.2.6
Manufacturing process
development
Supportive information
3.2.S.3
Characterisation
Supportive information
3.2.S.3.1

3.2.S.3.2
Elucidation of structure and
other characteristics
Impurities

Supportive information

3.2.S.4
Control of Drug Substance
3.2.S.4.1
Specification
Drug Substance Specification
For each Quality Attribute on the specification
•
Test Method
•
Acceptance Criteria
3.2.S.4.2
Analytical Procedures
Reference is made to Chapter 3, section 3.2.3.2 Identification of ECs for Analytical Procedures
3.2.S.4.3
Validation of analytical
procedure
Supportive information
3.2.S.4.4
Batch analyses
Supportive information
ICH Q12 Guideline

CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

3.2.S.4.5
Justification of specification
Supportive information
3.2.S.5
Reference Material
Reference Material specification (e.g., test, elements of analytical procedure, where appropriate, and acceptance criteria)

3.2.S.6
Container Closure
Material of construction and specification
3.2.S.7
Stability
3.2.S.7.1
Stability Summary and
Conclusions
Drug Substance storage conditions and shelf-life (or Retest period for chemicals)
3.2.S.7.2
Post-approval stability protocol
and stability commitments

Supportive information (also see Chapter 3, section 3.2.2)

3.2.S.7.3
Stability data
Supportive information
3.2.P
DRUG PRODUCT
3.2.P.1
Description and Composition of
Drug Product
Drug Product qualitative and quantitative composition
3.2.P.2
Pharmaceutical development
3.2.P.2.1
Components of the drug
product

Supportive information
3.2.P.2.2
Drug product
3.2.P.2.3
Manufacturing process
development
3.2.P.2.4
Container closure system
3.2.P.2.5
Microbiological attributes
3.3.P.2.6
Compatibility
3.2.P.3
Manufacture
ICH Q12 Guideline

CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

3.2.P.3.1
Manufacturer(s)
Drug Product Manufacturing sites (including those for testing, primary and secondary packaging, device assembly for drug
product-device combination products
3.2.P.3.2
Batch Formula
Drug Product Batch Formula (Qualitative and Quantitative)
3.2.P.3.3
Description of manufacturing
process and process controls
Individual unit operations and their sequence in the manufacturing process
For levels/details of ECs for inputs (process parameters and material attributes) and outputs of individual unit operations,
reference is made to Chapter 3, section 3.2.3.1
3.2.P.3.4
Controls of Critical Steps and
Intermediates
Specifications (e.g., test, elements of analytical procedure and acceptance criteria) for critical steps and intermediates which
may include storage conditions of critical intermediates.
3.2.P.3.5
Process validation and/or
evaluation

Supportive information

3.2.P.4
Control of Excipients
3.2.P.4.1
Specifications

Excipient Specification
For each Quality Attribute on the specification

•
Test Method
•
Acceptance Criteria

Or, if applicable,

Reference to pharmacopoeial monograph
3.2.P.4.2
Analytical Procedures
Reference to pharmacopoeial monograph and if none exists, refer to Chapter 3, section 3.2.3.2
3.2.P.4.3
Validation of analytical
procedures
Supportive information
 3.2.P.4.4
Justification of specifications
Supportive information
3.2.P.4.5
Excipients of Human or Animal
Origin
Excipient source and controls
ICH Q12 Guideline

CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

 3.2.P.4.6
Novel excipients
(If Novel Excipient Specification is not described in 3.2.P.4.1)
Novel Excipient Specification

For each Quality Attribute on the specification

•
Test Method
•
Acceptance Criteria
3.2.P.5
Control of Drug Product
3.2.P.5.1
Specification(s)
Drug Product Specification
For each Quality Attribute on the specification
•
Test Method
•
Acceptance Criteria

3.2.P.5.2
Analytical Procedures
Reference is made to Chapter 3, section 3.2.3.2
3.2.P.5.3
Validation of analytical
procedures

Supportive information

3.3.P.5.4
Batch analyses
Supportive information
3.2.P.5.5
Characterisation of impurities
 3.2.P.5.6
Justification of specification(s)
3.2.P.6
Reference Materials
Reference material specification (e.g., test, elements of analytical procedure, where appropriate, and acceptance criteria)

3.2.P.7
Container Closure System
Material of construction and specification
Where applicable, supplier/manufacturer of primary container closure system
3.2.P.8
Stability
ICH Q12 Guideline

CTD
SECTION
SECTION TITLE
ESTABLISHED CONDITIONS – General List with notes

3.2.P.8.1
Stability Summary and
Conclusion
Drug product storage conditions and shelf-life Where applicable, in-use storage conditions and shelf-life
3.2.P.8.2
Post-approval stability protocol
and stability commitment

Supportive information (also see Chapter 3, section 3.2.2)

3.3 P.8.3
Stability data
Supportive information
3.2.A
APPENDICES
3.2.A.1
Facilities and equipment
Regional regulation and guidance apply
3.2.A.2
Adventitious agents safety
evaluation
Supportive information (Applicable to biotechnological/biological products)
3.2.A.3
Excipients
Supportive information
3.2.R
REGIONAL INFORMATION

Not Applicable
Regional regulation and guidance apply.

## APPENDIX 2: PRINCIPLES OF CHANGE MANAGEMENT

Consistent with the basic requirements of ICH Q10, an effective change management
system supports the principles of this guideline and is described below:
1. Captures stimuli for change, including those that can improve product performance
or process robustness;
2. Ensures full understanding of the scope of the change and its implications for all
aspects of the process and control strategy including the impact on ECs and aspects
that are not ECs in affected marketing authorisations;
3. Leverages existing process performance and product quality knowledge;
4. Requires science-based risk management and risk categorisation of the intended
change; considers the potential impact if the intended change is not implemented;
5. Determines data (existing and/or to be newly generated) needed to support the
change and accordingly develops study protocols describing the methods,
prospective acceptance criteria as well as additional post-implementation process
performance and/or product quality monitoring as necessary;
6. Ensures that an appropriate regulatory submission is filed when required;
7. Uses a defined change control process to approve or reject the intended change and
involve appropriate stakeholders, including but not restricted to Manufacturing,
Quality, and Regulatory Affairs personnel;
8. Ensures implementation of the change is based on:
a. Review that the change as implemented remains aligned with the relevant
study protocols, PLCM document, or PACMP;
b. Assessment of data generated to demonstrate that the change objective and
acceptance criteria were met;
9. Ensures that risk-mitigating steps are developed in the case of deviations from
acceptance criteria, or identification of unanticipated risks;
10. Verifies, post-implementation, that relevant changes have been effective in
achieving the desired outcome with no unintended consequences for product
quality;
If deviations associated with post-approval changes are detected, ensures that the
issue is managed via the company’s deviation management process and appropriate
corrective and/or preventive actions are identified and undertaken via the
company’s corrective and preventive action (CAPA) system;
11. Post-implementation:
a. Captures new product/process knowledge gained during implementation of
the change;
ICH Q12 Guideline

b. Where applicable, ensures that regulatory filings are updated, and an
assessment is made as to whether updates to the PLCM document are
needed;
c. Where applicable, ensures that the change is included and assessed as part
of the Product Quality Review (PQR);
12. The change management system should be available for review during
audit/inspection.
Use of Knowledge in Change Management
An effective change management system includes active knowledge management, in
which information from multiple sources is integrated to identify stimuli for changes
needed to improve product and/or process robustness.  The connection between knowledge
management and change management is illustrated in Figure 2.  These sources can include,
but are not limited to, developmental studies, process understanding documents, product
or process trending, and product-specific CAPA outcomes.  Provisions should be made for
sharing knowledge (e.g., in quality agreements and/or contracts) that relates to product and
process robustness or otherwise informs changes between the MAH and relevant
manufacturing stakeholders (research and development organisations, manufacturers,
CMOs, suppliers, etc.).
In addition to individual sources of information, there should be a mechanism to provide a
holistic view of quality performance for a specific product or product family on a regular
basis, as captured in the product quality review (PQR) and shown in Figure 2.  This should
include steps taken to identify and manage sources of variability, which allows for the
identification of further need for change not apparent when the data are viewed in isolation.
As described in ICH Quality Implementation Working Group on Q8, Q9, and Q10
Questions & Answers, there is no added regulatory requirement for a formal knowledge
management system.
Management Review
In addition to the guidance provided in ICH Q10 regarding an effective change
management system, the following should be considered in the Management Review:
• Monitoring the timeliness of the change management system to assure that changes
are implemented in a timely manner commensurate with the criticality/urgency
identified for the change.  When implementation is delayed, an assessment and
mitigation of any risks associated with the delay should be made;
•
Monitoring the performance of the change management system, such as assessing
the frequency of intended changes that are not approved for implementation by
the quality unit;
• Ensuring that post-implementation verification occurs and reviewing the results of
that verification as a measure of change management effectiveness (e.g., to identify
improvements to the change management system).

---

### Document: ICH Q13 Complete (ICH)

# ICH Harmonised Guideline Q13 (2022): Continuous Manufacturing of Drug Substances and Drug Products

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE

CONTINUOUS MANUFACTURING OF
DRUG SUBSTANCES AND DRUG PRODUCTS
Q13

Final version
Adopted on 16 November 2022

This Guideline has been developed by the appropriate ICH Expert Working Group and has been
subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4
of the Process the final draft is recommended for adoption to the regulatory bodies of ICH regions

Q13
Document History

Code
History
Date
Q13
Endorsement by the Members of the ICH
Assembly under Step 2 and release for public
consultation.
27 July 2021
Q13
Adoption by the Regulatory Members of the ICH
Assembly under Step 4.
16 November 2022

Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be
used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a
public license provided that ICH's copyright in the document is acknowledged at all times.  In case of any
adaption, modification or translation of the document, reasonable steps must be taken to clearly label,
demarcate or otherwise identify that changes were made to or based on the original document. Any
impression that the adaption, modification or translation of the original document is endorsed or sponsored
by the ICH must be avoided.
The document is provided "as is" without warranty of any kind.  In no event shall the ICH or the authors of
the original document be liable for any claim, damages or other liability arising from the use of the
document.
The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for
documents where the copyright vests in a third party, permission for reproduction must be obtained from
this copyright holder.
i

ICH HARMONISED GUIDELINE
CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES AND
DRUG PRODUCTS
Q13
ICH Consensus Guideline

TABLE OF CONTENTS

PART I: CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES AND DRUG
PRODUCTS................................................................................................................................... 1
1.
INTRODUCTION ................................................................................................................. 1
1.1. Objective .................................................................................................................................. 1
1.2. Scope ........................................................................................................................................ 1
2.
CM CONCEPTS .................................................................................................................... 1
2.1. Different Modes of CM ........................................................................................................... 1
2.2. Batch definition........................................................................................................................ 2
3.
SCIENTIFIC APPROACHES ............................................................................................. 2
3.1. Control Strategy ....................................................................................................................... 2
3.2. Changes in Production Output ................................................................................................. 6
3.3. Continuous Process Verification ............................................................................................. 7
4.
REGULATORY CONSIDERATIONS ............................................................................... 7
4.1. Description of Manufacturing Process and Process Controls .................................................. 8
4.2. Control Strategy ....................................................................................................................... 8
4.3. Batch Description and Batch Size ......................................................................................... 10
4.4. Process Models ...................................................................................................................... 10
4.5. Drug Substance and Drug Product Stability .......................................................................... 10
4.6. Conversion of a Batch Process to CM ................................................................................... 11
4.7. Process Validation ................................................................................................................. 11
4.8. Pharmaceutical Quality System ............................................................................................. 12
4.9. Lifecycle Management .......................................................................................................... 12
4.10. Submission of CM-Specific Information in the CTD .......................................................... 12
ii

5.
GLOSSARY ......................................................................................................................... 15
6.
REFERENCES .................................................................................................................... 16
PART II: ANNEXES .................................................................................................................. 18
ANNEX I: CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES (CHEMICAL
ENTITIES) .................................................................................................................................. 18
1.
INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW ....................................... 18
2.
CONTROL STRATEGY AND OTHER TECHNICAL CONSIDERATIONS ............ 19
2.1. Equipment Design and Integration ........................................................................................ 19
2.2. Process Control and Monitoring ............................................................................................ 19
2.3. Consideration of Other Controls ............................................................................................ 21
2.4. Process Validation ................................................................................................................. 21
3.
REGULATORY CONSIDERATIONS ............................................................................. 22
ANNEX II: CONTINUOUS MANUFACTURING OF DRUG PRODUCTS (CHEMICAL
ENTITIES) .................................................................................................................................. 23
1.
INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW ....................................... 23
2.
CONTROL STRATEGY AND OTHER TECHNICAL CONSIDERATIONS ............ 23
2.1. Material Characterisation and Control ................................................................................... 23
2.2. Equipment Design and Integration ........................................................................................ 24
2.3. Process Controls and Monitoring .......................................................................................... 25
2.4. Process Validation ................................................................................................................. 25
3.
REGULATORY CONSIDERATIONS ............................................................................. 26
ANNEX
III:
CONTINUOUS
MANUFACTURING
OF
DRUG
SUBSTANCES
(THERAPEUTIC PROTEINS) ................................................................................................. 27
1.
INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW ....................................... 27
2.
CONTROL STRATEGY .................................................................................................... 28
2.1. Adventitious Agent Control ................................................................................................... 28
2.2. Equipment Design and System Integration ........................................................................... 28
2.3. Process Monitoring and Real-Time Release Testing ............................................................. 29
3.
PROCESS VALIDATION .................................................................................................. 29
3.1. Approaches to Process Validation ......................................................................................... 29
3.2. Run Time Considerations ...................................................................................................... 30
3.3. Viral Clearance Validation .................................................................................................... 30
iii

ANNEX
IV:
INTEGRATED
DRUG
SUBSTANCE
AND
DRUG
PRODUCT
CONTINUOUS MANUFACTURING ...................................................................................... 31
1.
INTRODUCTION ............................................................................................................... 31
2.
INTEGRATED SMALL MOLECULE DRUG SUBSTANCE/DRUG PRODUCT
PROCESSES ............................................................................................................................... 31
2.1. Characteristics of Drug Substance and Drug Product Process Steps..................................... 31
2.2. Example of an Integrated Process .......................................................................................... 31
2.3. Process Design, Monitoring and Control ............................................................................... 33
2.4. Start-up and Shutdown........................................................................................................... 33
2.5. RTD Characterisation for System Dynamics and Material Traceability ............................... 33
3.
SPECIFICATION AND BATCH DATA .......................................................................... 33
3.1. Drug Substance Specification ................................................................................................ 33
3.2. Drug Product Specification .................................................................................................... 34
3.3. Example of a Drug Substance and Drug Product Specification ............................................ 34
3.4. Batch Data.............................................................................................................................. 35
4.
STABILITY REQUIREMENTS........................................................................................ 35
4.1. Drug Substance Stability ....................................................................................................... 35
4.2. Drug Product Stability ........................................................................................................... 36
5.
LOCATION OF DRUG SUBSTANCE AND DRUG PRODUCT INFORMATION IN
THE CTD ..................................................................................................................................... 36
ANNEX V: PERSPECTIVES ON MANAGING DISTURBANCES .................................... 37
1.
INTRODUCTION ............................................................................................................... 37
2.
BACKGROUND .................................................................................................................. 37
3.
MANAGEMENT OF DISTURBANCES .......................................................................... 38
3.1. Disturbance Example 1 .......................................................................................................... 38
3.2. Disturbance Example 2 .......................................................................................................... 39
3.3. Disturbance Example 3 .......................................................................................................... 40
ICH Q13 Guideline

PART I: CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES AND DRUG
PRODUCTS

1. INTRODUCTION
1.1. Objective
This guideline describes scientific and regulatory considerations for the development,
implementation, operation, and lifecycle management of continuous manufacturing (CM).
Building on existing ICH Quality guidelines, this guideline provides clarification on CM concepts
and describes scientific approaches and regulatory considerations specific to CM of drug
substances and drug products.
1.2. Scope
This guideline applies to CM of drug substances and drug products for chemical entities and
therapeutic proteins. It is applicable to CM for new products (e.g., new drugs, generic drugs,
biosimilars) and the conversion of batch manufacturing to CM for existing products. The principles
described in this guideline may also apply to other biological/biotechnological entities.

CM involves the continuous feeding of input materials into, the transformation of in-process
materials within, and the concomitant removal of output materials from a manufacturing process.
While this description may apply to an individual unit operation (e.g., process chromatography,
tableting, perfusion cell culture), this guideline focuses on the integrated aspects of a CM system
in which two or more unit operations are directly connected. In this context, any changes made in
a unit operation of a CM system may have impact on downstream and upstream unit operations
(e.g., back pressure resulting in forward mixing) and output material quality.

Fundamental aspects of CM that are generally not specific to technology, dosage form, or molecule
type are described within the main body of this guideline. Annexes are provided to augment the
main guideline by providing illustrative examples and considerations specific to certain modalities
(e.g., chemical entities, therapeutic proteins), technologies, and production methods (e.g.,
integration of drug substance and drug product manufacturing). The examples and approaches
described in these annexes are illustrative, and alternative approaches can be used. Topics that are
broadly applicable to both CM and batch manufacturing are not in the scope of this guideline, and
other existing ICH guidelines should be used as appropriate.

2. CM CONCEPTS
2.1. Different Modes of CM
CM can be applied to some or all unit operations in a manufacturing process. Examples of CM
modes include:

• A manufacturing approach in which some unit operations operate in a batch mode while
others are integrated and operate in a continuous mode

ICH Q13 Guideline

• A manufacturing approach in which all unit operations of a drug substance or drug product
manufacturing process are integrated and operate in a continuous mode

• A manufacturing approach in which drug substance and drug product unit operations are
integrated across the boundary between drug substance and drug product to form a single
CM process (i.e., the drug substance is continuously formed and processed into the drug
product through integrated unit operations)

A manufacturing approach may incorporate surge lines or tanks to maintain a constant flow of
material inputs and outputs in any mode of CM described above.
2.2. Batch definition
The ICH Q7 definition of a batch is applicable to all modes of CM, for both drug substances and
drug products. Based on this definition, the size of a batch produced by CM can be defined in
terms of one of the following:

• Quantity of output material
• Quantity of input material
• Run time at a defined mass flow rate

Other approaches to define batch size are possible, if scientifically justified based on the
characteristics of the CM process and Good Manufacturing Practice.

A batch size can also be defined as a range. For example, a batch size range can be established
by defining a minimum and maximum run time.

3. SCIENTIFIC APPROACHES
3.1. Control Strategy
The development of a control strategy for CM is enabled by a holistic approach, considering
aspects specific to CM (discussed below), principles outlined in ICH Q7, Q8, Q10 and Q11, and
quality risk management described in ICH Q9.
3.1.1.  State of Control
A state of control (ICH Q10) is a condition that provides assurance of continued process
performance and product quality. The condition may vary, depending on the mode of CM and the
specific process steps. For example, a state of control can be demonstrated for CM processes when
a set of parameters (e.g., process parameters, quality attributes) are changing within specified
ranges, but the processes are not necessarily in a steady state. Elements of the control strategy
monitor the state of control and, when necessary, take appropriate actions to maintain control of
the process. It is important to have mechanisms in place to evaluate the consistency of unit
operations and the system, and to identify when parameters drift or trend within the specified
range. In addition, the root cause of drift or trend, such as variation of inputs, equipment fatigue,
or aging of materials, should be identified. For example, in a therapeutic protein process, a change
in the elution profile may be due to resin aging.
ICH Q13 Guideline

3.1.2.  Process Dynamics
Knowledge of process dynamics is important to maintain a state of control in CM. Specifically,
understanding the impact of transient events helps to identify risks to material quality and to
develop an appropriate control strategy (see Section 3.1.5 for process monitoring and control
considerations). Transient events that occur during CM operation may be planned (e.g., process
start-up, shutdown and pause) or unplanned (e.g., disturbances) and can be described through time,
process parameter and quality attribute values.

Process dynamics should be characterised to understand how output material quality is impacted
by transient events. This characterisation could be done by determining properties such as
residence time distribution (RTD). RTD characterises the time available for material transport and
transformation, and is specific to the process, composition/formulation, material properties,
equipment design and configuration, etc. Additionally, understanding RTD and process dynamics
enables the tracking of material and supports the development of sampling and diversion strategies,
where applicable. Furthermore, such understanding is of importance from a process performance
perspective. For example, changes in process dynamics or RTD may impact process
characteristics, such as conversion/yield and impurity formation in the manufacture of drug
substances.

Process dynamics should be characterised over the planned operating ranges and anticipated input
material variability using scientifically justified approaches. Appropriate methodologies (e.g.,
RTD studies, in silico modeling with experimental confirmation) should be used to understand the
impact of process dynamics and its variation on material transport and transformation. These
methodologies should not interfere with the process dynamics, and the characterisation should be
relevant to the commercial process. For example, when conducting RTD studies, the tracer used
to replace a constituent of the solid or liquid stream should have highly similar flow properties as
those of the constituent replaced, be inert to the other components of the process, and not alter how
processed materials interact with equipment surfaces. Step testing by making changes to the
quantitative composition of the process stream (e.g., increments of a constituent) is another useful
technique to determine the RTD and avoid the addition of an external tracer to the process. Other
approaches can be used; the approach taken should be justified.
3.1.3.  Material Characterisation and Control
Material attributes can impact various aspects of CM operation and performance, such as material
feeding, process dynamics, and output material quality. Understanding the impact of material
attributes and their variability on process performance and product quality is important for the
development of the control strategy. Input materials may require evaluation and control of
attributes beyond those typically considered for a material specification used in batch
manufacturing. For example:

• In a solid dosage form process, particle size, cohesiveness, adhesiveness, hygroscopicity,
static charge, or specific surface area of drug substances and excipients may impact the
feeding of powders and material flow through the system.

• In a chemically synthesised drug substance process, viscosity, concentration, or the
multiphase nature of the feed may impact flow properties or conversion.
ICH Q13 Guideline

• In a therapeutic protein (e.g., monoclonal antibody) process, lot-to-lot variability of cell
culture media or feed components may impact cell culture performance, process
performance, or process consistency.
3.1.4. Equipment Design and System Integration
The design of equipment and their integration to form a CM system affect process dynamics,
material transport and transformation, output material quality, etc. When developing a CM process
and its control strategy, it is important to consider the characteristics of the integrated systems in
addition to the individual equipment that can affect process performance. These include the
system’s ability to maintain an integrated flow, manage potential disruption to CM operations, and
complete the intended transformation of the material stream within the respective planned
operational ranges of the equipment. In addition, transfer steps should also be evaluated, including
RTD, for the purposes of integration.  Examples of design considerations are given below:

• Design and configuration of equipment (e.g., compatibility and integrity of equipment
components for the maximum run time or cycles; geometry of constituent parts to promote
the desired transformation; spatial arrangement of equipment to facilitate material flow,
maintenance, and avoid build-up or fouling)

• Physical connections and digital control interfaces between equipment (e.g., use of a surge
tank between two unit operations to mitigate temporary differences in mass flow rates)

• Locations of material diversion and sampling points (e.g., selection of locations for a
diverter valve and sampling probe without disturbing material flow and transformation)

Furthermore, appropriate design or selection of equipment for a CM process may enable process
simplification (e.g., through a reduction in the number of unit operations), facilitate process
monitoring and material diversion, and improve process capability and performance. For example,
in a drug substance process, reactor design can effectively reduce formation and build-up of
impurities, resulting in fewer purification steps. Similarly, for therapeutic protein drug substance
manufacturing, system design can enable process intensification and reduce cycle times.
3.1.5.  Process Monitoring and Control
Process monitoring and control support the maintenance of a state of control during production
and allow real-time evaluation of system performance. Common approaches to process monitoring
and control—including establishment of target setpoints and control limits, design space, and
specifications for attributes being measured—are applicable to CM.

Process analytical technology (PAT) (ICH Q8) is well-suited for CM. Example applications
include in-line UV flow cells to monitor therapeutic protein concentration, in-line near-infrared
spectroscopy to assess blend uniformity or water content, and on-line HPLC to monitor conversion
of a chemical reaction. The use of PAT enables disturbances to be detected in real time. Therefore,
CM is readily amenable to automated process control strategies based on, for example, active
process control such as feedforward or feedback process control. Principles of control strategy as
described in ICH Q8 and ICH Q11 are applicable to CM processes.

ICH Q13 Guideline

An appropriate sampling strategy is an important aspect of process monitoring and control. The
variables monitored, monitoring method and frequency, amount of material sampled (either
physical sampling or data sampling using in-line measurement), sampling location, statistical
method, and acceptance criteria depend on the intended use of the data and process dynamics. The
intended use of data may include detection of rapid changes such as disturbances, assessment of
quality of a batch when real-time release testing (RTRT) (ICH Q8) is used, or analysis of process
trends or drifts. Further important considerations are the avoidance of measurement interference
with the process as well as the impact of physical sampling on the material stream potentially
affecting state of control. Assessment of risks associated with data gaps (e.g., PAT recalibration,
refill of a feeding system, failure of system components) should inform whether contingency
methods are warranted.
3.1.6. Material Traceability and Diversion
CM processes may include periods when non-conforming materials are produced, for example,
during system start-up and shutdown or when disturbances are not appropriately managed and
mitigated. The ability to detect and divert potential non-conforming material from the product
stream during production is an important characteristic of CM and should be considered when
developing the control strategy.

Understanding the RTD and process dynamics of individual unit operations and integrated systems
over planned operating conditions enables tracking of the distribution of materials over time. This
allows input materials to be traced throughout production. Material traceability, understanding
how disturbances affect material quality, and the use of appropriate measurements (e.g., PAT)
allow for real-time determination of when to start and stop material collection or diversion. The
amount of material diverted can be influenced by several factors, such as process dynamics, RTD,
control strategy, severity (e.g., magnitude, duration, frequency) of the disturbances, and location
of the sampling and diversion points. Additionally, it is important that the diversion strategy
accounts for the impact on material flow and process dynamics when material is diverted. Criteria
should be established to trigger the start and end of the diversion period and restart of product
collection.
3.1.7.  Process Models
Process models can be used for development of a CM process or as part of a control strategy for
commercial production, including the diversion strategy. Process models may also be used to
predict quality attributes in real time, enabling timely process adjustments to maintain a state of
control. During development, process models can support the establishment of a design space by
explaining how inputs (e.g., process parameters, material attributes) and outputs (e.g., product
quality attributes) are related. Process models can enhance process understanding and reduce the
number of experimental studies.

For general considerations regarding models (including implications of model impact to validation
requirements), refer to Points to Consider: ICH-Endorsed Guide for ICH Q8/Q9/Q10
Implementation. For CM applications, additional considerations are discussed below.

• A process model is specific to system design and configuration and relevant material
properties.

ICH Q13 Guideline

• Model development requires an understanding of the underlying model assumptions (e.g.,
plug flow versus mixed flow systems) and when these assumptions remain valid. Risk
assessments, sound scientific rationales, and relevant data inform the selection of model
inputs and model formulation. It is important to determine the relevant inputs that affect
the model performance, based on appropriate approaches such as sensitivity analysis.

• Model performance depends on factors such as mathematical constructs and the quality of
model inputs (e.g., noise, variability of data). When setting acceptance criteria for model
performance, the model’s intended use and the statistical approaches that account for
uncertainty in the experimental measurement and model prediction should be considered.

• Model validation assesses the fitness of the model for its intended use based on
predetermined acceptance criteria using statistically sound approaches. Model validation
activities are primarily concerned with demonstrating the appropriateness of the underlying
model assumptions and the degree to which sensitivity and uncertainty of the model and
the reference methods are understood.

• During commercial manufacture, model maintenance and monitoring of model
performance should occur on a routine and ongoing basis considering variability that could
impact the model and/or when a process change (e.g., input material, process parameter
change) is implemented. Effective and efficient lifecycle management of models is enabled
by risk assessment of the impact of a model change (e.g., optimisation of model
performance, change of the model’s intended use, change of underlying model
assumptions), considering the scope of model development and model validation criteria.
Depending on the extent of a change and its impact on model performance, a model may
need to be redeveloped and validated.
3.2. Changes in Production Output
Several approaches to changing production output are discussed below; other approaches are also
possible. For already approved products manufactured using a CM process, it is important to
justify the selected approach, assess risk and understand its impact on the overall control strategy
and process performance, and as needed, update the control strategy to ensure risk control. Some
changes may require process modification and process validation.

• Change in run time with no change to mass flow rates and equipment: Issues not
observed over shorter run times may become visible as run time increases. Additional risks
and constraints should be considered and may include, for example, process drift, increased
equipment temperatures, material build-up, exceeding the performance limit of
components (e.g., validated in vitro cell age, resin cycle number), material degradation,
membrane or sensor fouling, and microbial contamination. Decreasing production output
(below the longest run time previously validated) generally would not imply additional
risks, given the same equipment, process and control strategy are used.

• Increase mass flow rates with no change to overall run time and equipment: The risks
associated with this approach may impact output material quality and are related to changes
in process dynamics and system capability to handle increased mass flow rates. Therefore,
ICH Q13 Guideline

this approach may require re-evaluation and modification of the control strategy, including
process parameters and controls, material traceability, RTD, sampling, and diversion
strategies to reduce risk.

• Increase output through duplication of equipment (i.e., scale-out): Considerations for
two commonly used scale-out approaches are provided below.

o Replication of production lines (like-for-like): Replicating the integrated CM
production line (i.e., same equipment and setup as the original CM system) can be
used to increase production output. The replicate production lines follow the same
control strategy.

o Parallel unit operations on the same production line: When only some unit
operations are replicated on the same line, risks are associated with maintaining
control across parallel unit operations. Aspects to consider are maintenance of
uniform flow distribution among the parallel operations, synchronisation and re-
integration of parallel flow streams, changes to process dynamics, increasing the
rate of other unit operations to handle the increased capacity, and material
traceability.

• Scale-up by increasing equipment size/capacity: Depending on the process and
equipment design, increasing production by increasing equipment size may be possible.
General principles of equipment scale-up apply, as in the case of batch manufacturing. As
elements such as RTD, process dynamics, and system integration may change, various
aspects of the control strategy may be impacted. The risks of scale-up and applicability of
the original control strategy should be assessed at the new scale and the control strategy
should be modified where needed.
3.3. Continuous Process Verification
In CM, frequent process monitoring and control can be achieved through use of process
parameters, PAT tools such as in-line/online/at-line monitoring and control, soft sensors, and
process models. These tools allow real-time data collection for parameters relevant to process
dynamics and material quality, and hence ensure the state of control for every batch. Additionally,
since CM can facilitate changes to production output without increasing equipment size, there is
an opportunity to generate development knowledge at the same scale intended for commercial
manufacturing. These tools, together with the system design and the control strategy, facilitate
early execution of process validation activities and the adoption of continuous process verification
(ICH Q8) as an alternative approach to process validation.

4. REGULATORY CONSIDERATIONS
The dossier for a CM process should be in accordance with ICH M4Q. Some CM-specific
considerations are provided below.
ICH Q13 Guideline

4.1. Description of Manufacturing Process and Process Controls
In line with ICH M4Q, a sequential narrative description of the manufacturing process and process
controls should be included in sections 3.2.S.2.2 and 3.2.P.3.3 of the Common Technical
Document (CTD) and supported by pharmaceutical development data provided in CTD sections
3.2.S.2.6 or 3.2.P.2. In the case of CM, the information provided in sections 3.2.S.2.2 and 3.2.P.3.3
should be supplemented by the following, when applicable:

• A summary of start-up, shutdown, pause and restart procedures, as applicable, to describe
how the integrated CM process functions

• The strategy for material collection and diversion including the criteria that should be met
for product collection during routine manufacturing

• Process parameters related to continuous flow (e.g., mass flow rate(s) or flow rate range)

• When appropriate (e.g., movement of solid materials), a description of how the material is
transported from one piece of equipment to another

• A flow diagram with the following aspects identified, when applicable:

o
Points of material entry into the process and material exit from the process
(including material diversion and collection points)

o
Sequence of unit operations, including any surge lines or tanks

o
Direction of material movement through each process step

o
Clear indication of the continuous and batch process steps

o
Critical steps and location points at which process controls, intermediate tests, or
final product controls are conducted (e.g., PAT measurement, feedforward or
feedback process control)

• A suitably detailed description of any aspects of equipment design, configuration and
system integration that were shown during development to be critical to process control or
to impact product quality
4.2. Control Strategy
The control strategy of a CM process is designed to ensure that output materials made over time
are of the desired quality. The control strategy should consider the elements discussed in Section
3 of this guideline. The dossier should describe the relevant controls and operational aspects (e.g.,
material diversion) used during manufacturing. Some aspects of the control strategy are discussed
below.

ICH Q13 Guideline

• Input material attributes: Impact of input material attributes and their variability (e.g.,
inter-batch, different suppliers) on continuous processing and product quality should be
assessed and proposed material attribute acceptable ranges should be justified when
establishing the material specification. For input materials for which pharmacopoeial
requirements exist, characterisation and control may extend beyond those requirements.

• Process monitoring and control: An appropriate description should be provided in the
dossier to show a robust approach to process monitoring and maintaining a state of control.
How the control system uses process parameters, in-process material attribute
measurements, etc., to make process- and quality-related decisions (e.g., to pause the
process or divert material) should be described. Other important aspects should be defined,
such as the sampling strategy (e.g., location, sample size, frequency, statistical approach
and criteria, and their relevance to the intended use), summary of the models if used (e.g.,
type of model used, strategies for model evaluation and performance monitoring), and the
use of data in making in-process control decisions (e.g., to trigger material diversion).

The data analysis method used should appropriately detect the disturbances or variability
in the CM process. For example, when data averaging is used, averaging across appropriate
time intervals should be considered rather than data averaging across the entire CM run
time. The time intervals should consider the relevancy of PAT measurement frequency to
the RTD and process dynamics (i.e., process response time). Therefore, statistical sampling
plans and data analysis should be described and justified.

• System operation: Procedures should be established and maintained on site for managing
system start-up, shutdown, and pauses and for handling disturbances (see Annex V).
Relevant approaches for these operations (e.g., handling disturbances) should also be
described at an adequate level of detail in the dossier. The disposition of material impacted
by transient and pause events should be justified, considering potential risks to output
material quality (e.g., the impact of a disturbance as it propagates downstream).

• Material diversion and collection: The material diversion and collection strategy should
be summarised and justified in the dossier. The strategy described should include the
criteria for triggering material diversion, the basis for determining the extent of diverted
materials, the conditions for resuming material collection, etc. Factors such as sampling
frequency, RTD, and amplitude, duration and propagation of disturbances should be
considered in developing the diversion strategy. The extent of diverted material should
appropriately incorporate justified safety margins, considering the uncertainty of RTD and
other measurements. Procedures for managing material collection, diversion, and
disposition (e.g., quarantine, offline testing, investigations) do not need to be included in
the dossier but should be maintained within the pharmaceutical quality system (PQS) (ICH
Q10).

• RTRT: RTRT as described in ICH Q8 can be applied to an output material quality
attribute(s). RTRT is not a regulatory requirement for CM implementation. When RTRT
is proposed, the associated reference test method should be described. Development of the
data collection approach for RTRT implementation should include a risk assessment of
ICH Q13 Guideline

how any lapses in data collection (e.g., recalibrating a near infrared (NIR) probe) may
affect decisions relating to product quality. The proposed control strategy should include
alternative or additional quality controls to mitigate any risks posed by data lapses. If the
results from RTRT fail or are trending towards failure, appropriate investigations should
be conducted. Refer to Points to Consider: ICH-Endorsed Guide for ICH Q8/Q9/Q10
Implementation for discussion of models used as surrogates for traditional release testing
methods.

• Equipment and system integration: Aspects of equipment design and system integration
that are shown to be critical to output material quality and its control should be described
and justified in the context of the overall control strategy.

A summary of the control strategy should be provided in CTD section 3.2.S.2.6 or 3.2.P.2.3 with
links or references to the CTD sections that contain the detailed information to enable the
understanding and evaluation of the manufacturing process and how it is controlled.
4.3. Batch Description and Batch Size
The approach to define batch size (see examples in Section 2.2) and the proposed commercial
batch size or range should be described in the dossier.

If a range is proposed, it should be justified, and the approach for achieving the range should be
described (see Section 2.2). Changes in batch size within the approved batch size range can be
managed within the PQS. Any post-approval change beyond the approved range should be
supported by data (Section 3.2) and appropriately managed (i.e., prior approval or notification).

A suitable quantitative metric with acceptance criteria should be defined within the PQS to
establish batch-to-batch consistency and system robustness. For example, when a batch size is
defined by the amount of collected material, the amount of diverted materials relative to that of
collected materials for each batch should be considered.

The actual intended size of a given batch should be defined before manufacturing begins.
4.4. Process Models
The level of detail provided in the dossier regarding model development, validation, and
maintenance over the lifecycle should be commensurate with the model type and impact category.
The process model should be specific for the defined system (e.g., equipment, layout, connections).
Information to support models used as part of commercial manufacturing should be available
during site inspection and maintained at or be accessible to the manufacturing site. Refer to Points
to Consider: ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation for regulatory
expectations on process models.
4.5. Drug Substance and Drug Product Stability
Regulatory expectations for the stability data package generally do not differ between CM and
batch manufacturing modes (refer to ICH Q1A, ICH Q5C). Batches used to generate primary
stability data should be manufactured using a manufacturing process and equipment representative
ICH Q13 Guideline

of the commercial process. Primary stability batches should incorporate the variability described
in the ICH stability guidelines (e.g., different drug substance batches).

Additionally, for chemical drug substances or drug products:

• Stability batches could be obtained with a single start-up/shutdown sequence provided the
aforementioned variability is incorporated into the batches (e.g., by introducing different
batches of drug substances in a sequential manner).

• Stability batches may be produced from shorter manufacturing runs, provided that (1) the
control strategy, mass flow rate(s), and equipment used to generate stability batches are
representative of the commercial process, and (2) it is demonstrated that a state of control
is established and maintained when the process operates over the longer commercial run
times. The concept of pilot scale batch for stability studies (e.g., at a minimum, one-tenth
of a full production scale), as defined in other guidelines (e.g., ICH Q1A), may not be
necessarily applicable in this scenario.

• If modes of increasing production output discussed in Section 3.2 other than increasing run
time are being used (e.g., increasing equipment size), applicants should justify their
approach for defining primary stability batches. Applicants are encouraged to discuss their
scale-up and primary stability batches approach with regulatory authorities.
4.6. Conversion of a Batch Process to CM
Changing the manufacturing mode from batch to continuous necessitates the development of an
appropriate control strategy, considering factors identified in Section 3. The output materials from
the batch and continuous processes should have comparable quality. A science and risk-based
approach should be used for establishing product comparability and assessing the need for
additional bioequivalence, non-clinical and/or clinical studies, and stability data. Additional details
regarding how to establish product comparability for therapeutic proteins can be found in ICH
Q5E.

Manufacturers should seek regulatory approval before implementing a conversion of an approved
batch process to a CM process. Manufacturers can seek advice from the regulatory authority to
gain clarification on the regulatory expectations and acceptability of their strategy and data
package for the proposed changes (e.g., when potential changes in formulation are necessary to
enable conversion to CM and the impact of these changes on product registration).
4.7. Process Validation
The requirements for process validation as established by region are similar for CM and batch
manufacturing processes. Approaches such as traditional process validation that uses a fixed
number of validation batches or continuous process verification can be used.

When continuous process verification is used, the CM system performance and output material
quality is continuously monitored, such that the real-time data collected demonstrate the
maintenance of a state of control and production of output material with the desired quality for the
run time duration. The use of continuous process verification should be justified based on the
ICH Q13 Guideline

product and process understanding, system design, and overall control strategy. This justification
should be provided in the dossier (see Table 1 below).

When a continuous process verification approach is used to support initial product launch,
applicants should justify the appropriateness of the validation activities to provide confidence in
the commercial manufacturing process.
4.8. Pharmaceutical Quality System
PQS expectations are the same for batch and CM processes and should follow pertinent ICH
guidelines. One important operational aspect of CM is that non-conforming materials can be
diverted from the rest of the batch when material traceability, process monitoring, and material
diversion strategies are well established. Procedures for material diversion, when required, should
be established under the PQS (see Section 4.2). An overarching plan or decision tree that describes
how disturbances are managed for various types of material diversion should be maintained under
the PQS. Diverted materials resulting from planned events (e.g., system start-up and shutdown)
generally do not require investigation when the events meet established process performance
criteria. Examples of approaches for managing disturbances are provided in Annex V. As
described therein, when unexpected and/or frequent disturbances occur, appropriate investigation,
root cause analysis, and corrective action and preventive action (CAPA) should be instituted.
4.9. Lifecycle Management
The principles and approaches described in ICH Q12 are applicable to the lifecycle management
of CM.
4.10.
Submission of CM-Specific Information in the CTD
The dossier should include information as outlined in ICH M4Q. Additional elements relevant to
CM should also be provided in the dossier when applicable. Examples of these elements are listed
in Table 1. In the case of integrated drug substance and drug product CM processes, some
information and data, such as an integrated flow diagram, may be presented in CTD section 3.2.P
with a cross reference in 3.2.S (see Annex IV for additional details).

Table 1: Recommended CM-Related Information in the CTD
CTD section
Information and Data
3.2.S.2.6
3.2.P.2.3
Manufacturing Process Development
• Summary of the overall process development
• Summary and justification of the control strategy, with links or
references to the CTD sections that contain comprehensive
information on the control strategy elements, for example:
o
Strategy for system start-up, shutdown and pause
o
RTD and material traceability information
o
Disturbance management (e.g., material diversion and
collection strategy)
o
Sampling strategy, including sampling frequency
ICH Q13 Guideline

o
Equipment design and system integration aspects that are
shown to be critical to output material quality
o
Process controls such as feedforward and feedback process
control based on a measured attribute, if used
o
Development and justification of models# where used in the
control strategy (e.g., process model used for feedforward
control, model associated with a PAT analytical method used
for in-process testing and/or real-time release)
o
Justification for range of batch sizes, where claimed
3.2.S.2.2
3.2.P.3.2
Batch Definition
• Batch size or range, and approach to achieving the intended batch
size or range
3.2.S.2.2
3.2.P.3.3
Description of Manufacturing Process and Process Controls
• Narrative description of the commercial manufacturing process and
flow diagram as described in ICH M4Q, clearly indicating which
portion of the manufacturing process is continuous
• Examples of CM-specific aspects of the commercial manufacturing
process to be described are:
o Equipment design and system integration aspects when critical
to the output material quality
o CM-related process parameters, controls and criteria (e.g.,
input rates/mass flow rates, relevant feeder operating ranges),
and location points at which process controls or testing is
conducted
o Location of active process controls if used
o Criteria for product collection, including strategy for diversion
3.2.S.2.4
3.2.P.3.4
Controls of Critical Steps and Intermediates
• Critical process parameters
• In-process testing (e.g., sampling frequency, sample size, analytical
method)
• Relevant information, parameters, and criteria associated with
ensuring correct application of process models used as part of the
control strategy# including contingency plan when the model is not
available
• Relevant information on active process controls, when applicable
(e.g., limits of acceptability for controls that ensure monitored
ICH Q13 Guideline

critical process parameters and critical quality attributes stay within
desired ranges)
3.2.S.4
3.2.P.5
Control of Drug Substance or Drug Product
• When models are associated with the analytical procedures for
release testing of the drug substance or the drug product (e.g., NIR
model, dissolution model):
o Summary and justification of the model and the sampling
strategy
o Contingency testing and monitoring plans instituted for when
the model is not available (e.g., when gaps in PAT data occur
or in case of PAT equipment failure)
o Analytical model validation information
3.2.R
 Regional Information
• Validation data for high impact process models, if used.
• Continuous process verification scheme, if applicable.
# The purpose of a model may vary (e.g., testing the quality of in-process material, drug substance intermediate, drug
substance or drug product, real-time release testing, process control). Not all categories are covered in this table;
information relating to the models should be submitted in the appropriate CTD sections identified in ICH M4Q
guideline for these categories. For example:
•
Models used for drug substance release testing in 3.2.S.4;
•
Models used for in-process testing in 3.2.S.2.4 or 3.2.P.3.4;
•
Model used for both in-process testing and real-time release testing in relevant 3.2.S.4 or 3.2.P.5 sections,
and incorporated by reference into the applicable Control of Critical Steps and Intermediates section;
•
Models used only for process development in 3.2.S.2.6 and 3.2.P.2.3.

ICH Q13 Guideline

5. GLOSSARY
Active Process Controls:
A system consisting of hardware and software architecture, mechanisms, and algorithms
that automatically adjust a process to maintain the process output within a desired range.
Examples include feedforward and feedback process controls.

Disturbances:
Unplanned changes to process inputs beyond normal operating range or conditions (e.g.,
process parameter, material property, equipment condition, or environment) that are
introduced into a system.

Diversion:
Procedure in which materials are isolated and separated from the product stream in the
manufacturing process.

Material Traceability:
The ability to track materials throughout the manufacturing process.

Model Maintenance:
A set of planned activities over the product lifecycle to monitor and sustain the model’s
performance to continually ensure its suitability for the intended and approved purpose.

Multivariate Statistical Process Control:
The application of multivariate statistical techniques to analyse complex process data with
potentially correlated variables. (Ph. Eur.)

Process Dynamics:
The response of a manufacturing process to changing inputs or conditions or transient
events.

Residence Time Distribution (RTD):
A measure of the range of residence times experienced by material passing through a
specific process environment/vessel/unit operation.

Run Time:
The time interval used to produce a quantity of output material.

Soft Sensors:
A model that is used in lieu of physical measurement to estimate a variable or attribute
(e.g., a quality attribute of material) based on measured data (e.g., process data). The model
development, including selection of such data variables, is driven by comprehensive
product and process understanding.
ICH Q13 Guideline

Steady State:
A stable condition that does not change over time.

System:
A manufacturing architecture that, in the context of CM, consists of individual pieces of
equipment, their connections to one another, monitoring and control systems, and spatial
layout.

Transient Events:
A temporary condition in which a process goes through a dynamic change. This change
may be due to a disturbance or an intentional alteration in the selected operating conditions
(e.g., start-up, shutdown, changes from one operating condition to another).

Unit Operation:
A basic step in a process. Unit operations involve a physical, chemical or biological
transformation such as: reaction, crystallisation, filtration, blending, granulation, tableting,
cell culture, purification or virus inactivation.

6. REFERENCES
ICH M4Q: The Common Technical Document for The Registration of Pharmaceuticals for Human
Use: Quality

ICH Q1A: Stability Testing of New Drug Substances and Products

ICH Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological
Products

ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their
Manufacturing Process

ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances

ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients

ICH Q8: Pharmaceutical Development

ICH Q9: Quality Risk Management

ICH Q10: Pharmaceutical Quality System

ICH Q13 Guideline

ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities)

ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management

Ph. Eur.: European Pharmacopoeia

Points to Consider: ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation

ICH Q13 Guideline

PART II: ANNEXES

ANNEX I: CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES (CHEMICAL
ENTITIES)

1. INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW
This annex exemplifies one approach to implement CM of drug substances for chemical entities
based on the scientific principles described in the main guideline. The examples and approaches
in this annex are illustrative, and alternative approaches can be used.

*[Figure 1 illustrates a drug substance manufacturing process containing both continuous and batch]*

operations. It is not intended to represent a regulatory flow diagram. The continuous process
segment consists of unit operations that can be characterised as having two plug-flow reactors
(PFRs), two liquid phase extraction operations, continuous crystallisation, and two agitated filter
dryers. Manufacture of Intermediate 2 is performed in batch mode, as is final processing including
milling and packaging. This annex focuses on the continuous elements of this process.

*[Figure 1: Example of a drug substance CM system for chemical entities]*

ICH Q13 Guideline

2. CONTROL STRATEGY AND OTHER TECHNICAL CONSIDERATIONS
The CM system and its control strategy were designed to control parameters that impact the
manufacture and quality of the drug substance, including impurity profile and physicochemical
properties. The overall control strategy was developed in accordance with the main guideline and
ICH Q7–Q11.
2.1. Equipment Design and Integration
Within the continuous process segment in Figure 1, the following processes occur:

• Reaction 1: Starting materials 1 and 2 are coupled in a PFR to produce Intermediate 1.
Diversion Point D1 is located after the PFR to permit material diversion when PFR
conditions are outside predefined acceptance criteria. The reaction is quenched as an
integrated operation after the PFR, and unwanted by-products are removed by liquid-liquid
extraction. The resultant solution (Intermediate 1) is used as an input for the second
reaction without isolation.

• Reaction 2: Intermediate 1 and Intermediate 2 (prepared upstream through separate batch
unit operations) are coupled in a second PFR to form the crude drug substance. The online
PAT near the reactor exit (T1) monitors conversion of Intermediate 1 to the crude drug
substance. Diversion Point D2 located after PAT is used to divert non-conforming material.

• Drug Substance Isolation: The crude drug substance is purified by liquid-liquid extraction
and continuous two-stage crystallisation. Distillation prior to crystallisation provides
desired concentration of the crude drug substance solution. Diversion Point D3 allows for
material diversion at the crystalliser. The crystal slurry is filtered using two agitated filter
dryers operating in an alternating fashion to enable continuous operation. The isolated drug
substance is then milled using batch operations to achieve the desired particle size
distribution prior to packaging.

Two surge points (each containing multiple surge tanks) are used: one before Reaction 2 and
another before continuous crystallisation. These are important components of the system design
and control strategy, as they improve process robustness and mitigate temporary differences in
mass flow rates by decoupling upstream and downstream operations.

The design of the overall system and each unit operation, along with the control strategy, optimise
material quality. For example, PFR design elements (i.e., dimension and configuration) allow
control of temperature, heat and mass transfer rates, and reaction time. These parameters were
shown during development to be important to the drug substance impurity profile.
2.2. Process Control and Monitoring
Holistic controls used across Reactions 1 and 2 ensure consistent operations and quality of the
resulting crude drug substance. The stoichiometry of Reaction 1 is controlled via control of
concentrations and flow rates of the feeds. Conversion of starting materials to Intermediate 1 with
minimal impurity formation is ensured through control of the reaction temperature and flowrate
(i.e., reaction time). Reaction 2 is controlled through feedback control of the addition rate of
Intermediate 2 based on the PAT measurement of residual Intermediate 1 levels. This ensures
ICH Q13 Guideline

correct stoichiometry for that reaction and minimises the impact of variability of the Intermediate
1 feed solution on drug substance purity. The PAT also measures levels of crude drug substance
and impurities, which confirm successful operation of all preceding steps and consistent product
quality.  Liquid/Liquid extraction ensures appropriate purity control after Reaction 2.

RTD was used to develop a suitable strategy for disturbance detection, corrective actions, and
material diversion. RTD characterisation was based on mathematical modeling of all unit
operations and surge points across the entire CM process over planned mass flow rates. The RTD
was then confirmed through experimental tracer studies for appropriate segments of the
commercial equipment. Decisions for triggering material diversion are based on comparing
process parameters and PAT measurements to predefined acceptance criteria with timing and
duration of diversion informed by the RTD. Importantly, the RTD is also used for material
traceability purposes.

Understanding of process dynamics and its impact on quality attributes of material produced
throughout the entire process was also used to guide start-up and shutdown strategies. For example,
during start-up of Reactions 1 and 2, a small amount of Intermediate 1 or crude drug substance is
diverted at Diversion Points 1 or 2, respectively, to allow those materials to reach the target
concentrations before processing into subsequent operations. The criteria for diversion were
established based on time considering the RTD. This approach was supported by development
studies and appropriately confirmed in commercial process equipment. PAT monitoring after
Reaction 2 provides additional verification that appropriate criteria have been met during start-up.
Collection of material proceeds to the end of the process as subsequently described.

Sampling and process measurement needs were evaluated, considering relevant factors such as
residence times (i.e., surge points, process dynamics, and the type and purpose of the
measurement). The measurement frequency of the PAT at Reaction 2 enables detection of certain
disturbances, informs process adjustments, and ensures timely diversion of material based on
predefined criteria. The criteria for material diversion are based on the magnitude and duration of
the disturbance, an understanding of RTD and process dynamics of downstream unit operations
and surge points, and the impurity purging capability of the crystallisation operation. As a result
of this control strategy, all crude drug substance solution that enters continuous crystallisation
meets acceptable quality criteria and can be processed through the crystalliser.

Appropriate controls and monitoring requirements for the continuous crystallisation were
extensively investigated during development in similar, but smaller scale equipment and
appropriately verified using commercial equipment. Process development included spiking studies
using impurity-enriched feed solutions and intentional perturbations in process parameters (i.e.,
feed flow rates, their ratios, and temperatures). An evaluation of the encrusted solids in the
crystalliser over extended run times demonstrated the solids were the same form and purity as the
free-flowing drug substance slurry. The set of process parameters and ranges identified by these
studies were appropriately scaled up. Implementation of these controls along with post-
crystallisation material tests (e.g., crystal form, purity) ensure consistent quality of the resulting
drug substance throughout continuous crystallisation and subsequent filtration.

ICH Q13 Guideline

The resulting material is milled using a batch operation to provide a drug substance of the
appropriate particle size for use in drug product manufacturing. Procedures were developed to
allow diversion of material at Diversion Point D3 in the event desired process conditions or
material attributes are not met. Diversion of the drug substance from the crystalliser was found to
be unnecessary either during start-up or shutdown.
2.3. Consideration of Other Controls
Process robustness and performance over time are important considerations. A risk assessment
was performed to ensure that adequate controls are in place to support the proposed run time
(which can be up to several months). It identified a number of considerations and corresponding
controls/measures. Examples are summarised in Table 2.

Table 2: Examples of other controls for consideration
Consideration
Controls/Measures
Cleaning and
fouling potential
• Establishment of a risk-based cleaning strategy, including
understanding of the impact of build-up on drug substance quality
• Additional monitoring to assess fouling and cleanliness (e.g., pressure
sensors at the discharge of feed pumps, periodic visual checks for the
continuous crystalliser)
• Reduction of other risk factors (e.g., filtering feed streams to further
reduce fouling risk)
Stability of in-
process materials
• Hold times at key points in the process (e.g., feed streams;
accumulated material at the surge points, reactors, and crystalliser)
managed through batch record and process automation
• Risk assessment of microbiological growth (i.e., negligible risk based
on the nature of the process materials and conditions)
Calibration and
potential for
changes/drift in
instrumentation
• Periodic checks at selected points (e.g., process parameter
measurements for the PFR, system suitability for the PAT analyser)
• Dual sensors at selected locations (e.g., temperature probes for the
PFR) so that appropriate corrective actions can be taken
Equipment
maintenance
•
Maintenance requirements for target run time
•
Use of redundant equipment (e.g., backup pumps) at key locations

Additionally, specifications for input materials were evaluated during process development. There
were no differences between batch and continuous processing for this example.

Collectively, the process understanding developed along with implementation of the various
controls described provide a robust and reliable control strategy. This ensures consistent quality of
the resulting drug substance including the impurity profile, physicochemical properties, and ability
of the system to identify and appropriately react to unexpected events.
2.4. Process Validation
The combination of process controls, online PAT measurements, comprehensive monitoring of
process parameters and material attributes, and end-product testing results in a data-rich
environment for this process. Together with system understanding generated during development,
ICH Q13 Guideline

this enabled the use of a traditional process validation for commercial product launch and
continuous process verification to validate process changes over the product lifecycle.

A range of batch sizes was initially established based on material demands and the quantities of
material necessary to match input needs of the final batch unit operations. The process was
validated using a fixed number of batches. A single planned start-up and shutdown of the
commercial CM system was used to manufacture the process validation batches. This approach
was supported by the totality of evidence demonstrating the start-up and shutdown capabilities of
the system. This included development work on smaller equipment (with appropriate technical
justification for being representative), commercial equipment and system qualification data, results
of a pre-validation demonstration run, and extensive process monitoring of the CM system that
can verify success of each start-up and shutdown in real time.

Subsequently, a continuous process verification approach was adopted after product approval to
validate increases in batch size with extension of run time. The batch size increase was possible
without impact to the equipment scale for downstream batch operations.  This approach used a risk
assessment for the longer run time, which concluded that process performance and material quality
would not be impacted. Under the continuous process verification approach, data generated during
the manufacture of each batch was used to support successful validation of that batch with the
extended run time. This included information such as system performance monitoring and data
logs, along with other controls that ensure material quality with appropriate detection and
corrective action. Additionally, appropriate regulatory actions were taken to communicate this
batch size increase with run time change and use of the continuous process verification approach.
3. REGULATORY CONSIDERATIONS
Refer to Section 4 of the main guideline. In consideration of the specific CM process design,
additional elements may need to be included in a dossier. For instance, in this example, the
influence of surge points on the material diversion and collection strategy, including the fate of
materials, was described.

ICH Q13 Guideline

ANNEX II: CONTINUOUS MANUFACTURING OF DRUG PRODUCTS (CHEMICAL
ENTITIES)

1. INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW
This annex exemplifies one approach to implement CM for a tablet drug product based on the
scientific principles described in the main guideline. The examples and approaches in this annex
are illustrative, and alternative approaches can be used. Specific considerations relating to the
implementation of a continuous direct compression process for a chemical entity are presented.

*[Figure 2 illustrates a continuous direct compression process that consists of continuous feeding,]*

blending, and tablet compression unit operations, with batch mode film coating. It is not intended
to represent a regulatory flow diagram.

*[Figure 2: Example of a tablet drug product CM system]*

A PAT tool using an NIR method monitors blend uniformity and triggers tablet diversion. Run
time at a predefined mass flow rate is used to define the batch size range; in this case, the overall
marketing demand requires batch sizes between 360 and 1080 kg of the drug product.
2. CONTROL STRATEGY AND OTHER TECHNICAL CONSIDERATIONS
The CM system and its control strategy were designed to mitigate the impact of disturbances to
ensure output material quality. The overall control strategy was developed in accordance with the
main guideline and ICH Q8–Q10.
2.1. Material Characterisation and Control
ICH Q13 Guideline

During process design and development, a quality-by-design approach was adopted that identified
equipment and process parameters critical to control of the process. Furthermore, the relationships
between material quality attributes and their impact on unit operations (particularly the loss-in-
weight feeders (LIWFs) and blender) and product critical quality attributes (CQAs) were
evaluated. Bulk density of the primary excipient and particle size distribution (PSD) of the drug
substance were identified as critical to blend and content uniformity. A defined bulk density range
and three-tier (d10, d50, d90) PSD specification were implemented for the excipient and drug
substance, respectively.
2.2. Equipment Design and Integration
Unit operations and system components (e.g., NIR probe) were designed or selected to mitigate
the impact of disturbances on final product quality. The overall design principle is, where possible,
to use gravity to move material. During system integration, the material flow was coordinated
across all unit operations to avoid material accumulation or emptying. System mass balance was
obtained through understanding of material flow (i.e., RTD) at the intended operating conditions
of each unit operation. The impact of equipment design and operation on process dynamics was
characterised by the RTD of individual unit operations, as well as the RTD of process segments
between individual unit operations and the diversion point. The RTDs were determined by
replacing the drug substance in the formulation with a tracer that has highly similar flow properties
to those of the drug substance.

The following aspects of equipment design and integration were emphasised:

• LIWF: Feeder mass flow rates and their variability were characterised. LIWFs are
controlled to deliver the theoretical amount of each input material per the formulation; it
was demonstrated that the risks of minor variations to product composition were mitigated
by blender mixing capability. Feeder mass flow rates were evaluated using design of
experiment (DOE) studies and the proven acceptable ranges of target flow rates were
defined. Modelling and statistical approaches were used to help determine the limits for
the magnitude and duration of disturbances in mass flow rates, for which material
diversion, operator investigation, or process stop are needed. These limits were visualized
(e.g., funnel plots) to aid understanding. LIWFs operate in gravimetric mode unless they
are refilling (volumetric mode). Refill aspects (e.g., duration and mass of refill) were
evaluated to minimise the impact on feeding.

• Blender: A horizontal blender was selected for the CM system and the blender design was
evaluated (e.g., paddle versus ribbon, number and orientation of paddles in the blender,
rotation speed). It was determined that a paddle blender is critical to ensure desired blend
uniformity. Rotation speed, number and orientation of the paddles were evaluated for their
impact on blend uniformity over the ranges studied, and the corresponding design space
for the blending process was defined. RTD characterisation provided information on the
degree of forward and back mixing and disturbance propagation, and the RTD was used to
define the material traceability and diversion strategy.

• NIR probe: The NIR probe was placed in the tablet press feed frame. The chosen NIR
equipment met the PAT application requirements (e.g., analysis speed, sampling method,
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mass flow rate). Probe location and height are fixed; the impact of material build-up was
evaluated and found not significant. The system intended for commercial production was
used to generate data for the development, calibration, and validation of the NIR method.

• Diversion point: The RTD between the NIR probe and the diversion point was
characterised using a tracer. The material diversion strategy links LIWF and NIR limits to
the RTD between the LIWF and NIR as well as the RTD between the probe and diversion
point, respectively.

• Coater: The mass in the coater corresponds to 1 hour of production. Coating was designed
to be complete in 45 minutes; whilst coating, the next aliquot of tablet cores is filled into
the tablet hopper.
2.3. Process Controls and Monitoring
In this system, the LIWFs may introduce fast dynamic disturbances. These may also occur during
changes in operating conditions (e.g., during start-up or process pauses). Therefore, monitoring
and control of these events are important elements of the control strategy. The control strategy
includes NIR measurements, in-process controls (e.g., individual and total flow rates), process
parameters including critical process parameters (e.g., blender rotation speed), and active process
controls (e.g., feedback control of tablet weight). The sampling strategy for monitoring and control
reflects the observed process dynamics, therefore ensuring adequate detectability of all relevant
disturbances. Together, these aspects enable proactive control of the system and ensure continuous
operation in a state of control and accurate material diversion to waste based on the predefined
criteria. Unique codes are assigned to predefined batch segments to ensure material traceability
and identification of conforming and non-conforming materials. Start-up/restart, pause/stop, and
shutdown strategies for this example are defined in Table 3.

Table 3: Start-up/restart, pause/stop, and shutdown strategies
Action
Activity
Start-up/Restart
Material tracking and data collection begins; manufactured material is
diverted until it meets the predefined acceptance criteria for material
collection.
Pause/Stop
A process pause or stop is executed either manually or automatically,
according to predefined criteria.
Shutdown
Material collection continues until manufactured material fails the
predefined acceptance criteria, and then manufacturing ends.

2.4. Process Validation
In this example, a continuous process verification approach was adopted, considering elements
such as prior facility experience in implementing a similar CM process and control system (i.e.,
platform approach), availability of product-specific data arising from late-stage product
development using the commercial equipment, the scale independence of the commercial process
(i.e., batch size varies by run time), a comprehensive control strategy with high-frequency data
collection, and the use of real-time data from every manufacturing run to further support
continuous process verification. The control strategy provides real-time monitoring, trending, and
ICH Q13 Guideline

prediction analysis through the use of NIR measurements, LIWF data, and other data sources
arising from monitoring process parameters (e.g., blender torque), thus providing a high degree of
assurance of real-time CM system stability and performance and output material quality. The
continuous process verification approach, coupled with appropriate regulatory action for reporting
manufacturing changes, was used to validate run time extensions beyond current experience.
3. REGULATORY CONSIDERATIONS
Refer to Section 4 of the main guideline. In consideration of the specific CM process design,
additional elements may need to be included in a dossier. For instance, in this example, elements
that can significantly impact process dynamics and homogeneity (e.g., design space, number of
paddles and their orientation in the horizontal paddle blender) were described.

ICH Q13 Guideline

ANNEX III: CONTINUOUS MANUFACTURING OF DRUG SUBSTANCES
(THERAPEUTIC PROTEINS)

1. INTRODUCTION AND EXAMPLE SYSTEM OVERVIEW
Annex III supplements the main guideline by providing additional regulatory and scientific
considerations that are relevant to CM processes for therapeutic protein drug substances and
recombinant proteins used as intermediates for subsequent conjugation. It describes aspects that
could be applied in fully or partially integrated CM systems. The discussion points and examples
presented in the annex are provided for illustrative purposes and are not exhaustive. Alternative
approaches can be used.

*[Figure 3 illustrates a continuous manufacturing process for therapeutic proteins that consists of]*

unit operations characterised by a bioreactor compatible with a perfusion culture system,
continuous capture chromatography, virus inactivation, and polishing purification chromatography
columns, virus filtration, and buffer exchange and concentration through tangential flow filtration.
It is not intended to represent a regulatory flow diagram.

This process integrates a perfusion cell culture with continuous downstream chromatography and
other purification steps to continuously capture and purify the target protein. Each individual unit
operation is integrated with adjacent unit operations or with a surge line or tank that connects unit
operations. Diversion point D1 and PAT (T1) are located after chromatography (Chrom) #1. Using
a surge line or tank allows continuous operations to accommodate differences in mass flow rates
or process dynamics. Other examples of CM systems may use integrated unit operations for
selected steps.

In CM processes, a single thaw of one or multiple vials from the same cell bank may result in
either a single harvest or multiple harvests. The number or range of cell bank vials used to produce
the specified number of drug substance batches should be defined. The cell bank vials used should
be traceable to the output drug substance batches.

ICH Q13 Guideline

*[Figure 3: Example of a drug substance CM system for therapeutic proteins]*

2. CONTROL STRATEGY
2.1. Adventitious Agent Control
In general, all principles used to ensure safety in batch manufacturing are applicable to CM. Safety
is demonstrated by a threefold approach based on the principles outlined in ICH Q5A. Control of
adventitious agents (e.g., bacteria, viruses, fungi, mycoplasma) should be based on a risk
assessment of all potential sources of contamination (e.g., starting and raw materials,
manufacturing operations), the ability of the process to remove and inactivate adventitious agents,
and the testing capability to ensure the absence of adventitious agents. Based on this assessment,
a strategy should be developed to include the type and frequency of adventitious agent testing
undertaken to demonstrate that the process remains free of contamination during cell culture and
other downstream steps. An aspect unique to CM is extended cell culture duration and continuous
processing of harvested cell culture material to obtain drug substances. This means that design
measures should be in place to demonstrate the acceptability of all cell culture material used to
generate a given drug substance batch. New technologies for real-time decision making, such as
rapid testing for adventitious agents, may be used to mitigate the impact of contamination events
by earlier detection and appropriate responses during continuous operation.
2.2. Equipment Design and System Integration
The integrity of single-use equipment during use should be ensured to prevent contamination.
Single-use connections (e.g., tube welds, connectors) and components may experience long
ICH Q13 Guideline

durations or high change-out frequencies and should be evaluated as potential contamination risks.
Filtration steps in CM may be subject to longer filtration periods and potentially increased
throughput per unit area or a greater number of filter changes than those under batch
manufacturing. Given these factors, a control strategy and a clearly defined scheme should be put
in place to allow for filter changes and pre- and post-use integrity testing, as appropriate, without
interrupting the process. In the event of a filter failure, a clear strategy for material diversion and
refiltration (reprocessing) should be defined.

The CM system should contain appropriate sampling locations based on risk assessment to enable
detection of contamination, while avoiding unnecessary contamination risk introduced through the
sampling procedure. The sampling locations and frequency may be adjusted based on improved
product and process understanding.

Integrated systems may use surge tanks for flow rate adjustments or other purposes between
processing steps. When surge tanks are used, the relevant RTD, uniformity and microbial risks to
the product in these surge tanks should be evaluated and defined in advance.
2.3. Process Monitoring and Real-Time Release Testing
CM lends itself to various monitoring schemes with different levels of automation. Examples
include in-line sensors placed directly in a process vessel or flowing material stream and online
analysers that conduct automatic sampling. Regardless of the approach used, appropriate
monitoring at suitable stages of the CM process enables timely data analysis to ensure operations
are in a state of control. In certain cases, relevant process parameters may be adjusted to ensure
the quality of in-process or output materials. Enhancing in-line/online PAT capabilities and
development of automation systems for process monitoring enable a continuous monitoring
scheme in support of a release testing strategy that may include RTRT for some quality attributes.
For example, drug substance in-line release tests for pH, osmolality, protein concentration and
online release tests for purity, charge heterogeneity, aggregation, and low-molecular weight
impurities can be performed at specific points in the drug substance manufacturing process shown
to be critical for control of the product quality attributes.

An in-process test that is demonstrated to be representative of a release test performed on the
output material may be used as a surrogate for a traditional release testing method. Conventional
offline testing for product release is necessary for quality attributes for which analytical
technologies are not available for online or in-line measurements (e.g., potency). Likewise,
conventional tests for monitoring and control (e.g., microbiological analytical methods and other
tests that require long processing times) might also be needed.
3. PROCESS VALIDATION
3.1. Approaches to Process Validation
Process validation approaches used for batch processes are also applicable to CM processes with
additional considerations for equipment performance over extended run times, integration of
automation systems, and material flow throughout a CM system. Therefore, the scope of validation
continues to demonstrate the ability of the CM system to consistently manufacture a product with
the desired quality.

ICH Q13 Guideline

For therapeutic protein CM, any approach chosen to demonstrate the consistency of process
performance and product quality should also consider sources of variability that may have a
potential impact on product quality. This may include variability between batches purified from
harvest materials collected up to the limit of in vitro cell age from a single cell bank thaw, as well
as the potential variability between different batches purified from harvests of multiple cell bank
thaws. Variability may be evaluated either as part of process validation or through alternative
studies, if justified.

Alternative process validation approaches (e.g., continuous process verification) may be
considered when justified. Elements such as risk assessment, applicability of development data,
control strategy, and prior knowledge may be considered in determining the suitability of an
alternative process validation approach.
3.2. Run Time Considerations
Bioreactors for CM may operate for significantly longer periods of time than bioreactors for batch
manufacturing. The approach to establish a limit of in vitro cell age for production cells does not
differ, regardless of the mode of bioreactor operation. Previously established limits of in vitro cell
age for a bioreactor operating in a batch mode run may not be applicable to a bioreactor operating
in a continuous mode under different culture conditions. The limit of in vitro cell age used for
production should be based on data derived from production cells expanded under pilot-plant scale
or commercial-scale conditions to the proposed in vitro cell age or beyond as outlined in ICH Q5A,
Q5B and Q5D.

Run time considerations should include factors such as the control of all adventitious agents (e.g.,
viruses, bacteria, fungi, mycoplasma) and resin and membrane lifetimes. Viral testing should be
conducted as outlined by ICH Q5A, and an appropriate microbial control strategy should be
established.
3.3. Viral Clearance Validation
The general recommendations outlined in ICH Q5A for viral safety and clearance remain
applicable for CM. Where recommendations may not be applicable to a CM system, scientifically
justified alternatives may be proposed.

ICH Q13 Guideline

ANNEX IV: INTEGRATED DRUG SUBSTANCE AND DRUG PRODUCT
CONTINUOUS MANUFACTURING

1. INTRODUCTION
Annex IV supplements the main guideline by providing additional regulatory and scientific
considerations that are relevant for the development and implementation of integrated drug
substance and drug product CM processes (referred to as integrated process(es) hereafter).

This annex also provides an example of an integrated process for a small molecule tablet dosage
form. The example and approaches described in this annex are not exhaustive. Alternative
approaches can be used.
2. INTEGRATED SMALL MOLECULE DRUG SUBSTANCE/DRUG PRODUCT
PROCESSES
2.1. Characteristics of Drug Substance and Drug Product Process Steps
Considering the differences between the drug substance and drug product process steps enables
appropriate design of an integrated process. For example, process steps for drug substance and
drug product manufacturing can have different RTDs, and a prevalence for liquid or solid input
material addition can lead to a different frequency of in-process measurements. These differences
are expected to influence the selection of equipment, equipment connections, surge lines or tanks,
and the locations of in-process measurements and material diversion.
2.2. Example of an Integrated Process
Figure 4, which is not intended to represent a regulatory flow diagram, illustrates a fully continuous
integrated drug substance and drug product process. It shows the following elements:

• Material addition points for liquids and solids

• Each process step used for drug substance and drug product manufacturing

• Process design for the interface between the drug substance and drug product

• Sampling locations for all in-line/at-line/offline measurements, including PAT (shown by
T1–T5)

• All diversion points (shown by D1–D4)

In this example, chemical reaction using flow reactors, continuous crystallisation, and crossflow
filtration are used to obtain the drug substance as a highly concentrated crystal slurry. A wet
granulation process consisting of blending, granulation, drying, milling, compression and coating
unit operations is used to obtain a tablet drug product. The selection of a wet granulation process
for the manufacture of the drug product permits the drug substance and drug product processes to
be integrated through the continuous filtration line. The concentrated crystal slurry functions as
both the drug substance source and the granulation fluid. No surge lines or tanks are used.

ICH Q13 Guideline

Other process schemes—including, for example, different purification methods, surge tanks, mix
of batch and continuous unit operations—could also be used in the design of an integrated process.
Details should be provided on how drug substance purity is ensured.

*[Figure 4: Example of an integrated drug substance and drug product CM system]*

ICH Q13 Guideline

2.3. Process Design, Monitoring and Control
Monitoring points create several process segments, as illustrated in Figure 4 (i.e., from the first
drug substance reactor up to location T1, process steps from T1 to T2, etc.). The sampling strategy
could be based on RTD characterisation of individual steps, process segments, or the entire
process. In this example, the RTD of the drug substance process segment provides a suitable time
frame to monitor drug substance quality in real time, considering an appropriate sampling
frequency, test method, time needed for measurement, and instrument capability. Location T1/D1
is used for sampling drug substance for offline testing or for diversion of drug substance, as
necessary. Diversion of material impacts mass flow and may require a compensation strategy in
the downstream operations considering the RTD.

Allowable variations (including minor disturbances) identified through DOE or other suitable
studies are incorporated into the process control strategy. In this example, the process parameter
ranges for material additions and reactors, as well as the magnitude and duration of an allowable
disturbance, are based on the variations shown to be within the purification capability of the
crystallisation step, so there would be no adverse impact on the drug substance purity and impurity
profile. An additional risk-based safety margin is included in the established thresholds to ensure
all non-conforming material is diverted. Variations outside these thresholds result in material
diversion using a suitable method for material traceability (e.g., RTD model).

Ongoing assessment of equipment performance helps predict and prevent potential problems and
ensures the ability of a CM process to operate as intended over time. Two such examples are: (1)
during continuous filtration, monitoring filter back pressure to evaluate filter saturation (maximum
pressure) and prevent filter failure; and (2) during material feeding using LIWFs, monitoring the
feeder screw speed in relation to its maximum capacity to inform low feeder fill-level. Monitoring
of equipment performance could be used to support how process control will be ensured, especially
during long run times.
2.4. Start-up and Shutdown
Individual unit operations of an integrated drug substance and drug product process could achieve
desired operating conditions at different times due to differences in the type of transformation (e.g.,
chemical versus physical transformation) and the residence time in the equipment. When such
differences occur, careful planning of start-up and shutdown sequences reduces waste.
2.5. RTD Characterisation for System Dynamics and Material Traceability
Refer to the main guideline for RTD characterisation. As an integrated process has liquid and solid
process streams, different approaches or tracers may be used to characterise various process
segments considering the physical state of material in the flow stream (e.g., solution, slurry, solid).
3. SPECIFICATION AND BATCH DATA
3.1. Drug Substance Specification
Even though the drug substance is not isolated in an integrated drug substance and drug product
process, a drug substance specification should be defined and justified in accordance with ICH
Q6A and other relevant ICH guidelines. Institution of a drug substance specification defines the
quality of the drug substance, as well as facilitates the management of lifecycle activities (e.g.,
ICH Q13 Guideline

facility changes), investigation of adverse events and product recalls, development of
pharmacopeial monographs, and the establishment of a reference standard.

Although a drug substance specification should be instituted, drug substance testing may not be
required on a routine basis when the integrated process is appropriately controlled. A set of process
performance criteria may be defined such that the drug substance could be considered “conforms
to specification, if tested” when those process performance criteria are met. To ensure there is a
comprehensive monitoring of the quality of the drug substance during the lifecycle of the product,
conformance to the drug substance specification should be verified on a periodic and event-driven
basis by testing the purified drug substance at an appropriate location using a relevant sampling
plan. The frequency of the periodic verification should be defined and justified. Drug substance
periodic verification can be based on pre-selected batches and/or at predetermined time intervals
(e.g., every 5th batch or if manufactured infrequently, annually). Event-based verifications could
be triggered by a change in supplier, starting material, synthesis conditions, or other factors
considering risk. Refer to ICH Q6A for additional details on periodic testing.

Appropriate sampling locations should be incorporated into the process design to enable testing of
the drug substance (e.g., location T1 in Figure 4). Any modifications made to the sample to enable
the test (e.g., drying of the crystal slurry for testing crystalline form) should be incorporated into
the test methodology. Sampling locations should be identified in the drug substance specification.

Although the drug substance is not isolated, the origin and fate of potential impurities (e.g., related
substances, residual solvents, catalysts), robustness of impurity clearance, and impurity carryover
from the drug substance into the drug product should be provided in the dossier. The control of
impurities formation and clearance should be integrated into the overall control strategy.
3.2. Drug Product Specification
In integrated processes, attributes typically associated with the drug substance quality are generally
included in the drug product specification unless justified per ICH Q6A. Therefore, the drug
product specification in an integrated process should include drug substance-related substances,
residual solvents (used in drug substance synthesis), elemental impurities, etc., when appropriate.
The specified impurities in the drug product specification may differ from the specified impurities
in the drug substance specification.

Sampling location should be appropriately identified in the drug product specification table, as
some testing (e.g., testing for drug substance periodic verification as described above) may need
to be performed following the drug substance purification step (before drug product formation).
3.3. Example of a Drug Substance and Drug Product Specification
An example of a drug substance and drug product testing approach for an integrated process based
on Figure 4 is shown in Table 4. The test attributes listed are considered relevant for this example.
The specific details of each integrated process should be considered in the selection of the
appropriate test attributes and testing plan.

ICH Q13 Guideline

Table 4: Example of a testing approach for an integrated CM
Test Attribute1

Drug Substance Specification
for Periodic Testing
Drug Product Specification
for Routine Testing of Every Batch
Test
Sampling Location
Test
Sampling Location
Description
N/A
N/A

Coated tablets
Identity

Use drug product test result

PAT at tablet feed frame (T4)
Crystalline Form2

Sampling Location T1
N/A
Not tested when justified
Chirality3

Sampling Location T1
N/A
Not tested when justified
Particle Size

Sampling Location T1
N/A
Not tested
Purity

Sampling Location T1
N/A
Not tested
Assay
N/A
N/A

Core tablets, Sampling Location
combination of T4 (blend
uniformity) and T5 (tablet weight)
Impurities4
Impurity specification for drug substances and drug products may differ
Related
Substance

Sampling Location T1 (at-line high
performance liquid
chromatography (HPLC))4


Sampling Location T1 (at-line
HPLC)4
or
Coated Tablets (offline HPLC
testing), as appropriate
Residual
Solvents


Elemental
Impurities


Mutagenic
Impurities


Dissolution
N/A
N/A

Coated Tablets
Uniformity of
dosage units
N/A
N/A

Uncoated Tablets
Water content
N/A
N/A

Coated Tablets
Microbial limits
N/A
N/A

Coated Tablets
1 Include tests that are necessary to ensure the identity, strength, quality and purity of the drug substance and
bioavailability of the drug product as per ICH Q6A.
2 In this example, crystalline form is considered a critical quality attribute for the drug substance and hence tested
periodically. Crystalline form is not tested in the drug product as lack of form change during drug product
processing has been demonstrated.
3 In this example, chirality is considered a critical quality attribute for the drug substance.
4 Tests that are common to both drug substance and drug product specification need to be tested only at one location;
the same test result can be used for the drug substance and drug product.

3.4. Batch Data
Although the drug substance is not isolated, small, planned diversions during process development
should be used to obtain batch data that is representative of commercial drug substance.
4.
STABILITY REQUIREMENTS
4.1. Drug Substance Stability
Drug substance stability data to define a re-test period is not applicable as the drug substance is
not isolated and stored in an integrated process. Drug substance stability data may be appropriate
ICH Q13 Guideline

for other aspects, such as to support the storage of in-house reference standards and to gain an
understanding of product stability profiles. Institution of a hold time enables temporary storage of
drug substance during an interruption in production.
4.2. Drug Product Stability
The ICH stability guidelines and Section 4.5 of the main guideline are applicable to drug product
made by an integrated process.
5. LOCATION OF DRUG SUBSTANCE AND DRUG PRODUCT INFORMATION IN
THE CTD
Drug substance and drug product information could be provided in the respective CTD sections
3.2.S and 3.2.P of the dossier. A description of the process step that integrates the drug substance
and drug product could be based on its relevancy to the respective section. For example, in the
process example provided in this annex, the continuous filtration process could be described in
CTD section 3.2.S as it is related to concentration of the drug substance. The integrated flow
diagram can be provided in CTD section 3.2.P and referenced in section 3.2.S.

ICH Q13 Guideline

ANNEX V: PERSPECTIVES ON MANAGING DISTURBANCES

1. INTRODUCTION
This annex describes examples of approaches for managing transient disturbances (hereafter
referred to as disturbances in this annex) that may occur during CM. The discussion points
presented here are not exhaustive. Alternative approaches can be used.
2. BACKGROUND
Disturbances may result in a variation in material quality. The impact of some variations on
material quality in an earlier process step may be resolved by downstream process steps. The extent
of variations and the ability to resolve them in subsequent steps are impacted by the amplitude,
duration, and frequency of the disturbance. Identification of tolerable ranges for these parameters
and establishing appropriate acceptance criteria will enable the development of an effective
strategy for managing disturbances.

Manufacturers may use various methodologies (e.g., DOE, RTD studies, a combination of both)
to understand the impact of disturbances. Funnel plot predictions based on an RTD model can be
a useful tool to understand the qualitative and quantitative impact of the amplitude and duration of
a disturbance on material quality. Figure 5 shows a funnel plot for drug substance feeding in a drug
product CM process (similar to the example in Annex II). Funnel plots are specific to the
formulation, process conditions, and system configuration used in RTD model development.
Information from the funnel plot helps to inform the selection of appropriate acceptance criteria
for disturbances. For example, the dotted lines in the following funnel plot show that a disturbance
of +/- 20% lasting less than 90 seconds would not cause the drug concentration in the blend to
exceed the 90–110% label claim (LC).

*[Figure 5: Example of a funnel plot for the feeding of a drug substance]*

ICH Q13 Guideline

3. MANAGEMENT OF DISTURBANCES
Manufacturers may develop various approaches to manage disturbances considering the specific
details of the CM system and the risk to material quality from disturbances. Three examples
considering different risks of a disturbance are provided below:

• Example 1: The amplitude and duration of the disturbance meet predefined acceptance
criteria for the disturbance, and the occurrence of such disturbances is infrequent.

• Example 2: The amplitude or duration of the disturbance exceeds the predefined
acceptance criteria for the disturbance, and the occurrence of such disturbances is
infrequent.

• Example 3: The amplitude and duration of each disturbance meet predefined acceptance
criteria for the disturbance, but multiple, frequent disturbances are observed.

These examples focus on the impact of disturbance from a loss-in-weight feeder (LIWF) on the
drug concentration in the blend for a CM process similar to that described in Annex II, given that
all other parameters being monitored meet the predefined acceptance criteria. These examples use
the information in the funnel plot (Figure 5) and, for the purpose of discussion, assume that the
acceptance criteria for the magnitude and duration of an LIWF disturbance is +/- 20% lasting for
80 seconds. These examples help illustrate the important considerations in management of
disturbances under selected scenarios, which may also be applicable to drug substances and other
CM processes.
3.1. Disturbance Example 1

*[Figure 6: Example of an infrequent disturbance that is within the acceptance criteria for]*

disturbances

ICH Q13 Guideline

Description: Figure 6 illustrates a drug substance LIWF with an infrequent transient +20% flow
spike lasting 40 seconds, which is within the predefined acceptance criteria for disturbances. This
disturbance causes an increase in the amount of the drug substance fed into the blender, before
returning to normal operating condition. The funnel plot (Figure 5) shows that following this
disturbance, the drug substance concentration in the blend remains within the 90–110% acceptance
criteria, due to back mixing. An additional quality check, such as measurement of the drug
substance concentration at a suitable location (e.g., NIR measurements at the tablet press feed
frame) could be considered, to confirm the blend is within 90–110%.

Impact: Although this disturbance represents an excursion from normal operation, the quality of
the output material is not affected as the magnitude/amplitude of the disturbance and product
quality meet their predefined acceptance criteria.

Action: No material is diverted. Collection of the output material continues, and the process
continues to operate. No investigation is needed, because such a disturbance has been evaluated
during development and impact on material quality is understood.
3.2. Disturbance Example 2

*[Figure 7: Example of an unexpected disturbance that is outside the acceptance criteria for]*

disturbances

Description: Figure 7 illustrates a drug substance LIWF with an unexpected transient +20% flow
spike lasting 300 seconds. The disturbance is outside the predefined acceptance criteria for
disturbances. This disturbance causes an increase in the amount of the drug substance fed into the
blender before returning to normal operating condition. The funnel plot (Figure 5) shows that
following this disturbance, the drug substance concentration in the blend exceeds the 90–110%
ICH Q13 Guideline

acceptance criterion. An additional quality check, such as measurement of the drug substance
concentration at a suitable location (e.g., NIR measurements at the tablet press feed frame),
confirms the blend exceeds 110%.

Impact: The quality of the output material is adversely impacted as the disturbance duration
exceeds the predefined acceptance criteria.

Action: The process continues to operate while the non-conforming material is diverted according
to a pre-established procedure, and the time to start and end diversion is controlled by the
automation system. The system returns to normal material collection mode when the non-
conforming material is completely diverted. If needed, a concurrent investigation is initiated to
determine root cause.

Diverted Amount: The amount of material diverted depends on the control strategy used (including
specific triggers for material diversion) and on the process dynamics from the point of disturbance
detection and the point at which material diversion ends. Inclusion of confidence intervals in the
RTD provides a safety margin to ensure all non-conforming material is diverted from the batch.
Additional factors, such as the sampling strategy and the ability to trace and remove materials, are
considered in establishing the criteria for material diversion.
3.3. Disturbance Example 3

*[Figure 8: Example of disturbances that are within the acceptance criteria for disturbances,]*

but occur frequently

Description: Figure 8 illustrates a drug substance LIWF with multiple frequent transient +20%
flow spikes, each lasting 40 seconds, resulting in variability in the amount of material fed into the
blender.
ICH Q13 Guideline

Impact: Although each disturbance meets the predefined acceptance criteria for disturbances, it
occurs with a high frequency over a short time period. In this example, the system cannot dampen
these multiple disturbances sufficiently, thus resulting in non-conforming materials.

Action: The impact of these disturbances on system performance and output material quality is
monitored closely (e.g., NIR method, other elements of the control strategy). Process operation
and product collection continue until one or more elements of the control strategy do not meet the
predefined acceptance criteria. When a criterion is no longer met, the material is diverted according
to a pre-established procedure. If high-frequency disturbances persist, process operation may be
paused. An investigation is conducted to understand the root cause for these frequent disturbances.
Such investigations enable preventative actions to be taken to avoid equipment failure and adverse
impact on critical quality attributes, ensure process performance (e.g., robustness), etc. Assessment
of process capability or other evaluations may also be warranted. Setting acceptance criteria for
the frequency of disturbances could also be considered to aid the management of disturbances.

Diverted Amount: The amount diverted is the same as described in Section 3.2 of this annex. The
disposition of the diverted material and the entire batch is assessed upon completion of the
investigation.

---

### Document: ICH Q14 Complete (ICH)

# ICH Harmonised Guideline Q14 (2023): Analytical Procedure Development

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE

ANALYTICAL PROCEDURE DEVELOPMENT
Q14

Final Version
Adopted on 1 November 2023

This Guideline has been developed by the appropriate ICH Expert Working Group and
has been subject to consultation by the regulatory parties, in accordance with the ICH
Process. At Step 4 of the Process the final draft is recommended for adoption to the
regulatory bodies of ICH regions.

Q14
Document History

Code
History
Date
Q14
Endorsement by the Members of the ICH
Assembly under Step 2 and release for public
consultation
24 March 2022
Q14
Adoption by the Regulatory Members of the
ICH Assembly under Step 4
1 November 2023
Q14
Error Corrections: Alignment of glossary
terms (Intermediate precision, Performance
Characteristic, Range, Reportable Range and
Working Range) with ICH Q2(R2), Minor
Format corrections to Table 1 and Table 6 and

*[Figure 3 alignment to Table 6.]*

4 April 2025

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The document is provided "as is" without warranty of any kind.  In no event shall the ICH or the
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obtained from this copyright holder.

i
ICH HARMONISED GUIDELINE
ANALYTICAL PROCEDURE DEVELOPMENT
Q14
ICH Consensus Guideline

TABLE OF CONTENTS
1.
INTRODUCTION .................................................................................................................. 1
1.1
Objective  ................................................................................................................................. 1
1.2
Scope ........................................................................................................................................ 1
2.
GENERAL CONSIDERATIONS FOR ANALYTICAL PROCEDURES ........................ 1
2.1 Minimal versus Enhanced Approaches to Analytical Procedure Development ....................... 2
2.2
The Analytical Procedure Lifecycle ......................................................................................... 2
3.
ANALYTICAL TARGET PROFILE ................................................................................... 3
4.
KNOWLEDGE AND RISK MANAGEMENT IN ANALYTICAL PROCEDURE
DEVELOPMENT AND CONTINUAL IMPROVEMENT .......................................................... 4
4.1
Knowledge Management ......................................................................................................... 4
4.2
Risk Management .................................................................................................................... 4
5.
EVALUATION OF ROBUSTNESS AND PARAMETER RANGES OF ANALYTICAL
PROCEDURES ................................................................................................................................. 5
5.1
Robustness ............................................................................................................................... 5
5.2
Analytical Procedure Parameter Ranges .................................................................................. 5
6.
ANALYTICAL PROCEDURE CONTROL STRATEGY ................................................. 6
6.1
Established Conditions for Analytical Procedures ................................................................... 7
7.
LIFECYCLE MANAGEMENT AND POST-APPROVAL CHANGES OF
ANALYTICAL PROCEDURES ...................................................................................................... 7
8.
DEVELOPMENT OF MULTIVARIATE ANALYTICAL PROCEDURES:
ADDITIONAL CONSIDERATIONS ............................................................................................. 11
9.
DEVELOPMENT OF ANALYTICAL PROCEDURES FOR REAL TIME RELEASE
TESTING: ADDITIONAL CONSIDERATIONS ........................................................................ 14
10.
SUBMISSION OF ANALYTICAL PROCEDURE RELATED INFORMATION ........ 15
10.1 General Regulatory Considerations and Documentation ....................................................... 15
10.2 Documentation for the Enhanced Approach .......................................................................... 15
10.3 Documentation for Multivariate Analytical Procedures  ....................................................... 15
11.
GLOSSARY .......................................................................................................................... 16
12.
REFERENCES ..................................................................................................................... 22
13.
ANNEX ................................................................................................................................. 23
ICH Q14 Guideline

ii

13.1 Annex A: Examples of application of ICH Q14 principles .................................................... 23

#### 13.1.1 Measurement of Stereoisomers as Specific Process Related Impurities in a Small

Molecule Drug Substance (DS) .............................................................................................. 25
13.1.2 Measurement of Potency for an anti-TNF-alpha Monoclonal Antibody .................... 30
13.2 Annex B: Example of Multivariate Model Lifecycle Components ....................................... 36

ICH Q14 Guideline

1. INTRODUCTION

### 1.1 Objective

This guideline describes science and risk-based approaches for developing and maintaining
analytical procedures suitable for the evaluation of the quality of drug substances and drug
products. The systematic approach suggested in ICH Q8 Pharmaceutical Development together
with principles of ICH Q9 Quality Risk Management can also be applied to the development
and lifecycle management of analytical procedures. When developing an analytical procedure,
a minimal (also known as traditional) approach or elements of an enhanced approach can be
applied. Furthermore, the guideline describes additional considerations for the development of
multivariate analytical procedures and for real time release testing (RTRT).
This guideline complements ICH Q2 Validation of Analytical Procedures.
Using the tools described in ICH Q12 Technical and Regulatory Considerations for
Pharmaceutical Product Lifecycle Management, the guideline describes principles to support
change management of analytical procedures based on risk management, comprehensive
understanding of the analytical procedure and adherence to predefined criteria for performance
characteristics. Knowledge gained from application of an enhanced approach to analytical
procedure development can provide better assurance of the performance of the procedure, can
serve as a basis for the analytical procedure control strategy and can provide an opportunity
for more efficient regulatory approaches to related post approval changes.
The guideline also describes submission of analytical procedure development and related
lifecycle information in the Common Technical Document (CTD) format (ICH M4Q, The
Common Technical Document for the Registration of Pharmaceuticals for Human Use).
Information related to analytical procedure development and knowledge may be submitted to
regulatory authorities to provide additional evidence that the analytical procedure is fit for the
intended purpose. While the minimal approach remains a valid approach, an applicant can
decide to submit additional development data and knowledge which may facilitate regulatory
communication for post approval change management.

### 1.2 Scope

This guideline applies to analytical procedures used for release and stability testing of
commercial drug substances and products, hereafter referred to as ‘products’. The guideline can
also be applied to other analytical procedures used as part of the control strategy (ICH Q10
Pharmaceutical Quality System) following a risk-based approach. The scientific principles
described in this guideline can be applied in a phase-appropriate manner to analytical
procedures used during clinical development.
2. GENERAL CONSIDERATIONS FOR ANALYTICAL PROCEDURES
The goal of development is to obtain an analytical procedure fit for the intended purpose: to
measure an attribute or attributes of the material with the needed specificity/selectivity,
accuracy, precision over the reportable range. Details of the performance characteristics
considered for analytical procedure validation are described in ICH Q2.
In this section the minimal and enhanced approaches to analytical procedure development are
described. While the minimal approach remains an acceptable approach to development of a
robust analytical procedure that is fit for the intended purpose, some or all elements of the
enhanced approach might be used to support development and lifecycle management of
analytical procedures.
ICH Q14 Guideline

In certain cases, an analytical procedure can be applied to multiple products with little or no
modification of measurement conditions. For a new application of such platform analytical
procedures, the subsequent development can be abbreviated, and certain validation tests can be
omitted based on a science- and risk-based justification.
Data gained during the development studies (e.g., robustness data from a design of experiments
(DoE) study) could be used as part of the validation data for the related analytical procedure
performance characteristics and studies do not necessarily need to be repeated.

### 2.1 Minimal versus Enhanced Approaches to Analytical Procedure Development

Analytical procedure development should include the following elements as a minimum:
• Identifying the attributes of the product which need to be tested;
• Selecting an appropriate technology and related instruments or suitable apparatus;
• Conducting studies to evaluate analytical procedure performance characteristics such as
specificity, accuracy and precision over the reportable range (including the calibration
model, lower and/or higher range limits) and robustness;
• Documenting the analytical procedure including the analytical procedure control
strategy.
The enhanced approach offers a systematic way of developing and refining knowledge of an
analytical procedure and demonstrating procedure understanding. Product and process
understanding informs the quality attributes to be tested. The anticipated performance criteria
for relevant performance characteristics should be documented in an analytical target profile
(ATP). In addition to the elements of the minimal approach, an enhanced approach may include
the following elements as appropriate:
• Conducting risk assessment and evaluating prior knowledge to identify the analytical
procedure parameters that can impact performance of the procedure;
• Conducting uni- or multi-variate experiments and/or modelling to explore ranges and
interactions between identified analytical procedure parameters;
• Defining an analytical procedure control strategy including set-points and/or ranges for
relevant analytical procedure parameters. These could include proven acceptable
ranges for analytical procedures (PARs) and/or method operable design regions
(MODRs).
Applying elements of the enhanced approach to development can lead to a better understanding
of the impact of analytical procedure parameters on the analytical procedure performance and
more flexibility for lifecycle management, such as wider operating ranges and a more
appropriate set of established conditions (ECs) with associated reporting categories.

### 2.2 The Analytical Procedure Lifecycle

*[Figure 1 depicts elements of the analytical procedure lifecycle as related to the product lifecycle.]*

Analytical procedure development and change management approaches are described in this
guideline whereas analytical procedure validation is described in ICH Q2. Depending on the
intended purpose of the analytical procedure and the development approach taken, the order
and extent of each element could vary, and several elements could occur simultaneously.

ICH Q14 Guideline

*[Figure 1: The analytical procedure lifecycle]*

3. ANALYTICAL TARGET PROFILE
Product and process understanding (ICH Q8 and ICH Q11 Development and Manufacture of
Drug Substances) leads to the identification of critical quality attributes (CQAs) requiring
analytical measurement for control which may be included in the quality target product profile
(QTPP). Measurement needs can be captured in an ATP which forms the basis for development
of the analytical procedure. An ATP consists of a description of the intended purpose of the
analytical procedure, appropriate details on the product attributes to be measured and relevant
performance characteristics with associated performance criteria. The ATP includes
measurement requirements for one or more quality attributes. The ATP drives the choice of
analytical technology. Multiple available analytical techniques may meet the performance
criteria. Consideration of the operating environment (e.g., at-line, in-line or off-line) should be
included in the technology selection. Once a technology has been selected, the ATP serves as a
foundation to derive the analytical procedure attributes and performance criteria for analytical
procedure validation (ICH Q2). Formal documentation and submission of an ATP is optional
but can facilitate regulatory communication irrespective of the chosen development approach.
The ATP also facilitates ongoing monitoring and continual improvement of the analytical
procedure. The ATP is maintained over the lifecycle and can also be used as a basis for lifecycle
management to ensure that the existing, revised or new analytical procedure remains fit for the
intended purpose.
Illustrative examples of ATPs are provided in Annex A.

ICH Q14 Guideline

4. KNOWLEDGE AND RISK MANAGEMENT IN ANALYTICAL PROCEDURE
DEVELOPMENT AND CONTINUAL IMPROVEMENT

### 4.1 Knowledge Management

As with product and manufacturing process development, knowledge management (ICH Q10)
plays a critical role in analytical procedure development and during the lifecycle of the
analytical procedure.
Prior knowledge is explicitly or implicitly used for informing decisions during analytical
procedure development and lifecycle management. Prior knowledge can be internal knowledge
from a company’s proprietary development and analytical experience, external knowledge such
as reference to scientific and technical publications or established scientific principles.
Prior product knowledge plays an important role in identifying suitable analytical techniques.
Knowledge of best practices, state-of-the-art technologies and regulatory expectations
contribute to the selection of the most suitable technology for a given purpose. Existing
platform analytical procedures (e.g., protein content measurement by UV spectroscopy) can be
leveraged to evaluate the attributes of a specific product without conducting additional
procedure development.
As additional information is obtained, knowledge related to analytical procedures should be
actively managed throughout the product lifecycle.

### 4.2 Risk Management

The use of quality risk management (QRM) is encouraged to aid in the development of a robust
analytical procedure to reduce risk of poor performance and reporting incorrect results. Risk
assessment is typically performed early in analytical procedure development and is updated as
more information becomes available. Risk assessment can be formal or informal and can be
supported by prior knowledge.
Risk assessment tools as described in ICH Q9 Annex 1 can be used to:
• identify analytical procedure parameters (factors and operational steps) with potential
impact on its performance, e.g., Annex A Figure 2 (Ishikawa diagram);
• assess the potential impact of analytical procedure parameters on the analytical
procedure performance;
• identify and prioritise analytical procedure parameters to be investigated
experimentally;
• inform the need and the extent of ongoing monitoring as part of risk review.
Risk communication should be used to support continual improvement of the analytical
procedure performance throughout its lifecycle. The outcome of quality risk management
should be documented in the relevant parts of the applicant’s pharmaceutical quality system
(PQS) (ICH Q10).

ICH Q14 Guideline

5. EVALUATION
OF
ROBUSTNESS
AND
PARAMETER
RANGES
OF
ANALYTICAL PROCEDURES

### 5.1 Robustness

The robustness of an analytical procedure is a measure of its capacity to meet the expected
performance criteria during normal use. Robustness is tested by deliberate variations of
analytical procedure parameters and should consider the duration of the analysis (including
stability of sample preparations and reagents). Prior knowledge and risk assessment can inform
the selection of parameters to investigate during the robustness study. Those parameters likely
to influence procedure performance over the intended period of use should be studied.
For most procedures, robustness evaluation is conducted during development. If the evaluation
of robustness was already conducted during development, it does not need to be repeated during
validation (as discussed in ICH Q2). Data from validation studies (e.g., intermediate precision)
can complement robustness evaluation. For some analytical procedures with inherent high
parameter variability (e.g., those requiring biological reagents) wider parameter ranges may
need to be investigated during robustness studies. Robustness of multivariate procedures may
require additional considerations (see Chapter 8). The outcome of the evaluation of robustness
should be documented and also reflected in the analytical procedure control strategy.

### 5.2 Analytical Procedure Parameter Ranges

Experiments to investigate parameter ranges can provide additional knowledge about the
analytical procedure performance. The respective analytical procedure attributes and associated
criteria could be derived from the ATP. Univariate examination of a single parameter can
establish a PAR for the analytical procedure.
In an enhanced approach, the ranges for the relevant parameters and their interactions can be
investigated in multivariate experiments (DoE). Risk assessment and prior knowledge should
be used to identify analytical procedure parameters, attributes and associated ranges to be
investigated experimentally. Categorical variables (e.g., different instruments) can also be
considered as part of the experimental design.
The outcome of development studies should provide an understanding of the relationships
between analytical procedure parameters (inputs) and the responses of the analytical procedure
(outputs). Based on the results, fixed set-points may be defined for some parameters. For others,
PARs could be defined while still others could be included into an MODR. An MODR consists
of combined ranges for two or more analytical procedure parameters within which the analytical
procedure is shown to be fit for the intended purpose.
Set-points, PARs and/or MODRs of an analytical procedure proposed by the applicant based
on development and validation data are subject to regulatory approval. Moving within an
approved PAR or MODR does not require regulatory notification.
Analytical procedure validation for a PAR and/or an MODR is required only for those
performance characteristics not covered by data from analytical procedure development. For
practical reasons and following a risk-based approach, it may not be necessary or possible to
validate the entirety of an MODR. The part of a PAR or an MODR intended for routine use
(typically the intended operational conditions or the set point) in the analytical procedure must
be covered by validation data. The extent of validation tests should be justified on a case-by-
case basis.
For future changes to operational conditions within a PAR or an MODR an assessment of the
need for and extent of additional validation tests should be performed. An analytical procedure
ICH Q14 Guideline

validation strategy, e.g., as part of the analytical procedure validation protocol, can define the
necessary extent of additional validation.
6. ANALYTICAL PROCEDURE CONTROL STRATEGY
An analytical procedure control strategy should ensure that the analytical procedure is fit for
the intended purpose during routine use throughout its lifecycle. It consists of a set of controls,
derived from current understanding of the analytical procedure including development data,
risk assessment, robustness and prior knowledge. The analytical procedure control strategy
should be defined before validation (ICH Q2) and should be confirmed after validation has been
finalised.
The analytical procedure control strategy includes analytical procedure parameters needing
control and the system suitability test (SST) which is part of the analytical procedure. The
analytical procedure should describe the steps necessary to perform each analytical test. This
can include (but is not limited to) the sample, the reference materials and the reagents, sample
and control preparations, use of the apparatus, generation of the calibration curve, the number
of replicates, use of the formulae for the calculation of the reportable results and other
necessary steps. The level of detail should enable a skilled analyst to perform the analysis and
interpret the results (such as the level of detail in a regional pharmacopoeia for a similar
product).
The SST depends on the type and intent of the analytical procedure and is typically conducted
with one or more predefined materials (including use of positive and/or negative controls). The
SST is designed to verify selected analytical procedure attributes. The acceptance criteria
should be based on analytical procedure performance criteria. The components of the SST
should be selected using risk assessment as well as knowledge and understanding from
development data. The test is used to verify that the measurement system and the analytical
operations associated with the analytical procedure are fit for the intended purpose during the
time period of analysis and enable the detection of unacceptable performance. Validity of the
results of the analytical procedure depends on the outcome of the SST. In the enhanced
approach, a well-designed set of SST parameters and criteria to ensure analytical procedure
performance could represent an important aspect of risk mitigation. For analytical procedures
relying on multivariate models, data quality should be verified using suitable software tools.
In addition to SST, sample suitability assessment may be required to ensure acceptable sample
response. A sample and/or sample preparation is considered suitable if the measurement
response of the sample satisfies pre-defined acceptance criteria for the analytical procedure
attributes that have been developed for the validated analytical procedure (often used for
biologics). In these cases, sample suitability is a prerequisite for the validity of the result along
with a satisfactory outcome of the SST. Sample suitability assessment generally consists of the
assessment of the similarity of the response between a reference material and the test sample
and may include a requirement for acceptable levels of interfering signals arising from the
sample matrix. For analytical procedures relying on multivariate models, sample suitability
assessment can be verified using suitable software tools which check if the sample fits within
the model space. This is commonly called data quality check.
Ongoing monitoring of selected analytical procedure outputs is recommended to look for any
trends, in line with PQS expectations. Review of analytical procedure outputs facilitates the
procedure lifecycle management and enables proactive intervention to avoid failures.
ICH Q14 Guideline

### 6.1 Established Conditions for Analytical Procedures

In line with ICH Q12, applicants may propose ECs for an analytical procedure. ECs can be
identified using tools highlighted in Chapter 2 including risk assessment, prior knowledge, and
results from uni- and/or multi-variate experimentation. The nature and extent of ECs will
depend on the development approach, the complexity of the analytical procedure and a
demonstrated understanding of how parameters and other factors impact the analytical
procedure performance.
With a minimal approach to analytical procedure development, the number of ECs may be
extensive with fixed analytical procedure parameters and set points.
With an enhanced approach, there should be an increased understanding of the measurement
requirements, the suitability of available technologies and the relationship between analytical
procedure parameters and performance. This knowledge facilitates the identification of an
appropriate set of ECs and related reporting categories (see Chapter 7). ECs can be reduced and
focused on analytical procedure performance (e.g., acceptable ranges for analytical procedure
parameters, performance characteristics with associated criteria) when justified by analytical
procedure understanding (including prior knowledge and product/process knowledge) and risk
management.
ECs could consist of:
• Performance characteristics and associated criteria (e.g., included in an ATP);
• Analytical procedure principle (i.e., the physicochemical basis or specific technology);
• SST and sample suitability assessment criteria;
• Set points and/or ranges for one or more analytical procedure parameters.
Analytical procedure parameters which need to be controlled to ensure the performance of the
procedure as well as those where the need for control cannot be reasonably excluded should be
identified as ECs. If the application of analytical procedure performance criteria and/or the SST
demonstrate that a specific parameter is under control, that parameter or the parameter value
may not necessarily need to be defined as an EC or may be assigned a lower reporting category
as appropriate. ECs and related reporting categories are proposed by the applicant and assessed
by the regulatory authorities for approval based on the scientific justification provided.
Use of the enhanced approach should not lead to providing a less detailed description of
analytical procedures in a regulatory submission. Suitably detailed descriptions of the analytical
procedures in Module 3 of the CTD are expected to provide a clear understanding regardless of
the approach used to identify ECs for analytical procedures. A description of an analytical
procedure includes supportive information as well as identified ECs.
Identification of reporting categories for ECs and the utilisation of ECs in change management
are described in the next chapter.
7. LIFECYCLE
MANAGEMENT
AND
POST-APPROVAL
CHANGES
OF
ANALYTICAL PROCEDURES
Changes to analytical procedures can occur throughout the product lifecycle and could involve
modification of existing procedures or a complete replacement including introduction of a new
technology. Major changes in the performance characteristics or additional information on
quality attributes could lead to reevaluation of the ATP and/or a new procedure. Typically,
process knowledge, analytical procedure knowledge and continual improvement are drivers for
change. If possible, changes should lead to improved analytical procedures in line with best
ICH Q14 Guideline

practices and instrumentation. The tools and enablers discussed in ICH Q12 are applicable to
analytical procedures, irrespective of the development approach and consist of:
• Existing risk-based categorisation of changes to analytical procedures (in regional
regulatory framework);
• ECs;
• Post-Approval Change Management Protocols (PACMPs);
• The Product Lifecycle Change Management (PLCM) document;
• The PQS (documentation of all changes including those not requiring regulatory
submission);
• Structured approaches for frequent Chemistry, Manufacturing and Controls (CMC) post
approval changes.
If ECs are not proposed in the dossier, any changes should be reported according to regional
reporting requirements. The use of different elements of the enhanced approach can facilitate
management and regulatory communication of post-approval changes as compared to the
minimal approach.

*[Figure 2: Risk-based approach for identification of ECs and reporting categories for]*

associated changes in the enhanced approach

1) Including analytical procedure control strategy

2) In some cases, moderate risk changes proposed by the company may require prior
                 approval based on health authority feedback
If justified and validated (see Chapter 5.2), a PAR or MODR allows movement within the
approved range(s) to be managed within a company’s PQS. Changes outside of the approved
ranges or expansion of those ranges require regulatory communication.
In cases where ECs are proposed, the risk associated with prospective changes should be
assessed up front to propose the appropriate reporting category. Factors to consider include the
criticality of the quality attribute being measured, the complexity of the technology and the
extent of the change (see Annex A). Relevant risk reduction measures should be identified
ICH Q14 Guideline

based on product and process knowledge as well as analytical procedure understanding and the
proposed analytical procedure control strategy. Finally, the level of risk (high, medium or low)
should be assigned.
In general, an understanding of the analytical procedure robustness and/or prior knowledge can
be used to support risk mitigation associated with future changes. Submitting the outcomes of
the risk assessments to regulatory authorities when ECs are proposed can help to justify
reporting categories for future changes to analytical procedures.

*[Figure 2 summarises how risk assessment and risk reduction measures can help to identify]*

appropriate reporting categories for ECs. The risk associated with changes can be reduced by
defining relevant performance criteria which are identified as ECs. Risk reduction is possible
when sufficient understanding is available (Table 1) to design future bridging studies (Table 2).
Adherence to the ATP and an analytical procedure control strategy ensures that the analytical
procedure remains fit for the intended purpose after changes. Changes to parameters that are
not ECs do not require regulatory communication.
The ATP could also form the basis of a PACMP which would allow changes (e.g., a change
between technologies) to be reported at a lower reporting category provided that the pre-defined
requirements for the change are met.
Examples are provided in Annex A on how appropriate reporting categories can be proposed.
Table 1: Relationship between knowledge (understanding), risk and extent of studies for
changes to analytical procedures
Knowledge1)
 Low                                          High
Risk associated with the change
Low                                                                                          High
Prior
knowledge
or
confirmatory study according
to a study plan derived from
prior knowledge

In depth study according to a study
plan derived from prior knowledge

Confirmatory study according
to a study plan

In depth study according to a study
plan
1) As described in ICH Q10
When initiating changes to analytical procedures, QRM can be used to evaluate the impact of
the changes and reconfirm that the originally agreed reporting category is still appropriate. The
outcome of this risk assessment informs the design and extent of the studies needed to support
the change including a bridging strategy to demonstrate that the revised or new procedure
remains fit for the intended purpose. When considering a bridging strategy, a greater
understanding of the analytical procedure can enable a reduced study design whereas a higher
risk change may need a more in-depth study (Table 1). The implementation of an already
validated analytical procedure at a different location, including the concept of analytical
procedure transfer, should follow a similar bridging strategy (Table 2).
ICH Q14 Guideline

For product and process changes, a reassessment and potential adaptation of the ATP, if used,
and a reassessment of the suitability of the analytical procedure may be necessary.
If an applicant proposes a new analytical procedure, a comprehensive risk assessment and
evaluation should be conducted to determine any impact on the performance. The analytical
procedure control strategy for the new procedure should be established. ECs associated with
the new procedure should be justified when communicating the change.
Table 2: Examples of analytical procedure change evaluation
Risk Factor: Extent of
change
Bridging strategy
Evidence of the suitability
of a new procedure
Change of analytical procedure
principle
(physicochemical/biochemical
basis)
Full validation of new procedure
And
Comparative analysis of representative
samples and reference materials.
And/or
Demonstration that the analytical
procedure’s ability to discriminate
between acceptable and non-acceptable
results remains comparable
Analytical procedure
performance characteristics are
evaluated and criteria are met
after the change
And
Results are comparable after
change or differences are
acceptable and potential
impact on specification
evaluated
Change within same analytical
procedure principle
Partial or full revalidation of the
analytical procedure performance
characteristics affected by the change
And, as appropriate
Comparative analysis of representative
samples and reference materials
And/or
Demonstration that the analytical
procedure’s ability to discriminate
between acceptable and non-acceptable
results remains comparable
Analytical procedure attributes
are evaluated and criteria are
met after change
And, as appropriate
Results are comparable after
change or differences are
acceptable and potential
impact on specification
evaluated
Transfer of analytical
procedure to a different site
with no change in procedure
itself

Partial or full revalidation of the
analytical procedure performance
characteristics
And/or
Comparative analysis of representative
samples and reference materials

Or

Justification for not performing
additional transfer experiments
Analytical procedure attributes
are evaluated and criteria are
met after change
And/or
Results are comparable
Table 2 provides examples of data recommended to support a change dependent on the extent
of the change and the identified risk category.
To support the use of the tools described in this guideline, the company´s PQS change
management process should be effective and in line with recommendations described in ICH
Q12.
ICH Q14 Guideline

8. DEVELOPMENT
OF
MULTIVARIATE
ANALYTICAL
PROCEDURES:
ADDITIONAL CONSIDERATIONS
Multivariate analytical procedures are those where a result is determined through a multivariate
calibration model utilising more than one input variable. The considerations provided here are
for models using latent variables that are mathematically related to directly measured variables.
Other approaches such as machine learning (e.g., neural networks) or optimisation techniques
could use similar principles although the specific approach may vary and will not be discussed
in detail.
Whereas this chapter includes aspects unique to multivariate analytical procedures, the
principles described in other parts of this guideline are also applicable. Development of a robust
multivariate analytical procedure includes scientifically justified sample selection and
distribution over the range, sample size, model variable selection and data pre-processing.
Sample and sample population
Multivariate models link measured model variables with values obtained from a validated
reference analytical procedure or from reference samples. Therefore, samples in multivariate
analysis consist of input measurements and their corresponding reference values, which are
numeric values for quantitative measurements (e.g., assay) and classification categories for
qualitative analytical procedures (e.g., identity). In some cases, one set of input measurements
could be used for multiple models provided that more than one reference value exists. The
reference values are determined using reference analytical procedure(s) or prepared reference
samples with known values. Care should be taken to ensure that uncertainty in the reference
analytical procedure is sufficiently low in relation to the intended performance of the
multivariate analytical procedure and that prepared reference samples are homogeneous. The
approach to the reference analytical procedure(s) or prepared reference samples should be
explained and justified.
The ranges of multivariate models are typically constructed by data from samples. Therefore, a
careful strategy for sample selection is essential for obtaining the relevant information from the
analytical data and contributes to the robustness of the resulting model. Based on the analytical
procedure and measurement principle, the sample population should encompass the sources of
variability likely to occur during manufacturing and analysis, such as raw material quality,
manufacturing process variability, storage conditions, sample preparation and testing. Use of
risk assessment tools can help to identify sources of variability with the potential to influence
the measurements and resulting model outputs.
Obtaining samples with appropriate variability at commercial scale can be challenging.
Therefore, development laboratory and pilot scale samples are often utilised to provide enough
variability to improve accuracy and robustness of the model. Inclusion of commercial scale
samples is recommended to capture variability related to specific equipment and/or processing
conditions. Careful consideration should also be given to sample distribution in the calibration
and validation sets, as this will influence the model’s predictive capability.
The number of samples used to create a calibration model for quantitative analysis will depend
on the complexity of the sample matrix and/or interference by the matrix in the analyte signal
of interest (i.e., for more complex sample matrices generally more samples are needed).
Sufficient samples should be available for creation of calibration and validation sets of
appropriate size and variability. Independent samples in the validation set are not incorporated
in the calibration set or the internal test set. A validation sample set generated with samples
from independent batches can be used to demonstrate model robustness.
ICH Q14 Guideline

Data transformation
The selection of the data transformation method(s) can be driven by the type of data, instrument
or sample, the intended purpose of the model and/or prior knowledge. Caution should be
exercised when performing any transformation because artefacts can be introduced, or essential
information can be lost. Any transformation of data should be documented and justified.
Variable selection
Variable selection is performed during model development. For example, wavelength range
selection is frequently applied in spectroscopic applications to select a region of a spectrum that
gives the best estimation of the selected chemical or physical property to be evaluated
(modelled). Variable selection depends on the measurement principle, application and other
factors, and should be justified.
Robustness
Model development should minimise the prediction error and provide a robust model that
consistently assures the long-term performance. The robustness should be built into the model
by including relevant sources of variability related to materials, process, environment,
instrumentation or other factors. Sources of variability can be identified from prior knowledge
and risk assessments and evaluated using statistical tools. Robustness depends on multiple
factors, e.g., composition of the calibration set, data transformation method, variable selection
and the number of latent variables.
Optimisation of the multivariate model often requires a trade-off between accuracy and
robustness. A critical factor is the number of latent variables to be used in the calibration model
which ensures the model is optimised for the intended purpose. Selection of the number of latent
variables occurs during model development and is confirmed during internal testing. Too many
latent variables can result in model overfitting, potentially resulting in decreased robustness and
a need for more frequent model updates. Justification for the final number of latent variables
used should be provided. Diagnostic plots provided by software packages can be useful to
support the justification.
Recalibration and model maintenance
Tracking the calibration model performance is an important part of ongoing monitoring for a
multivariate analytical procedure. Various statistical tools can be employed as diagnostics to
ensure that the model assumptions are upheld. For latent variable models, these diagnostic tools
can include:
• examination of residuals to determine unmodeled features of the data (e.g., x-residuals
or F-probability);
• outlier diagnostics to determine if the data is within the bounds of the model
construction (e.g., Hotelling’s T-squared or Mahalanobis distance).
Software packages allow for the application of diagnostic tools for model prediction.
Additionally, continued performance of the calibration model should be confirmed on a
periodic and event-driven basis by comparison of the model predictions with the known values
of the reference samples or reference analytical procedure results. This confirmatory testing
helps to ensure that the calibration model continues to perform as expected. Examples of events
that could trigger confirmatory testing include new known process variability, unexpected
process events or scheduled instrument maintenance.
ICH Q14 Guideline

Monitoring of the model can be used to trigger model rebuilding (recalibration) as a part of
continual improvement. In general, the same considerations hold as for the original model
building and internal testing. Based on the cause of the model update (e.g., a process shift), new
data may need to be included and old non-relevant data may be taken out.
Once the new calibration model is established, the updated analytical procedure can be
validated against the same performance criteria as the ones included in the original model.
Aspects that are not expected to change from the model update may not need to be evaluated
(e.g., specificity).

*[Figure 3: Multivariate (MV) model lifecycle]*

The multivariate model lifecycle (Figure 3) is iterative and can be broken down into 3 major
components: model establishment, routine use and model maintenance.
The choice of a multivariate model is based on the analytical procedure requirements and the
measurement technology selected. Prior to model development, the performance factors for the
model are defined, including the underlying model assumptions and desired ranges for model
applicability. An initial risk assessment can be valuable to understand potential sources of
variability in the materials and process that could affect the model performance and therefore
should be considered during the model calibration. Model development, including calibration
and internal testing, follows the considerations outlined in this chapter. Once the model is
developed, it is validated using independent data not previously used in the calibration set. The
last step in model establishment is development of a multivariate model maintenance plan,
which includes the procedures and limits for outlier diagnostics, and defines the frequency and
circumstances for confirmatory testing, if needed.
ICH Q14 Guideline

Routine analysis of the multivariate analytical procedure typically includes monitoring the
appropriateness of every measurement using outlier diagnostics. Model reassessment can be
triggered by failure of confirmatory testing or outlier diagnostics to meet the predefined criteria,
or from data trending indicating potential unacceptable performance of the model, the process
or the materials being measured (examples of multivariate model lifecycle components are
provided in Annex B).
Model reassessment is performed within the PQS and utilises knowledge management and risk
assessment. If unacceptable performance is identified, model development and revalidation
may be needed, for example, to add samples into the calibration set and remove those that are
no longer relevant. In some cases, the model may be performing appropriately, but additional
experience may identify the need to modify the model maintenance plan. In other cases, the
identified unacceptable performance could be related to the measurement system (e.g., a
misaligned sample interface) and no model update would be needed. The dashed arrows in
Figure. 3 illustrate reintroduction into the lifecycle flow based on the potential outcomes of the
model reassessment.
9. DEVELOPMENT OF ANALYTICAL PROCEDURES FOR REAL TIME RELEASE
TESTING: ADDITIONAL CONSIDERATIONS
Real Time Release Testing (RTRT) is the ability to evaluate and ensure the quality of in-process
and/or final product based on process data, which typically include a valid combination of
measured material attributes and process controls (ICH Q8). RTRT measurements work in
conjunction with all elements of the product control strategy (e.g., process monitoring or in-
process controls) to ensure product quality. RTRT can be applied to drug substances,
intermediates and drug products.
RTRT can be based on an appropriate combination of one or more process measurements and/or
material attributes to provide a value for one or more CQAs and should be specific for those
CQAs. The relationship between the RTRT approach and the CQAs, as well as acceptance
criteria, should be fully justified. An RTRT analytical procedure should be validated as
recommended in ICH Q2 and it should be demonstrated that the process measurements have
appropriate specificity for the targeted quality attribute.
Sampling and the sample interface are important considerations when designing any on-line or
in-line analytical procedure, including those used for RTRT. The measurement point(s) should
be chosen to be representative of the entire material being processed with the sample duration
or amount appropriately chosen (e.g., relative to a unit dose). Additionally, the sample interface
should remain consistent over the duration of manufacturing and should be robust to expected
processing and environmental variations.
The RTRT approach should be included in the product specification (ICH-Endorsed Guide for
ICH Q8/Q9/Q10 Implementation). In accordance with ICH Q6A Specifications: Test
Procedures and Acceptance Criteria For New Drug Substances and New Drug Products:
Chemical Substances and ICH Q6B Specifications: Test Procedures and Acceptance Criteria
For Biotechnological/Biological Products, this includes a reference to the analytical
procedure(s) and the related acceptance criteria. Quantitative RTRT results should be expressed
in the same units as those for traditional testing. The product specification will typically also
include the analytical procedures to be used for off-line testing. If the dossier includes a
registered alternative control strategy to RTRT (e.g., traditional end-product testing when
process analytics are unavailable), the related analytical procedures and when they would be
applied should also be included in the product specifications.
ICH Q14 Guideline

10. SUBMISSION OF ANALYTICAL PROCEDURE RELATED INFORMATION

### 10.1 General Regulatory Considerations and Documentation

The analytical procedure description(s) should be included in the ICH M4Q CTD section
3.2.S.4.2 for drug substance or section 3.2.P.5.2 for drug product. Validation data and
supportive information needed to justify the analytical procedure control strategy should be
included in the CTD section 3.2.S.4.3 for drug substance or section 3.2.P.5.3 for drug product.
Other analytical procedures used as part of the control strategy should be included in relevant
CTD sections (e.g., 3.2.S.2, 3.2.P.3 and 3.2.P.4). The analytical procedure should describe the
steps in sufficient detail for a skilled analyst to perform the analysis (including SST) as
elaborated in Chapter 6. Submission of validation data should reflect the guidance provided in
ICH Q2. The performance criteria used in the validation study should be included in the
submission. In some cases, depending on the intended purpose (e.g., dissolution testing) and/or
the selected technique, it may be appropriate to submit development data as justification.
Where ECs are proposed for analytical procedures as elaborated in Chapter 6, the ECs should
be clearly differentiated from supportive information. Additional development and validation
information can be included in sections 3.2.S.4.3 and 3.2.P.5.3 to justify ECs and their reporting
categories. When other lifecycle management elements as described in ICH Q12 are included
in the submission, the applicant should follow the principles described in ICH Q12 and Chapter
7 of this document.

### 10.2 Documentation for the Enhanced Approach

If the approach to development leads to the incorporation of enhanced elements into the
analytical procedure control strategy, then these should be justified.
Performance characteristics and acceptance criteria (e.g., described in an ATP) and other
elements of the enhanced approach (e.g., MODRs or PARs), should be described in the dossier
sections for analytical procedure description (e.g., 3.2.S.4.2 and 3.2.P.5.2). If ECs are proposed,
then these should also be included in the analytical procedure description, accompanied by
supportive information. The use of the enhanced approach should not lead to providing a less
detailed description of analytical procedures in a regulatory submission.
If ECs and related reporting categories are proposed, risk-based categorisation of changes and
corresponding reporting categories should be included in the submission. Justification should
be given for parameters that are ECs and those that are not ECs, as appropriate (see Chapter 6).
Appropriate information from analytical procedure risk assessment and development studies to
support the proposed lifecycle management strategy should be summarised and submitted in
the regulatory submission sections for analytical procedure validation (e.g., 3.2.S.4.3 and
3.2.P.5.3).

### 10.3 Documentation for Multivariate Analytical Procedures

Development information related to multivariate analytical procedures should be provided
commensurate with the level of impact of the model (ICH-Endorsed Guide for ICH Q8/Q9/Q10
Implementation). The process development section of the dossier (e.g., 3.2.S.2.6 or 3.2.P.2)
should include the model development information for multivariate models used as part of
manufacturing development studies or for in-process controls or tests. Supportive development
information for RTRT multivariate models can be included in either the appropriate analytical
procedure validation or process development section.
Validation information for analytical procedures used for release of drug substance or drug
product, including RTRT, should be included in the validation information section of the
ICH Q14 Guideline

dossier (e.g., 3.2.S.4.3 or 3.2.P.5.3). Additionally, these sections should include validation
information on analytical procedures used as reference analytical procedures. The model
development, calibration and validation information can be included directly in the CTD section
or in an appended document.
For multivariate models used as part of drug substance or drug product specifications, including
RTRT approaches, the description of the validation approach and results should include:
• Description of the validation set with independent samples;
• The performance criteria to be met during validation of the multivariate model;
• Evaluation of the model validation results against the performance criteria;
• Discussion of the relationship between the model performance criteria and the
attribute specification limits;
• High level overview of the PQS elements for model monitoring and maintenance, such
as diagnostic tools for determining the appropriateness of the sample data for the
model and the approach taken when outliers are identified.
The description of the analytical procedure used for RTRT should be provided in the CTD
section 3.2.S.4.2 for drug substance or section 3.2.P.5.2 for drug product and typically includes:
• The property or attribute of interest to be determined by the multivariate analytical
procedure and the desired quantitative ranges or limits;
• A description of the measurement principle and pertinent instrument operating
parameters (e.g., sample presentation, sample interrogation time and measurement
frequency);
• An overview of how the multivariate model calibration data are obtained (e.g., sample
preparation approach, reference analytical procedure);
• The type of multivariate model;
• A description of reference analytical procedure or high-level description of prepared
reference samples;
• Any calculations needed to adjust the model output into the reported value.
Additionally, section 3.2.S.4.2 for drug substance or section 3.2.P.5.2 for drug product should
include description of any analytical procedures that are part of a registered alternative control
strategy to RTRT. Information on validation of these alternative analytical procedures should
be included in the validation information section of the dossier (e.g., 3.2.S.4.3 or 3.2.P.5.3).
11. GLOSSARY
ACCURACY
The accuracy of an analytical procedure expresses the closeness of agreement between the value
which is accepted either as a conventional true value or as an accepted reference value and the
value or set of values measured. (ICH Q2)
ANALYTICAL PROCEDURE
The analytical procedure refers to the way of performing the analysis. The analytical procedure
should describe in sufficient detail the steps necessary to perform each analytical test. (ICH Q2)

ICH Q14 Guideline

ANALYTICAL PROCEDURE ATTRIBUTE
A technology specific property that should be within an appropriate limit, range, or distribution
to ensure the desired quality of the measured result. For example, attributes for chromatography
measurements may include peak symmetry factor and resolution. (ICH Q14)
ANALYTICAL PROCEDURE CONTROL STRATEGY
A planned set of controls derived from current analytical procedure understanding that ensures
the analytical procedure performance and the quality of the measured result. (ICH Q14)
ANALYTICAL PROCEDURE PARAMETER
Any analytical factor (including reagent quality) or analytical procedure operational condition
that can be varied continuously (e.g., flow rate) or specified at controllable, unique levels. (ICH
Q14)
ANALYTICAL PROCEDURE VALIDATION STRATEGY
An analytical procedure validation strategy describes the selection of analytical procedure
performance characteristics for validation. In the strategy, data gathered during development
studies and system suitability tests (SSTs) can be applied to validation and an appropriate set
of validation tests can be predefined. (ICH Q14)
ANALYTICAL TARGET PROFILE (ATP)
A prospective summary of the performance characteristics describing the intended purpose and
the anticipated performance criteria of an analytical measurement. (ICH Q14)
CALIBRATION MODEL
A model based on analytical measurements of known samples that relates the input data to a
value for the property of interest (i.e., the model output). (ICH Q2)
CONTROL STRATEGY
A planned set of controls, derived from current product and process understanding, that assures
process performance and product quality. The controls can include parameters and attributes
related to drug substance and drug product materials and components, facility and equipment
operating conditions, in-process controls, finished product specifications, and the associated
methods and frequency of monitoring and control. (ICH Q10)
CRITICAL QUALITY ATTRIBUTE (CQA)
A physical, chemical, biological or microbiological property or characteristic that should be
within an appropriate limit, range or distribution to ensure the desired product quality. (ICH
Q8)
CTD
Common Technical Document. (ICH M4Q)
DoE
Design of Experiments.

ICH Q14 Guideline

ESTABLISHED CONDITIONS (ECs)
ECs are legally binding information considered necessary to assure product quality. As a
consequence, any change to ECs necessitates a submission to the regulatory authority. (ICH
Q12)
INTERMEDIATE PRECISION
Intermediate precision expresses intra-laboratory variations. Factors to be considered should
include potential sources of variability, for example, different days, different environmental
conditions, different analysts and different equipment. (ICH Q2)
KNOWLEDGE MANAGEMENT
A systematic approach to acquiring, analysing, storing and disseminating information related
to products, manufacturing processes and components. (ICH Q10)
METHOD OPERABLE DESIGN REGION (MODR)
A combination of analytical procedure parameter ranges within which the analytical procedure
performance criteria are fulfilled and the quality of the measured result is assured. (ICH Q14)
ONGOING MONITORING
The collection and evaluation of analytical procedure performance data to ensure the quality of
measured results throughout the analytical procedure lifecycle. (ICH Q14)
PACMP
Post-Approval Change Management Protocol. (ICH Q12)
PERFORMANCE CHARACTERISTIC
A technology independent description of a characteristic that ensures the quality of the
measured result. Typically, accuracy, precision, specificity/selectivity and range may be
considered. Previous ICH Q2 versions referred to this as VALIDATION CHARACTERISTIC.
(ICH Q2)
PERFORMANCE CRITERION
An acceptance criterion describing a numerical range, limit or desired state to ensure the quality
of the measured result for a given performance characteristic. (ICH Q14)
PLATFORM ANALYTICAL PROCEDURE
An analytical procedure that is suitable to test quality attributes of different products without
significant change to its operational conditions, system suitability and reporting structure. This
type of analytical procedure can be used to analyse molecules that are sufficiently alike with
respect to the attributes that the platform analytical procedure is intended to measure. (ICH Q2)
PRECISION
The precision of an analytical procedure expresses the closeness of agreement (degree of
scatter) between a series of measurements obtained from multiple samplings of the same
homogeneous sample under the prescribed conditions. Precision can be considered at three
levels: repeatability, intermediate precision and reproducibility.
The precision of an analytical procedure is usually expressed as the variance, standard deviation
or coefficient of variation of a series of measurements. (ICH Q2)
ICH Q14 Guideline

PROVEN ACCEPTABLE RANGE FOR ANALYTICAL PROCEDURES (PAR)
A characterised range of an analytical procedure parameter for which operation within this
range, while keeping other parameters constant, will result in an analytical measurement
meeting relevant performance criteria. (ICH Q14)
QUALITY RISK MANAGEMENT (QRM)
A systematic process for the assessment, control, communication and review of risks to the
quality of the drug (medicinal) product across the product lifecycle. (ICH Q9)
RANGE
The range of an analytical procedure is the interval between the lowest and the highest results
in which the analytical procedure has a suitable level of precision, accuracy and response. (ICH
Q2)
REPORTABLE RANGE
The reportable range of an analytical procedure includes all values from the lowest to the
highest reportable result for which there is a suitable level of precision and accuracy.
Typically, the reportable range is given in the same unit as the specification acceptance
criterion. (ICH Q2)
WORKING RANGE
A working range corresponds to the lowest and the highest level of the quality attribute to
be measured (e.g., content or purity) as presented to the analytical instrument and for
which the analytical procedure provides reliable results. (ICH Q2)
REAL TIME RELEASE TESTING (RTRT)
The ability to evaluate and ensure the quality of the in-process and/or final product based on
process data, which typically include a valid combination of measured material attributes and
process controls. (ICH Q8)
REFERENCE MATERIAL
A suitably characterised material, sufficiently homogeneous and stable with regard to one or
more defined attributes, which has been established to be fit for the intended purpose. Reference
materials may include national/international reference standards, pharmacopoeial reference
standards, or in-house primary/secondary reference materials. (ICH Q2)
REPEATABILITY
Repeatability expresses the precision under the same operating conditions over a short interval
of time. Repeatability is also termed intra-assay precision. (ICH Q2)
REPORTABLE RESULT
The result as generated by the analytical procedure after calculation or processing and applying
the described sample replication. (ICH Q2)
REPRODUCIBILITY
Reproducibility expresses the precision between laboratories (e.g., inter-laboratory studies,
usually applied to standardisation of methodology). (ICH Q2)
ICH Q14 Guideline

RESPONSE
The response of an analytical procedure is its ability (within a given range) to obtain a signal
which is effectively related to the concentration (amount) or activity of analyte in the sample
by some known mathematical function. (ICH Q2)
REVALIDATION
Demonstration that an analytical procedure is still fit for the intended purpose after a change to
the product, process or the analytical procedure itself. Revalidation can involve all (full
revalidation) or a subset (partial revalidation) of performance characteristics. (ICH Q2)
ROBUSTNESS
The robustness of an analytical procedure is a measure of its capacity to meet the expected
performance criteria during normal use. Robustness is tested by deliberate variations of
analytical procedure parameters. (ICH Q14)
SAMPLE SUITABILITY ASSESSMENT
A sample or sample preparation is considered suitable if the measurement response on the
sample satisfies pre-defined acceptance criteria for the analytical procedure attributes that have
been developed for the validated analytical procedure. (ICH Q14)
SPECIFICITY/SELECTIVITY
Specificity and selectivity are both terms to describe the extent to which other substances
interfere with the determination of an analyte according to a given analytical procedure.
Specificity is typically used to describe the ultimate state, measuring unequivocally a desired
analyte. Selectivity is a relative term to describe the extent to which particular analytes in
mixtures or matrices can be measured without interferences from other components with similar
behaviour. (ICH Q2)
SYSTEM SUITABILITY TEST (SST)
System suitability tests are developed and used to verify that the measurement system and the
analytical operations associated with the analytical procedure are fit for the intended purpose
and increase the detectability of unacceptable performance. (ICH Q14)
VALIDATION STUDY
An evaluation of prior knowledge, data or deliberate experiments (i.e., validation tests) to
determine the suitability of an analytical procedure for the intended purpose. (ICH Q2)
VALIDATION TEST
Validation tests are deliberate experiments designed to authenticate the suitability of an
analytical procedure for the intended purpose. (ICH Q2)
MULTIVARIATE GLOSSARY
CALIBRATION SET
A set of data with matched known characteristics and measured analytical results. (ICH Q14)

ICH Q14 Guideline

DATA TRANSFORMATION
Mathematical operation on model input data to assume better correlation with the output data
and to simplify the model structure. (ICH Q14)
INDEPENDENT SAMPLE
Independent samples are samples not included in the calibration set of a multivariate model.
Independent samples can come from the same batch from which calibration samples are
selected. (ICH Q2)
INTERNAL TESTING
Internal testing is a process of checking if unique samples processed by the model yield the
correct predictions (qualitative or quantitative).
Internal testing serves as means to establish the optimal number of latent variables, estimate the
standard error and detect potential outliers. (ICH Q2)
INTERNAL TEST SET
A set of data obtained from samples that have physical and chemical characteristics that span a
range of variabilities similar to the samples used to construct the calibration set. (ICH Q14)
LATENT VARIABLES
Mathematically derived variables that are directly related to measured variables and are used in
further processing. (ICH Q2)
MODEL MAINTENANCE
The process of ensuring continued model performance over the lifecycle of a multivariate
model, which often includes outlier diagnostics and resulting actions for model redevelopment
or change in the maintenance plans. (ICH Q14)
MODEL VALIDATION
The process of determining the suitability of a model by challenging it with independent test
data and comparing the results against predetermined performance criteria. (ICH Q2)
MULTIVARIATE ANALYTICAL PROCEDURE
An analytical procedure where a result is determined through a multivariate calibration model
utilising more than one input variable. (ICH Q2)
OUTLIER DIAGNOSTIC
Tests that can identify unusual or atypical data in a multivariate analytical procedure. (ICH
Q14)
REFERENCE ANALYTICAL PROCEDURE
A separate analytical procedure used to obtain the reference values of the calibration and
validation samples for a multivariate analytical procedure. (ICH Q2)
REFERENCE SAMPLE
A sample representative of the test sample with a known value for the property of interest, used
for calibration. (ICH Q14)
ICH Q14 Guideline

VALIDATION SET
A set of data used to give an independent assessment of the performance of the calibration
model. (ICH Q2)
12. REFERENCES
ICH Q2 Validation of Analytical Procedures
ICH Q6A Specifications: Test Procedures and Acceptance Criteria For New Drug Substances
and New Drug Products: Chemical Substances
ICH Q6B Specifications: Test Procedures and Acceptance Criteria For
Biotechnological/Biological Products
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
ICH Q11 Development and Manufacture of Drug Substances
ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management
ICH M4Q The Common Technical Document For The Registration of Pharmaceuticals For
Human Use
ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation

ICH Q14 Guideline

13. ANNEX

### 13.1 Annex A: Examples of application of ICH Q14 principles

The examples provided in this Annex are for illustrative purposes only. Other approaches are
possible. They suggest how the concepts described in ICH Q14 could be applied and should not
be used as a template or the sole basis for a regulatory submission.
The examples have been created to illustrate:
• How analytical procedure performance characteristics, derived from the product
context and knowledge, could be summarised in an ATP;
• How performance characteristics described in the ATP could be applied to select a
suitable analytical technology, guide the development of an analytical procedure and
help define the analytical procedure control strategy;
• How to identify ECs for analytical procedures developed using elements of the
enhanced approach;
• How QRM and the adherence to associated criteria for relevant performance
characteristics and/or the subsequent execution of a bridging study can ensure the
post-change quality of the measured result and help to justify the respective reporting
categories for ECs and the post approval change management of analytical
procedures.
As described in Chapter 4 of ICH Q14, QRM can be used to evaluate the impact of prospective
changes for analytical procedures. The list below describes examples of risk factors and risk
reduction measures to identify the risks associated with the changes to an analytical procedure.
The outcome of the risk assessment (risk level: high, medium or low) feeds into the design and
extent of the studies needed to support the change.
Selected Risk (risk factors)
•
Relevance of the test
•
Potential clinical impact of the measured attribute (efficacy, safety,
pharmacokinetics and immunogenicity), e.g., controlling CQA vs. non CQA;
•
Extent of knowledge of the attribute;
•
Attribute ensured by other elements of the control strategy (testing or process
control);
•
Complexity of the technology
•
Platform technologies;
•
Novel vs. established technology (e.g., in pharmacopoeias);
•
Several attributes reported as a sum (e.g., charge variants for large
molecules);
•
Biological assays, cell-based assays, immunochemical assays;
•
Multi-attribute analytical procedure;
•
Multivariate analytical procedure;
•
Extent of the change
•
Change of one or several parameters outside the already proven acceptable
ranges;
•
Change of the analytical procedure within existing analytical procedure
performance characteristics and associated criteria;
•
Change to a new analytical procedure using a different technology;
•
Change to analytical procedure performance criteria (e.g., due to tightening a
specification limit).
ICH Q14 Guideline

Risk reduction
Risk reduction is defined in ICH Q9 as actions taken to lessen the probability of occurrence of
harm and the severity of that harm.
Different kinds of knowledge can lead to reduction of risk, for example:
•
Product and process knowledge
-
Knowledge about quality attributes of the drug substance/drug product and
acceptable ranges of CQAs;
-
Well justified analytical procedure performance criteria cover/link to CQAs
and their acceptable ranges;
-
Evidence to control the CQAs through the process parameter settings
-
Knowledge of the degradation pathways demonstrated by the analysis of
relevant stressed samples;
-
Other product knowledge (e.g., impurity profile, particle size and distribution);
• Analytical procedure understanding and analytical procedure control strategy
-
Knowledge about analytical procedure parameters and their impact on
measurement performance;
-
Proven analytical procedure robustness, e.g., harmonised procedures
(compendial tests);
-
Enhanced analytical procedure understanding (e.g., DoE studies) supporting
justification of acceptable ranges (e.g., PAR, MODR);
-
Other knowledge from development of analytical procedure;
-
System Suitability Test ensures relevant analytical procedure attributes;
-
Ongoing monitoring of analytical procedure output;
-
Clear link between signal and CQA to be measured (e.g., peak
characterisation available, specificity);
• Bridging strategy for changes to analytical procedures
-
Availability of reference material, relevant historical and or stressed samples
to support analytical procedure output assessment against performance
criteria (demonstrated ability to control the CQA);
-
Comparison to output of previous analytical procedure (understanding and
acceptance of risk for potential differences);
-
Demonstrated understanding of risks associated with parameter changes and
potential interactions with other parameters;
-
Prior experience with similar changes, analytes or technologies including
platform analytical procedures.

ICH Q14 Guideline

#### 13.1.1 Measurement of Stereoisomers as Specific Process Related Impurities in a Small Molecule

Drug Substance (DS)

Introduction and Background
“Sakuratinib Maleate” is a small molecule DS with multiple chiral centres. The chirality of the
molecule, its degradation pathway and the impurities are well characterised. From this
knowledge and the established manufacturing process controls, the six stereoisomers (Impurity
A-F) were found to be potentially present in the final product.
Table 1: Analytical target profile
Intended Purpose
Quantitation of the six stereoisomers A-F in Sakuratinib Maleate DS for release testing

Link to CQA (Stereoisomeric Purity)
The analytical procedure should allow for the quantitation of the individual stereoisomers A-F and determination of
the total sum to verify the CQA Stereoisomeric Purity ≥99.0%
Characteristics of the Reportable Results
Performance
Characteristics
Acceptance Criteria
Rationale
Accuracy
80–120% average recovery of spiked DS with Impurities
A-E (specified at NMT 0.1% each)
90–110% average recovery of spiked DS with Impurity F
(specified at NMT 0.5%)

For example, at a
specification level of 0.1%,
20% bias would lead to a
variation of the analytical
result of 0.02%, which was
found acceptable for a release
decision.
In a similar fashion, values
for precision were derived.
The recovery criteria for
accuracy were set with
respect to the reported result
and taking into consideration
any correction or response
factors
Precision
Intermediate Precision RSD:
Impurities A–E ≤15%
Impurity F ≤10%
Specificity
Analytical procedure should be able to quantitate impurities
A–F in presence of other likely process related substances
or DS degradation products with an acceptable bias of not
more than 0.02%
Potential interference with
quantitation of specified
impurities by other regular
components in the sample
Reportable Range
Impurities A–E: at least 0.05–0.12%
Impurity F: at least 0.05–0.6%
Reporting threshold to 120%
of specification limit

Technology Selection
Multiple analytical technologies are available for the separation of stereoisomers. In this
example, HPLC was chosen because development studies showed good potential for separation
of stereoisomers. As detection mode, UV detection was selected as it was known that the
molecule had sufficient UV absorption properties.

Analytical Procedure Development
The chiral HPLC procedure for quantitation of stereoisomers was developed using enhanced
principles. Below is a summary of the activities conducted during enhanced development.
•
An understanding of the chemistry, process, and impurities that have potential to be
present in the drug substance was established;
•
Reference materials were made available for development and validation;
ICH Q14 Guideline

•
Conducted risk assessment and evaluating prior knowledge to identify the analytical
procedure parameters that can impact performance of the procedure;
•
Conducted modelling and multi-variate experiments including robustness testing to
explore ranges and interactions between identified analytical procedure parameters;
•
Defined analytical procedure control strategy based on procedure understanding
including set-points for relevant analytical procedure parameters and SST.
Analytical Procedure
For the purpose of this example, a summary of the analytical procedure is provided below.
This does not reflect the entirety of the analytical procedure description in the dossier.
Table 2: Summary of the analytical procedure description

Column
Chiral Column, Amylose tris-(3,5-dimethylphenylcarbamate), immobilised on
porous, spherical, silica particles, 4.6 mm ID x 250 mm, 3 µm
Mobile Phase
n-hexane / ethanol / TFA (80/20/0.1)
Flow Rate
1 mL/min
Column temperature
30°C
Detection
UV 214 nm
Injection Volume
5 µL
Standard/Sample
Concentration
1.0 mg/mL
System Suitability Tests
Controlled Parameters

Resolution between critical peak pair: DS Main Peak
and Impurity D ≥ 2.0
Column, Temperature*, Mobile Phase, Flow Rate
S/N at QL; DS at 0.05% >10
Injection Volume, Column, Mobile Phase,
Standard/Sample Concentration, Detection
Wavelength
Repeatability of injection of DS at 0.5% level ≤ 5%
Injection Volume, Mobile Phase
* For example, the retention time models built from data collected during analytical procedure development
screens were used to assess the robustness of temperature and other parameters, that could potentially affect
the performance characteristics (e.g., specificity). The in silico robustness was verified experimentally by
confirming resolution at the centre point and design points that generated the minimum and maximum main
peak retention time.

Analytical Procedure Validation
After the analytical procedure development was finalised and the analytical procedure control
strategy established, a validation study was planned and completed according to the ICH Q2
guideline.

Description of Established Conditions (ECs), Reporting Categories, and Justifications
The applicant proposed and justified established conditions and reporting categories, as part of
the submission. For the purpose of this example, Table 3 describes the proposed ECs, their
proposed reporting categories and examples of parameters that are not ECs.
Note: The extent of ECs and associated reporting categories listed in this table depend on the
extent of knowledge gained, information and justification provided in the dossier. The dossier
is subject to regulatory review. The information provided in this example is only part of the
knowledge available that will be submitted and is provided for illustrative purposes only. The
extent of ECs (EC or not EC designation), actual reporting categories, and data requirements
ICH Q14 Guideline

may differ by region. Depending on the nature and extent of the change (e.g., change to a
different technology), a PACMP may be required.

Table 3: Evaluated risk, proposed established conditions and proposed reporting
categories
Established Condition
Overall
Risk
Category
Proposed
Reporting
Category1)
Comment
Performance Characteristics and
Criteria as described in the ATP:
Accuracy, Precision, Specificity,
Range (see Annex A , Table 1)
High
PA

The performance characteristics and criteria
ensure the quality of the reportable result and
link to the CQA.
If widening of the performance criteria is
necessary, it will be reported as PA
Technology: Chiral Liquid
Chromatography

Suitable chiral separation technique to
meet performance characteristics
defined in ATP

Medium
NM

A technique that meets the performance
characteristics and criteria ensures the quality of
the reportable result and link to the CQA.
There is a strong understanding between product
knowledge, intended purpose, and the analytical
procedure performance established to enable the
design of future bridging studies.
A change resulting in a widening of the
specification acceptance criteria might require a
higher reporting category
System Suitability Test and parameter-
control relationship (see Annex A,
Table 2)

Medium
NL/NM
SST was developed for the LC procedure based
on a risk analysis and ensures adherence to the
performance characteristics and criteria. Control
relationships were established through prior
knowledge (general principles of technique) and
during procedure development.
If the SST criteria are widened the reporting
category would be higher
LC Column: Amylose tris-(3,5-
dimethylphenylcarbamate),
immobilised on porous, spherical silica
particles

Mobile Phase Components: n-Hexane,

Method of detection: UV 214 nm
Low
NL/NM
The LC column, mobile phase components and
mode of detection are the main parameters,
defining the separation mechanism and
detection. Changing these parameters may result
in the need to adapt the SST

The other analytical procedure parameters defined as ECs are omitted for the purpose of this example

The following conditions are examples of parameters that are not ECs2):

Ratio of mobile phase components: n-
Hexane/Ethanol/TFA (80/20/0.1)

Instrumental conditions:
Temperature: 30°C

Column length, packing particle size
Low

-

These parameters are controlled by the SST.
Robustness testing supported by modelling was
performed at the centre point and the extrema
that generated the minimum and maximum main
band retention time
Preparation of test solutions and
reference materials: 1 mg/mL DS in
mobile phase
Low
-
The performance over the working range has
been demonstrated through the linearity
experiments during validation
1) PA: Prior Approval, NM: Notification Moderate; NL: Notification Low (as per ICH Q12 definitions)
2) Depending on the region, some of this information is included in an approval letter

ICH Q14 Guideline

Change Management and Bridging Strategy
The change described below is an example of one that could occur during the lifecycle of a
product and analytical procedure. When the product was initially submitted and approved,
Supercritical Fluid Chromatography (SFC) was not selected as the analytical technique due to
unavailability in the commercial facility. Years after approval, the applicant desires to change
the technique to SFC as it is a more environmentally-friendly technology and is now available
at the commercial site.
For this change, following development of the SFC procedure the applicant will perform a
structured risk assessment to evaluate potential impact on the performance characteristics and
the link to CQA (stereoisomeric purity) as defined in the ATP. As an outcome of the risk
assessment, experimental bridging studies to demonstrate adherence to the performance
characteristics and associated criteria will be performed. Validation of the new analytical
procedure and comparative analysis of representative samples and reference materials will be
performed.
The applicant should not implement the new analytical procedure using the predefined reporting
category unless adherence to the performance characteristics and associated criteria defined in
the ATP is demonstrated during the bridging studies. If the precondition of adherence to the ATP
cannot be met, a higher reporting category would apply.
The example in Annex A, Figure 1 illustrates a post-approval change in technique as well as the
steps an applicant would follow when implementing the change. The information in the table
above (ECs and reporting categories) would need to be agreed upon up front with the regulatory
authority.

ICH Q14 Guideline

*[Figure 1: Example of work process of applicant to change an approved analytical]*

procedure

ICH Q14 Guideline

#### 13.1.2 Measurement of Potency for an anti-TNF-alpha Monoclonal Antibody

Introduction and Background
The example presented refers to the measurement of the relative potency of the drug, in this
case an anti-TNF-alpha monoclonal antibody, in drug substance and in drug product at release
and for stability testing.
Assumptions for the example:
• Mode of action: the neutralisation of the biological activity of soluble TNF-alpha by
preventing TNF-alpha from binding to the TNF-alpha receptor;
• Fc-effector functions are out of scope;
• Specification limits for the relative potency: 80% to 125% compared to reference
material;
• Potency assay to be developed is able to detect a change and/or a shift in potency upon
forced degradation.

Table 4: Analytical target profile
Intended Purpose
Measurement of the potency of an anti-TNF-alpha monoclonal antibody in drug substance and in drug product at
release and for stability testing.
Link to CQA (biological activity)
The mode of action of the drug is the neutralisation of the biological activity of soluble TNF-alpha by preventing
TNF-alpha from binding to the TNF-alpha receptor. Target acceptance criteria: 80% to 125% relative potency1)
Characteristics of the Reportable Result
Performance
Characteristics
Acceptance criteria
Rationale
Accuracy
Accuracy is assessed via a linearity experiment that covers
the reportable range. No trend in relative bias is observed
over the tested relative potency range

The 95% confidence interval of the slope of the fitted
regression line between theoretical and measured potency
falls within a range of 0.8 to 1.25

The upper and lower 90% confidence interval for the relative
bias calculated at each potency level is not more than 20%1)
Parameters are assessed based
on compendial guidance

The acceptance criteria are
determined considering the
intended purpose of the
measurement

Selected performance
characteristic ensures that the
intended analytical procedure
delivers the quality of the
reportable result
Precision
Upper 95% confidence interval for the average intermediate
precision across levels across the reportable range (95% CI %
geometric coefficient of variation) is not more than 20%1)
Specificity
Analytical procedure is specific for the intended mechanism
of action of the active ingredient
Critical characteristic of a
bioassay to ensure specificity
towards the targeted
biological activity
No interference from relevant process related impurities or
matrix components
For example, process related
and matrix components do
not significantly affect the
characteristics of the dose
response curve
Assay is stability indicating i.e., capable of detecting a
change in potency and/or a change in the shape of the dose
response curve, confirmed using forced degraded samples
To ensure that the product
remains within specification
over its shelf-life
Reportable
range
The potency range is the range that meets accuracy and
precision. It should include the specification range (80% to
120% of the specification range in this case corresponding to
64% to 150% for a specification of 80% to 125% relative
potency1))
Stated range for which the
required accuracy and
precision characteristics are
demonstrated
1) Individual values are just an example and can be different from product to product.
ICH Q14 Guideline

Technology Selection
Binding assays and cell-based bioassays are suitable technologies for the measurement of the
relative potency of an anti-TNF-alpha monoclonal antibody when considering the ATP above.
The two assays rely on the binding of the anti-TNF-alpha monoclonal antibody to the soluble
TNF-alpha. While the signal of a binding assay directly measures the binding, the cell-based
assay may target a later stage event in the signalling cascade. Out of different formats of cell-
based assay, the cell-based proliferation assay was chosen as it is widely used and a well
characterised cell line was available.
Analytical Procedure Development
The development of the analytical procedure described has been performed using an enhanced
approach and was based on extensive knowledge of the molecule and relative potency assays,
considering the following points for example:
• Performance characteristics and associated criteria for the analytical procedure defined
in the ATP;
• Extensive analytical procedure understanding gained from prior knowledge and
development studies guided by QRM principles. Factors considered during risk
assessment are shown in Annex A, Figure 2: e.g.,
•
The cell and its performance (cell density, cell viability, number of passages);
•
Stability indicating properties using forced degradation samples;
• Robustness evaluation was conducted and its outcome was reflected in the analytical
procedure control strategy.

*[Figure 2: Ishikawa diagram]*

Analytical Procedure
For the purpose of this example, a summary of the analytical procedure is provided below.
This does not reflect the entirety of the procedure description in the dossier.

ICH Q14 Guideline

Table 5 Analytical procedure description
Unit Operation
Description
Cell preparation
Prepare a suspension of WEHI-164 cells containing 1x106 cells per
millilitre, using assay medium containing 2 µg/mL of actinomycin D
Reference
solution
and
test
solution preparation
Included in analytical procedure description in the dossier but not listed
in this table

Plate preparation
Plating cells
Absorbance measurement
Calculations
Solutions & reagents preparation
WEHI-164 cells (ATCC), TNF-alpha solution of suitable concentration,
assay and culture medium including components and concentrations-
Actinomycin D, Tetrazolium salt WST-8
Analytical Procedure Control Strategy
System suitability test
1. The dose-response curve obtained for the reference standard curve
corresponds to a sigmoid curve with upper and lower plateaus
corresponding to ‘cell only control’ and ‘cell + TNF-alpha control’,
respectively
2. The dose-response curve obtained for the test sample corresponds to a
sigmoid curve with upper and lower plateaus corresponding to ‘cell
only control’ and ‘cell treated with TNF-alpha control’, respectively.
3. The coefficient of determination calculated for each standard curve
(r2) is not less than 0.97 *
4. Maximum value (cell only) to minimum value (TNF-alpha control)
ratio: minimum 3.0*
Sample suitability assessment
Assessment of similarity/parallelism:
- The upper asymptote ratio (Astd/Atest): 0.8–1.2*
- The lower asymptote ratio (Dstd/Dtest): 0.8–1.2*
- The Hill slope ratio (Bstd/Btest): 0.8–1.2*
- The upper to lower asymptote ratio ((D–A)std/(D–A)test): 0.8–1.2*
* The ways of assessing of similarity/parallelism as well as individual values are just examples and can be
different from product to product.

Analytical Procedure Validation
After the analytical procedure development was finalised and the analytical procedure control
strategy established, a validation study was planned and completed according to the
recommendations in ICH Q2.

Description of Established Conditions, Reporting Categories, and Justifications
The applicant proposed and justified established conditions and reporting categories, as part of
the submission. For the purpose of this example, Annex A Table 6 describes a portion of the
proposed ECs, their proposed reporting and an example of a parameter that is not an EC.
Note: The extent of ECs and associated reporting categories listed in this table depend on the
extent of knowledge gained, information and justification provided in the dossier. The dossier
is subject to regulatory review. The information provided in this example is only part of the
knowledge available that will be submitted and is provided for illustrative purposes only. The
extent of ECs (EC or not EC designation), actual reporting categories, and data requirements
may differ by region. Depending on the nature and extent of the change (e.g., change to a
different technology), a PACMP may be required.

ICH Q14 Guideline

Table 6: Evaluated risk, proposed established conditions and proposed reporting
categories

Established condition
Overall
Risk
Category
Proposed
Reporting
Category1)
Comment
Performance characteristics
and associated criteria as
defined in the ATP (Annex
A Table 4)
High
PA
The performance characteristics and criteria ensure
the quality of the reportable result and link to the
CQA. Widening of performance characteristics
and criteria could have an impact on the control of
the CQA
Technology (principle)
Cell Based Assay
High or
Medium
PA or NM
Adherence to performance characteristics and
criteria ensured by control strategy and defined
bridging strategy (see below) to assess impact of
changes
Change would be reported as Notification Moderate
if no impact of the change on the specification
acceptance criteria and as Prior Approval if there is
an impact on the specification acceptance criteria
Analytical procedure control strategy elements (SST 1-4, sample suitability assessment)
System suitability test
(see Annex A Table 5)
Medium
NM2)
Performance of the analytical procedure is ensured
by
• Direct control of individual analytical procedure
steps through analytical procedure control strategy
elements listed in Annex A Table 5 (and the
dossier)
• Defined analytical procedure control strategy
elements which ensures the adherence to the ATP
• Adherence to the performance characteristics and
criteria after a change of analytical procedure
control strategy elements

If assurance of performance of the analytical
procedure cannot be demonstrated, the change
needs to be reported as Prior Approval
Sample suitability
assessment
(see Annex A Table 5)
Medium
NM2)
Cell Preparation
Cell line:
WEHI-164 cells (ATCC)
Medium
NM
Based on demonstrated understanding of the mode
of action (link to CQA) the suitability of the
responsive cell line will be confirmed by
responding to the TNF-alpha (survival of the cell
in presence of the drug and cell death without
drug)

Adherence to ATP ensured by control strategy and
defined bridging strategy (see below) to assess
impact of changes

System suitability test ensures the suitability of the
cell line and its performance (number of passages,
confluency, cell counting, cell viability, signal
amplitude, shape of the response curve)

ICH Q14 Guideline

Established condition
Overall
Risk
Category
Proposed
Reporting
Category1)
Comment
Preparation of cells:
sub culturing
Low
NL
Sufficient cell performance to detect changes in the
quality of the drug is ensured by:
• System suitability covers the suitability of the
cell preparation (number of passages,
confluency, cell counting, cell viability, signal
amplitude, shape of the response curve)
• Changes in cell metabolism that impact
performance of the analytical procedure and
link to CQA will be detected
• Changes that lead to insufficient cell
performance will not be implemented as they
could have an impact on the defined
performance characteristics and would require
prior approval
Analytical procedure control strategy ensures
adherence to performance characteristics and
criteria. The extent of the bridging study will
depend on the extent of the change
Medium composition:
RPMI 1640, L-glutamine,
heat-inactivated foetal
bovine serum, and a suitable
antibiotic
Low
NL
Preparation of a suspension
of WEHI-164 cells
containing 1x106 cells per
millilitre, using assay
medium containing 2 µg/mL
of actinomycin D.

Low
NL
The other analytical procedure parameters defined as ECs are omitted for the purpose of this example
The following is an example of a parameter that is not an EC:
Plating format
Low
-
No impact on assay output based on development
data
1) PA: Prior Approval, NM: Notification Moderate; NL: Notification Low (as per ICH Q12 definitions)
2) Based on regional requirements the proposed reporting category may need to be elevated to PA

Change Assessment and Bridging Strategy
For every change, the applicant will perform a risk assessment to evaluate potential impact on
the performance characteristics and the link to CQA (biological activity) as defined in the
respective ATP. The outcome of the risk assessment informs the extent of the bridging studies
used to demonstrate adherence to the performance characteristics and associated criteria. These
can include, if necessary, full or partial revalidation of the analytical procedure performance
characteristics affected by the change and/or comparative analysis of representative samples
and reference material.
The applicant should not implement the new analytical procedure using the predefined reporting
category unless adherence to the performance characteristics and associated criteria defined in
the ATP are demonstrated during the bridging studies. If the precondition of adherence to the
ATP cannot be met, a higher reporting category would apply.
The example in Annex A Figure 3 illustrates a post-approval change in the cell preparation from
subculture to ready to use cells and includes the steps an applicant would follow when actually
implementing the change.
The ECs and reporting categories (see Annex A Table 6) would need to be proposed following
ICH Q14 Figure 2 and agreed up front with the regulatory authority.
ICH Q14 Guideline

*[Figure 3: Example of work process of applicant to change an approved analytical]*

procedure

ICH Q14 Guideline

### 13.2 Annex B: Example of multivariate model lifecycle components

Example 1
Example 2
Example 3
Model
Description
On-line NIR to determine blending
ranges to achieve blend uniformity
during development
Measurement of Content Uniformity
and Assay of uncoated tablets by NIR
used for product release
Glucose Raman model used for qualitative
identification testing on incoming raw
material release for GMP use
Model Category - Low Impact
Model Category - High Impact
Model Category - High impact
User requirements
Defined model requirements (e.g.,
ATP)
Defined model requirements (e.g., ATP)
Risk
Assessment
Initial assessment based on existing
knowledge, laboratory and pilot
studies, or DoE, as appropriate
Formal risk assessment based on
knowledge gained during initial
development
Formal risk assessment with knowledge
gained during initial development
Model
Development -
Calibration
Scientifically sound approach based
on laboratory and pilot data and
previous experience
Formal design-based approach (e.g.,
DoE) covering appropriate ranges of
relevant variability sources with
established acceptance criteria that are
suitable for the intended purpose
Formal design-based approach covering
appropriate ranges of relevant variability
sources (raw material, lots, packaging,
instrument-to-instrument, user, software
limitation) with established acceptance
criteria that are suitable for the intended
purpose. Establish an identification
threshold that has the same probability of
detection as the existing analytical
procedure and a suitable alternative
analytical procedure should the Raman
analytical procedure fail
Validation
Assess specificity and robustness,
optionally assess linearity and/or
precision
Full validation covering applicable
performance characteristics across
reportable ranges with established
acceptance criteria (ICH Q2)
Full validation covering applicable
performance characteristics across
reportable ranges with established
acceptance criteria (ICH Q2). Include
establishing suitable comparability of
Raman procedure to existing analytical
procedure for release (can be reference
analytical procedure)
Performance
Monitoring
Routine monitoring - maintain data
sources (instruments), automation
connectivity, and data integrity
Routine monitoring - maintain data
sources (instruments), automation
connectivity, and data integrity
Routine monitoring - maintain data
sources (instruments), automation
connectivity, and data integrity
Real-time diagnostics - implement
initial diagnostics to confirm model
performance in real-time
Real-time diagnostics - implement
routine diagnostics to confirm model
performance in real-time
Real-time diagnostics - implement routine
diagnostics to confirm model performance
in real-time
Periodic monitoring - if applicable,
compare model predicted results to
reference analytical procedure at a
frequency that is scientifically
justified or on an event driven basis
as needed
Periodic monitoring - compare model
predicted results to reference
analytical procedure at a frequency
that is scientifically justified or on an
event driven basis
Periodic monitoring - compare model
predicted results to reference analytical
procedure at a frequency that is
scientifically justified or on an event
driven basis
Model
Maintenance
Model Update - updates are common
during the process development
stage as new experimental data
becomes available
Model Update - updates should be
triggered based on Model Monitoring
and Maintenance Strategy
Model Update - updates should be
triggered based on Model Monitoring and
Maintenance Strategy
Change Management per PQS
Change Management per PQS. with
regulatory communication as required
Change Management per PQS, with
regulatory communication as required

---

### Document: ICH Q8R2 Complete (ICH)

# ICH Q8(R2) Pharmaceutical Development: Pharmaceutical Development Guideline

=== PAGE 1 ===

 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL
REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED TRIPARTITE GUIDELINE

PHARMACEUTICAL DEVELOPMENT
Q8(R2)

Current Step 4 version
dated August 2009

This Guideline has been developed by the appropriate ICH Expert Working Group
and has been subject to consultation by the regulatory parties, in accordance with the
ICH Process.  At Step 4 of the Process the final draft is recommended for adoption to
the regulatory bodies of the European Union, Japan and USA.

=== PAGE 2 ===

Q8(R2)
Document History

First
Codification
History
Date
Parent Guideline: Pharmaceutical Development
Q8
Approval of the Guideline by the Steering Committee under
Step 2 and release for public consultation.
November
2004
Q8
Approval of the Guideline by the Steering Committee under
Step 4 and recommendation for adoption to the three ICH
regulatory bodies.
November
2005
Annex to the Parent Guideline: Pharmaceutical Development
Annex to Q8
Approval of the Annex by the Steering Committee under Step
2 and release for public consultation.
November
2007
Annex to Q8
Approval of the Annex by the Steering Committee under Step
4 and recommendation for adoption to the three ICH
regulatory bodies.
November
2008
Addition of Annex to the Parent Guideline

Q8(R1)
The parent guideline “Pharmaceutical Development” was
recoded Q8(R1) following the addition of the Annex to the
parent guideline.
November
2008
Current Step 4 version

Q8(R2)
Corrigendum to titles of “Figure 2a” and “Figure 2b” of
“Example 2” on page 23.
August
2009

=== PAGE 3 ===
i
PHARMACEUTICAL DEVELOPMENT
ICH Harmonised Tripartite Guideline

TABLE OF CONTENTS
PART I:
PHARMACEUTICAL DEVELOPMENT
1.
INTRODUCTION.................................................................................................. 1
1.1
Objective of the Guideline ........................................................................................1
1.2
Scope .........................................................................................................................1
2.
PHARMACEUTICAL DEVELOPMENT............................................................ 1
2.1
Components of the Drug Product.............................................................................3
2.1.1 Drug Substance............................................................................................ 3
2.1.2 Excipients ..................................................................................................... 3
2.2
Drug Product ............................................................................................................3
2.2.1 Formulation Development............................................................................ 3
2.2.2 Overages ....................................................................................................... 4
2.2.3 Physicochemical and Biological Properties ................................................. 4
2.3
Manufacturing Process Development ......................................................................5
2.4
Container Closure System........................................................................................6
2.5
Microbiological Attributes........................................................................................6
2.6
Compatibility............................................................................................................7
3.
GLOSSARY ............................................................................................................ 7

PART II:
ANNEX TO PHARMACEUTICAL DEVELOPMENT
1.
INTRODUCTION.................................................................................................. 9
2.
ELEMENTS OF PHARMACEUTICAL DEVELOPMENT ............................ 10
2.1
Quality Target Product Profile...............................................................................10
2.2
Critical Quality Attributes.....................................................................................11

### 2.3 Risk Assessment: Linking Material Attributes and Process Parameters to Drug

Product CQAs .........................................................................................................11

=== PAGE 4 ===

ii
2.4
Design Space...........................................................................................................12
2.4.1 Selection of Variables................................................................................. 12
2.4.2 Describing a Design Space in a Submission.............................................. 12
2.4.3 Unit Operation Design Space(s)................................................................. 12
2.4.4 Relationship of Design Space to Scale and Equipment............................. 12
2.4.5 Design Space Versus Proven Acceptable Ranges ....................................... 13
2.4.6 Design Space and Edge of Failure............................................................. 13
2.5
Control Strategy .....................................................................................................13
2.6 Product Lifecycle Management and Continual Improvement...............................14
3.
SUBMISSION OF PHARMACEUTICAL DEVELOPMENT AND RELATED
INFORMATION IN COMMON TECHNICAL DOCUMENTS (CTD)
FORMAT .............................................................................................................. 14
3.1 Quality Risk Management and Product and Process Development......................15
3.2
Design Space...........................................................................................................15
3.3
Control Strategy .....................................................................................................15
3.4
Drug Substance Related Information ....................................................................15
4.
GLOSSARY .......................................................................................................... 16
Appendix 1. Differing Approaches to Pharmaceutical Development ...................................18
Appendix 2. Illustrative Examples........................................................................................19

=== PAGE 5 ===

PART I:
PHARMACEUTICAL DEVELOPMENT
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
on 10 November 2005, this guideline is recommended for
adoption to the three regulatory parties to ICH
1.
INTRODUCTION

### 1.1 Objective of the Guideline

This guideline describes the suggested contents for the 3.2.P.2 (Pharmaceutical
Development) section of a regulatory submission in the ICH M4 Common Technical
Document (CTD) format.
The Pharmaceutical Development section provides an opportunity to present the
knowledge gained through the application of scientific approaches and quality risk
management (for definition, see ICH Q9) to the development of a product and its
manufacturing process. It is first produced for the original marketing application and
can be updated to support new knowledge gained over the lifecycle* of a product. The
Pharmaceutical Development section is intended to provide a comprehensive
understanding of the product and manufacturing process for reviewers and
inspectors. The guideline also indicates areas where the demonstration of greater
understanding of pharmaceutical and manufacturing sciences can create a basis for
flexible regulatory approaches. The degree of regulatory flexibility is predicated on
the level of relevant scientific knowledge provided.

### 1.2 Scope

This guideline is intended to provide guidance on the contents of Section 3.2.P.2
(Pharmaceutical Development) for drug products as defined in the scope of Module 3
of the Common Technical Document (ICH guideline M4). The guideline does not apply
to contents of submissions for drug products during the clinical research stages of
drug development. However, the principles in this guideline are important to consider
during those stages as well. This guideline might also be appropriate for other types
of products. To determine the applicability of this guideline to a particular type of
product, applicants can consult with the appropriate regulatory authorities.
2.
PHARMACEUTICAL DEVELOPMENT
The aim of pharmaceutical development is to design a quality product and its
manufacturing process to consistently deliver the intended performance of the
product. The information and knowledge gained from pharmaceutical development
studies and manufacturing experience provide scientific understanding to support the
establishment of the design space*, specifications, and manufacturing controls.
Information from pharmaceutical development studies can be a basis for quality risk
management. It is important to recognize that quality* cannot be tested into products;

* See Glossary for definition

=== PAGE 6 ===
Pharmaceutical Development

i.e., quality should be built in by design. Changes in formulation and manufacturing
processes during development and lifecycle management should be looked upon as
opportunities to gain additional knowledge and further support establishment of the
design space. Similarly, inclusion of relevant knowledge gained from experiments
giving unexpected results can also be useful. Design space is proposed by the
applicant and is subject to regulatory assessment and approval. Working within the
design space is not considered as a change. Movement out of the design space is
considered to be a change and would normally initiate a regulatory post approval
change process.
The Pharmaceutical Development section should describe the knowledge that
establishes that the type of dosage form selected and the formulation proposed are
suitable for the intended use. This section should include sufficient information in
each part to provide an understanding of the development of the drug product and its
manufacturing process. Summary tables and graphs are encouraged where they add
clarity and facilitate review.
At a minimum, those aspects of drug substances, excipients, container closure
systems, and manufacturing processes that are critical to product quality should be
determined and control strategies justified. Critical formulation attributes and
process parameters are generally identified through an assessment of the extent to
which their variation can have impact on the quality of the drug product.
In addition, the applicant can choose to conduct pharmaceutical development studies
that can lead to an enhanced knowledge of product performance over a wider range of
material attributes, processing options and process parameters. Inclusion of this
additional information in this section provides an opportunity to demonstrate a
higher degree of understanding of material attributes, manufacturing processes and
their controls. This scientific understanding facilitates establishment of an expanded
design space. In these situations, opportunities exist to develop more flexible
regulatory approaches, for example, to facilitate:
•
risk-based regulatory decisions (reviews and inspections);
•
manufacturing process improvements, within the approved design space
described in the dossier, without further regulatory review;
•
reduction of post-approval submissions;
•
real-time quality control, leading to a reduction of end-product release testing.
To realise this flexibility, the applicant should demonstrate an enhanced knowledge of
product performance over a range of material attributes, manufacturing process
options and process parameters. This understanding can be gained by application of,
for example, formal experimental designs*, process analytical technology (PAT)*,
and/or prior knowledge. Appropriate use of quality risk management principles can be
helpful in prioritising the additional pharmaceutical development studies to collect
such knowledge.
The design and conduct of pharmaceutical development studies should be consistent
with their intended scientific purpose. It should be recognized that the level of

* See Glossary for definition

=== PAGE 7 ===
Pharmaceutical Development

knowledge gained, and not the volume of data, provides the basis for science-based
submissions and their regulatory evaluation.

### 2.1 Components of the Drug Product

#### 2.1.1 Drug Substance

The physicochemical and biological properties of the drug substance that can
influence the performance of the drug product and its manufacturability, or were
specifically designed into the drug substance (e.g., solid state properties), should be
identified and discussed.  Examples of physicochemical and biological properties that
might need to be examined include solubility, water content, particle size, crystal
properties, biological activity, and permeability. These properties could be inter-
related and might need to be considered in combination.
To evaluate the potential effect of drug substance physicochemical properties on the
performance of the drug product, studies on drug product might be warranted. For
example, the ICH Q6A Specifications: Test Procedures and Acceptance Criteria for
New Drug Substances and New Drug Products: Chemical Substances describes some
of the circumstances in which drug product studies are recommended (e.g., Decision
Tree #3 and #4 (Part 2)). This approach applies equally for the ICH Q6B
Specifications: Test Procedures and Acceptance Criteria for Biotechnology/Biological
Products. The knowledge gained from the studies investigating the potential effect of
drug substance properties on drug product performance can be used, as appropriate,
to justify elements of the drug substance specification (3.2.S.4.5).
The compatibility of the drug substance with excipients listed in 3.2.P.1 should be
evaluated. For products that contain more than one drug substance, the compatibility
of the drug substances with each other should also be evaluated.

#### 2.1.2 Excipients

The excipients chosen, their concentration, and the characteristics that can influence
the drug product performance (e.g., stability, bioavailability) or manufacturability
should be discussed relative to the respective function of each excipient. This should
include all substances used in the manufacture of the drug product, whether they
appear in the finished product or not (e.g., processing aids). Compatibility of
excipients with other excipients, where relevant (for example, combination of
preservatives in a dual preservative system), should be established. The ability of
excipients
(e.g.,
antioxidants,
penetration
enhancers,
disintegrants,
release
controlling agents) to provide their intended functionality, and to perform throughout
the intended drug product shelf life, should also be demonstrated. The information on
excipient performance can be used, as appropriate, to justify the choice and quality
attributes of the excipient, and to support the justification of the drug product
specification (3.2.P.5.6).
Information to support the safety of excipients, when appropriate, should be cross-
referenced (3.2.P.4.6).

### 2.2 Drug Product

#### 2.2.1 Formulation Development

A summary should be provided describing the development of the formulation,
including identification of those attributes that are critical to the quality of the drug

=== PAGE 8 ===
Pharmaceutical Development

product, taking into consideration intended usage and route of administration.
Information from formal experimental designs can be useful in identifying critical or
interacting variables that might be important to ensure the quality of the drug
product.
The summary should highlight the evolution of the formulation design from initial
concept up to the final design. This summary should also take into consideration the
choice of drug product components (e.g., the properties of the drug substance,
excipients, container closure system, any relevant dosing device), the manufacturing
process, and, if appropriate, knowledge gained from the development of similar drug
product(s).
Any excipient ranges included in the batch formula (3.2.P.3.2) should be justified in
this section of the application; this justification can often be based on the experience
gained during development or manufacture.
A summary of formulations used in clinical safety and efficacy and in any relevant
bioavailability or bioequivalence studies should be provided. Any changes between the
proposed commercial formulation and those formulations used in pivotal clinical
batches and primary stability batches should be clearly described and the rationale
for the changes provided.
Information from comparative in vitro studies (e.g., dissolution) or comparative in
vivo studies (e.g., bioequivalence) that links clinical formulations to the proposed
commercial formulation described in 3.2.P.1 should be summarized and a cross-
reference to the studies (with study numbers) should be provided. Where attempts
have been made to establish an in vitro/in vivo correlation, the results of those
studies, and a cross-reference to the studies (with study numbers), should be provided
in this section. A successful correlation can assist in the selection of appropriate
dissolution acceptance criteria, and can potentially reduce the need for further
bioequivalence studies following changes to the product or its manufacturing process.
Any special design features of the drug product (e.g., tablet score line, overfill, anti-
counterfeiting measure as it affects the drug product) should be identified and a
rationale provided for their use.

#### 2.2.2 Overages

In general, use of an overage of a drug substance to compensate for degradation
during manufacture or a product’s shelf life, or to extend shelf life, is discouraged.
Any overages in the manufacture of the drug product, whether they appear in the
final formulated product or not, should be justified considering the safety and efficacy
of the product. Information should be provided on the 1) amount of overage, 2) reason
for the overage (e.g., to compensate for expected and documented manufacturing
losses), and 3) justification for the amount of overage. The overage should be included
in the amount of drug substance listed in the batch formula (3.2.P.3.2).

#### 2.2.3 Physicochemical and Biological Properties

The physicochemical and biological properties relevant to the safety, performance or
manufacturability of the drug product should be identified and discussed. This
includes the physiological implications of drug substance and formulation attributes.
Studies could include, for example, the development of a test for respirable fraction of
an inhaled product. Similarly, information supporting the selection of dissolution vs.

=== PAGE 9 ===
Pharmaceutical Development

disintegration testing, or other means to assure drug release, and the development
and suitability of the chosen test, could be provided in this section. See also ICH Q6A
Specifications: Test Procedures And Acceptance Criteria For New Drug Substances
And New Drug Products: Chemical Substances; Decision Tree #4 (Part 3) and Decision
Tree #7 (Part 1) or ICH Q6B Specifications: Test Procedures and Acceptance Criteria
for Biotechnology/Biological Products. The discussion should cross-reference any
relevant stability data in 3.2.P.8.3.

### 2.3 Manufacturing Process Development

The selection, the control, and any improvement of the manufacturing process
described in 3.2.P.3.3 (i.e., intended for commercial production batches) should be
explained. It is important to consider the critical formulation attributes, together with
the available manufacturing process options, in order to address the selection of the
manufacturing process and confirm the appropriateness of the components.
Appropriateness of the equipment used for the intended products should be discussed.
Process development studies should provide the basis for process improvement,
process validation, continuous process verification* (where applicable), and any
process control requirements. Where appropriate, such studies should address
microbiological as well as physical and chemical attributes. The knowledge gained
from process development studies can be used, as appropriate, to justify the drug
product specification (3.2.P.5.6).
The manufacturing process development programme or process improvement
programme should identify any critical process parameters that should be monitored
or controlled (e.g., granulation end point) to ensure that the product is of the desired
quality.
For those products intended to be sterile an appropriate method of sterilization for the
drug product and primary packaging material should be chosen and the choice
justified.
Significant differences between the manufacturing processes used to produce batches
for pivotal clinical trials (safety, efficacy, bioavailability, bioequivalence) or primary
stability studies and the process described in 3.2.P.3.3 should be discussed. The
discussion should summarise the influence of the differences on the performance,
manufacturability and quality of the product. The information should be presented in
a way that facilitates comparison of the processes and the corresponding batch
analyses information (3.2.P.5.4). The information should include, for example, (1) the
identity (e.g., batch number) and use of the batches produced (e.g., bioequivalence
study batch number), (2) the manufacturing site, (3) the batch size, and (4) any
significant equipment differences (e.g., different design, operating principle, size).
In order to provide flexibility for future process improvement, when describing the
development of the manufacturing process, it is useful to describe measurement
systems that allow monitoring of critical attributes or process end-points. Collection of
process monitoring data during the development of the manufacturing process can
provide useful information to enhance process understanding. The process control
strategies that provide process adjustment capabilities to ensure control of all critical
attributes should be described.

* See Glossary for definition

=== PAGE 10 ===
Pharmaceutical Development

An assessment of the ability of the process to reliably produce a product of the
intended quality (e.g., the performance of the manufacturing process under different
operating conditions, at different scales, or with different equipment) can be provided.
An understanding of process robustness* can be useful in risk assessment and risk
reduction (see ICH Q9 Quality Risk Management glossary for definition) and to
support future manufacturing and process improvement, especially in conjunction
with the use of risk management tools (see ICH Q9 Quality Risk Management).

### 2.4 Container Closure System

The choice and rationale for selection of the container closure system for the
commercial product (described in 3.2.P.7) should be discussed. Consideration should
be given to the intended use of the drug product and the suitability of the container
closure system for storage and transportation (shipping), including the storage and
shipping container for bulk drug product, where appropriate.
The choice of materials for primary packaging should be justified. The discussion
should describe studies performed to demonstrate the integrity of the container and
closure. A possible interaction between product and container or label should be
considered.
The choice of primary packaging materials should consider, e.g., choice of materials,
protection from moisture and light, compatibility of the materials of construction with
the dosage form (including sorption to container and leaching), and safety of materials
of construction. Justification for secondary packaging materials should be included,
when relevant.
If a dosing device is used (e.g., dropper pipette, pen injection device, dry powder
inhaler), it is important to demonstrate that a reproducible and accurate dose of the
product is delivered under testing conditions which, as far as possible, simulate the
use of the product.

### 2.5 Microbiological Attributes

Where appropriate, the microbiological attributes of the drug product should be
discussed in this section (3.2.P.2.5). The discussion should include, for example:
•
The rationale for performing or not performing microbial limits testing for non
sterile drug products (e.g., Decision Tree #8 in ICH Q6A Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances and New Drug
Products: Chemical Substances and ICH Q6B Specifications: Test Procedures
and Acceptance Criteria for Biotechnology/Biological Products);
•
The selection and effectiveness of preservative systems in products containing
antimicrobial preservative or the antimicrobial effectiveness of products that
are inherently antimicrobial;
•
For sterile products, the integrity of the container closure system as it relates
to preventing microbial contamination.
Although chemical testing for preservative content is the attribute normally included
in the drug product specification, antimicrobial preservative effectiveness should be
demonstrated
during
development.
The
lowest
specified
concentration
of
antimicrobial preservative should be demonstrated to be effective in controlling micro-

* See Glossary for definition

=== PAGE 11 ===
Pharmaceutical Development

organisms
by
using
an
antimicrobial
preservative
effectiveness
test.
The
concentration used should be justified in terms of efficacy and safety, such that the
minimum concentration of preservative that gives the required level of efficacy
throughout the intended shelf life of the product is used. Where relevant, microbial
challenge testing under testing conditions that, as far as possible, simulate patient
use should be performed during development and documented in this section.

### 2.6 Compatibility

The compatibility of the drug product with reconstitution diluents (e.g., precipitation,
stability) should be addressed to provide appropriate and supportive information for
the labelling. This information should cover the recommended in-use shelf life, at the
recommended storage temperature and at the likely extremes of concentration.
Similarly, admixture or dilution of products prior to administration (e.g., product
added to large volume infusion containers) might need to be addressed.
3.
GLOSSARY
Continuous Process Verification:
An alternative approach to process validation in which manufacturing process
performance is continuously monitored and evaluated.
Design Space:
The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance
of quality. Working within the design space is not considered as a change. Movement
out of the design space is considered to be a change and would normally initiate a
regulatory post approval change process. Design space is proposed by the applicant
and is subject to regulatory assessment and approval.
Formal Experimental Design:
A structured, organized method for determining the relationship between factors
affecting a process and the output of that process. Also known as “Design of
Experiments”.
Lifecycle:
All phases in the life of a product from the initial development through marketing
until the product’s discontinuation.
Process Analytical Technology (PAT):
A system for designing, analyzing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical quality and performance attributes
of raw and in-process materials and processes with the goal of ensuring final product
quality.
Process Robustness:
Ability of a process to tolerate variability of materials and changes of the process and
equipment without negative impact on quality.

=== PAGE 12 ===
Pharmaceutical Development

Quality:
The suitability of either a drug substance or drug product for its intended use. This
term includes such attributes as the identity, strength, and purity (from ICH Q6A
Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and
New Drug Products: Chemical Substances).

=== PAGE 13 ===

PART II:
PHARMACEUTICAL DEVELOPMENT - ANNEX
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting
on 13 November 2008, this guideline is recommended for
adoption to the three regulatory parties to ICH

1.
INTRODUCTION
This guideline is an annex to ICH Q8 Pharmaceutical Development and provides
further clarification of key concepts outlined in the core guideline. In addition, this
annex describes the principles of quality by design1 (QbD). The annex is not intended
to establish new standards or to introduce new regulatory requirements; however, it
shows how concepts and tools (e.g., design space1) outlined in the parent Q8 document
could be put into practice by the applicant for all dosage forms. Where a company
chooses to apply quality by design and quality risk management (ICH Q9, Quality
Risk Management), linked to an appropriate pharmaceutical quality system,
opportunities arise to enhance science- and risk-based regulatory approaches (see ICH
Q10, Pharmaceutical Quality System).
Approaches to Pharmaceutical Development
In all cases, the product should be designed to meet patients’ needs and the intended
product performance. Strategies for product development vary from company to
company and from product to product. The approach to, and extent of, development
can also vary and should be outlined in the submission. An applicant might choose
either an empirical approach or a more systematic approach to product development,
or a combination of both. An illustration of the potential contrasts of these approaches
is shown in Appendix 1. A more systematic approach to development (also defined as
quality by design) can include, for example, incorporation of prior knowledge, results
of studies using design of experiments, use of quality risk management, and use of
knowledge management (see ICH Q10) throughout the lifecycle1 of the product. Such
a systematic approach can enhance achieving the desired quality of the product and
help the regulators to better understand a company’s strategy. Product and process
understanding can be updated with the knowledge gained over the product lifecycle.
A greater understanding of the product and its manufacturing process can create a
basis for more flexible regulatory approaches. The degree of regulatory flexibility is
predicated on the level of relevant scientific knowledge provided in the registration
application. It is the knowledge gained and submitted to the authorities, and not the
volume of data collected, that forms the basis for science- and risk-based submissions
and regulatory evaluations. Nevertheless, appropriate data demonstrating that this
knowledge is based on sound scientific principles should be presented with each
application.
Pharmaceutical development should include, at a minimum, the following elements:

1 See glossary

=== PAGE 14 ===
Pharmaceutical Development

•
Defining the quality target product profile1 (QTPP) as it relates to quality,
safety and efficacy, considering e.g., the route of administration, dosage form,
bioavailability, strength, and stability;
•
Identifying potential critical quality attributes1 (CQAs) of the drug product, so
that those product characteristics having an impact on product quality can be
studied and controlled;
•
Determining the critical quality attributes of the drug substance, excipients
etc., and selecting the type and amount of excipients to deliver drug product of
the desired quality1;
•
Selecting an appropriate manufacturing process ;
•
Defining a control strategy1.
An enhanced, quality by design approach to product development would additionally
include the following elements:
•
A systematic evaluation, understanding and refining of the formulation and
manufacturing process, including;
o Identifying, through e.g., prior knowledge, experimentation, and risk
assessment, the material attributes and process parameters that can
have an effect on product CQAs;
o Determining the functional relationships that link material attributes
and process parameters to product CQAs;
•
Using the enhanced product and process understanding in combination with
quality risk management to establish an appropriate control strategy which
can, for example, include a proposal for a design space(s) and/or real-time
release testing1.
As a result, this more systematic approach could facilitate continual improvement and
innovation throughout the product lifecycle (See ICH Q10).
2.
ELEMENTS OF PHARMACEUTICAL DEVELOPMENT
The section that follows elaborates on possible approaches to gaining a more
systematic, enhanced understanding of the product and process under development.
The examples given are purely illustrative and are not intended to create new
regulatory requirements.

### 2.1 Quality Target Product Profile

The quality target product profile forms the basis of design for the development of the
product. Considerations for the quality target product profile could include:
•
Intended use in clinical setting, route of administration, dosage form, delivery
systems;
•
Dosage strength(s);
•
Container closure system;

1 See glossary

=== PAGE 15 ===
Pharmaceutical Development

•
Therapeutic
moiety
release
or
delivery
and
attributes
affecting
pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance)
appropriate to the drug product dosage form being developed;
•
Drug product quality criteria (e.g., sterility, purity, stability and drug release)
appropriate for the intended marketed product.

### 2.2 Critical Quality Attributes

A CQA is a physical, chemical, biological, or microbiological property or characteristic
that should be within an appropriate limit, range, or distribution to ensure the
desired product quality.  CQAs are generally associated with the drug substance,
excipients, intermediates (in-process materials) and drug product.
CQAs of solid oral dosage forms are typically those aspects affecting product purity,
strength, drug release and stability. CQAs for other delivery systems can additionally
include more product specific aspects, such as aerodynamic properties for inhaled
products, sterility for parenterals, and adhesion properties for transdermal patches.
For drug substances, raw materials and intermediates, the CQAs can additionally
include those properties (e.g., particle size distribution, bulk density) that affect drug
product CQAs.
Potential drug product CQAs derived from the quality target product profile and/or
prior knowledge are used to guide the product and process development. The list of
potential CQAs can be modified when the formulation and manufacturing process are
selected and as product knowledge and process understanding increase.  Quality risk
management can be used to prioritize the list of potential CQAs for subsequent
evaluation.   Relevant CQAs can be identified by an iterative process of quality risk
management and experimentation that assesses the extent to which their variation
can have an impact on the quality of the drug product.

### 2.3 Risk Assessment: Linking Material Attributes and Process Parameters

to Drug Product CQAs
Risk assessment is a valuable science-based process used in quality risk management
(see ICH Q9) that can aid in identifying which material attributes and process
parameters potentially have an effect on product CQAs. Risk assessment is typically
performed early in the pharmaceutical development process and is repeated as more
information becomes available and greater knowledge is obtained.
Risk assessment tools can be used to identify and rank parameters (e.g., process,
equipment, input materials) with potential to have an impact on product quality,
based on prior knowledge and initial experimental data. For an illustrative example,
see Appendix 2. The initial list of potential parameters can be quite extensive, but can
be modified and prioritized by further studies (e.g., through a combination of design of
experiments, mechanistic models). The list can be refined further through
experimentation to determine the significance of individual variables and potential
interactions.  Once the significant parameters are identified, they can be further
studied (e.g., through a combination of design of experiments, mathematical models,
or studies that lead to mechanistic understanding) to achieve a higher level of process
understanding.

=== PAGE 16 ===
Pharmaceutical Development

### 2.4 Design Space

The relationship between the process inputs (material attributes and process
parameters) and the critical quality attributes can be described in the design space
(see examples in Appendix 2).

#### 2.4.1 Selection of Variables

The risk assessment and process development experiments described in Section 2.3
can lead to an understanding of the linkage and effect of process parameters and
material attributes on product CQAs, and also help identify the variables and their
ranges within which consistent quality can be achieved.  These process parameters
and material attributes can thus be selected for inclusion in the design space.
A description should be provided in the application of the process parameters and
material attributes considered for the design space, those that were included, and
their effect on product quality. The rationale for inclusion in the design space should
be presented. In some cases it is helpful to provide also the rationale as to why some
parameters were excluded. Knowledge gained from studies should be described in the
submission. Process parameters and material attributes that were not varied through
development should be highlighted.

#### 2.4.2 Describing a Design Space in a Submission

A design space can be described in terms of ranges of material attributes and process
parameters, or through more complex mathematical relationships. It is possible to
describe a design space as a time dependent function (e.g., temperature and pressure
cycle of a lyophilisation cycle), or as a combination of variables such as components of
a multivariate model.  Scaling factors can also be included if the design space is
intended to span multiple operational scales. Analysis of historical data can
contribute to the establishment of a design space. Regardless of how a design space is
developed, it is expected that operation within the design space will result in a
product meeting the defined quality.
Examples of different potential approaches to presentation of a design space are
presented in Appendix 2.
2.4.3 Unit Operation Design Space(s)
The applicant can choose to establish independent design spaces for one or more unit
operations, or to establish a single design space that spans multiple operations. While
a separate design space for each unit operation is often simpler to develop, a design
space that spans the entire process can provide more operational flexibility. For
example, in the case of a drug product that undergoes degradation in solution before
lyophilisation, the design space to control the extent of degradation (e.g.,
concentration, time, temperature) could be expressed for each unit operation or as a
sum over all unit operations.

#### 2.4.4 Relationship of Design Space to Scale and Equipment

When describing a design space, the applicant should consider the type of operational
flexibility desired. A design space can be developed at any scale. The applicant should
justify the relevance of a design space developed at small or pilot scale to the proposed
production scale manufacturing process and discuss the potential risks in the scale-up
operation.

=== PAGE 17 ===
Pharmaceutical Development

If the applicant proposes the design space to be applicable to multiple operational
scales, the design space should be described in terms of relevant scale-independent
parameters. For example, if a product was determined to be shear sensitive in a
mixing operation, the design space could include shear rate, rather than agitation
rate. Dimensionless numbers and/or models for scaling can be included as part of the
design space description.

#### 2.4.5 Design Space Versus Proven Acceptable Ranges

A combination of proven acceptable ranges
1 does not constitute a design space.
However, proven acceptable ranges based on univariate experimentation can provide
useful knowledge about the process.

#### 2.4.6 Design Space and Edge of Failure

It can be helpful to determine the edge of failure for process parameters or material
attributes, beyond which the relevant quality attributes cannot be met. However,
determining the edge of failure or demonstrating failure modes are not essential parts
of establishing a design space.

### 2.5 Control Strategy

A control strategy is designed to ensure that a product of required quality will be
produced consistently. The elements of the control strategy discussed in Section P.2 of
the dossier should describe and justify how in-process controls and the controls of
input materials (drug substance and excipients), intermediates (in-process materials),
container closure system, and drug products contribute to the final product quality.
These controls should be based on product, formulation and process understanding
and should include, at a minimum, control of the critical process parameters1 and
material attributes.
A comprehensive pharmaceutical development approach will generate process and
product understanding and identify sources of variability. Sources of variability that
can impact product quality should be identified, appropriately understood, and
subsequently controlled. Understanding sources of variability and their impact on
downstream processes or processing, in-process materials, and drug product quality
can provide an opportunity to shift controls upstream and minimise the need for end
product testing. Product and process understanding, in combination with quality risk
management (see ICH Q9), will support the control of the process such that the
variability (e.g., of raw materials) can be compensated for in an adaptable manner to
deliver consistent product quality.
This process understanding can enable an alternative manufacturing paradigm where
the variability of input materials could be less tightly constrained. Instead it can be
possible to design an adaptive process step (a step that is responsive to the input
materials) with appropriate process control to ensure consistent product quality.
Enhanced understanding of product performance can justify the use of alternative
approaches to determine that the material is meeting its quality attributes. The use of
such alternatives could support real time release testing. For example, disintegration
could serve as a surrogate for dissolution for fast-disintegrating solid forms with
highly soluble drug substances. Unit dose uniformity performed in-process (e.g., using

1 See glossary

=== PAGE 18 ===
Pharmaceutical Development

weight variation coupled with near infrared (NIR) assay) can enable real time release
testing and provide an increased level of quality assurance compared to the
traditional end-product testing using compendial content uniformity standards. Real
time release testing can replace end product testing, but does not replace the review
and quality control steps called for under GMP to release the batch.
A control strategy can include, but is not limited to, the following:
•
Control of input material attributes (e.g., drug substance, excipients, primary
packaging materials) based on an understanding of their impact on
processability or product quality;
•
Product specification(s);
•
Controls for unit operations that have an impact on downstream processing or
product quality (e.g., the impact of drying on degradation, particle size
distribution of the granulate on dissolution);
•
In-process or real-time release testing in lieu of end-product testing (e.g.
measurement and control of CQAs during processing);
•
A monitoring program (e.g., full product testing at regular intervals) for
verifying multivariate prediction models.
A control strategy can include different elements. For example, one element of the
control strategy could rely on end-product testing, whereas another could depend on
real-time release testing.  The rationale for using these alternative approaches should
be described in the submission.
Adoption of the principles in this guideline can support the justification of alternative
approaches to the setting of specification attributes and acceptance criteria as
described in Q6A and Q6B.

### 2.6 Product Lifecycle Management and Continual Improvement

Throughout the product lifecycle, companies have opportunities to evaluate
innovative approaches to improve product quality (see ICH Q10).
Process performance can be monitored to ensure that it is working as anticipated to
deliver product quality attributes as predicted by the design space. This monitoring
could include trend analysis of the manufacturing process as additional experience is
gained during routine manufacture. For certain design spaces using mathematical
models, periodic maintenance could be useful to ensure the model’s performance. The
model maintenance is an example of activity that can be managed within a company‘s
own internal quality system provided the design space is unchanged.
Expansion, reduction or redefinition of the design space could be desired upon gaining
additional process knowledge. Change of design space is subject to regional
requirements.
3.
SUBMISSION
OF
PHARMACEUTICAL
DEVELOPMENT
AND
RELATED INFORMATION IN COMMON TECHNICAL DOCUMENTS
(CTD) FORMAT
Pharmaceutical development information is submitted in Section P.2 of the CTD.
Other information resulting from pharmaceutical development studies could be
accommodated by the CTD format in a number of different ways and some specific

=== PAGE 19 ===
Pharmaceutical Development

suggestions are provided below. However, the applicant should clearly indicate where
the different information is located. In addition to what is submitted in the
application,
certain
aspects
(e.g.,
product
lifecycle
management,
continual
improvement) of this guideline are handled under the applicant’s pharmaceutical
quality system (see ICH Q10).

### 3.1 Quality Risk Management and Product and Process Development

Quality risk management can be used at different stages during product and process
development and manufacturing implementation. The assessments used to guide and
justify development decisions can be included in the relevant sections of P.2. For
example, risk analyses and functional relationships linking material attributes and
process parameters to product CQAs can be included in P.2.1, P.2.2, and P.2.3. Risk
analyses linking the design of the manufacturing process to product quality can be
included in P.2.3.

### 3.2 Design Space

As an element of the proposed manufacturing process, the design space(s) can be
described in the section of the application that includes the description of the
manufacturing process and process controls (P.3.3). If appropriate, additional
information can be provided in the section of the application that addresses the
controls of critical steps and intermediates (P.3.4). The product and manufacturing
process development sections of the application (P.2.1, P.2.2, and P.2.3) are
appropriate places to summarise and describe product and process development
studies that provide the basis for the design space(s). The relationship of the design
space(s) to the overall control strategy can be discussed in the section of the
application that includes the justification of the drug product specification (P.5.6).

### 3.3 Control Strategy

The section of the application that includes the justification of the drug product
specification (P.5.6) is a good place to summarise the overall drug product control
strategy. However, detailed information about input material controls and process
controls should still be provided in the appropriate CTD format sections (e.g., drug
substance section (S), control of excipients (P.4), description of manufacturing process
and process controls (P.3.3), controls of critical steps and intermediates (P.3.4)).

### 3.4 Drug Substance Related Information

If drug substance CQAs have the potential to affect the CQAs or manufacturing
process of the drug product, some discussion of drug substance CQAs can be
appropriate in the pharmaceutical development section of the application (e.g., P.2.1).

=== PAGE 20 ===
Pharmaceutical Development

4.
GLOSSARY
Control Strategy:
A planned set of controls, derived from current product and process understanding
that ensures process performance and product quality. The controls can include
parameters and attributes related to drug substance and drug product materials and
components, facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of monitoring and
control. (ICH Q10)
Critical Process Parameter (CPP):
A process parameter whose variability has an impact on a critical quality attribute
and therefore should be monitored or controlled to ensure the process produces the
desired quality.
Critical Quality Attribute (CQA):
A physical, chemical, biological or microbiological property or characteristic that
should be within an appropriate limit, range, or distribution to ensure the desired
product quality.
Design Space:
The multidimensional combination and interaction of input variables (e.g., material
attributes) and process parameters that have been demonstrated to provide assurance
of quality. Working within the design space is not considered as a change. Movement
out of the design space is considered to be a change and would normally initiate a
regulatory post approval change process. Design space is proposed by the applicant
and is subject to regulatory assessment and approval (ICH Q8).
Lifecycle:
All phases in the life of a product from the initial development through marketing
until the product’s discontinuation (ICH Q8).
Proven Acceptable Range:
A characterised range of a process parameter for which operation within this range,
while keeping other parameters constant, will result in producing a material meeting
relevant quality criteria.
Quality:
The suitability of either a drug substance or a drug product for its intended use. This
term includes such attributes as the identity, strength, and purity (ICH Q6A).
Quality by Design (QbD):
A systematic approach to development that begins with predefined objectives and
emphasizes product and process understanding and process control, based on sound
science and quality risk management.
Quality Target Product Profile (QTPP):
A prospective summary of the quality characteristics of a drug product that ideally
will be achieved to ensure the desired quality, taking into account safety and efficacy
of the drug product.

=== PAGE 21 ===
Pharmaceutical Development

Real Time Release Testing:
The ability to evaluate and ensure the quality of in-process and/or final product based
on process data, which typically include a valid combination of measured material
attributes and process controls.

=== PAGE 22 ===
Pharmaceutical Development

Appendix 1. Differing Approaches to Pharmaceutical Development
The following table has been developed to illustrate some potential contrasts between
what might be considered a minimal approach and an enhanced, quality by design
approach regarding different aspects of pharmaceutical development and lifecycle
management. The comparisons are shown merely to aid in the understanding of a
range of potential approaches to pharmaceutical development and should not be
considered to be all-encompassing. The table is not intended to specifically define the
only approach a company could choose to follow. In the enhanced approach,
establishing a design space or using real time release testing is not necesserily
expected. Current practices in the pharmaceutical industry vary and typically lie
between the two approaches presented in the table.

Aspect
Minimal Approaches
Enhanced, Quality by Design Approaches
Overall
Pharmaceutical
Development
• Mainly empirical
• Developmental research often
conducted one variable at a
time

• Systematic, relating mechanistic
understanding of material attributes and
process parameters to drug product CQAs
• Multivariate experiments to understand
product and process
• Establishment of design space
• PAT tools utilised
Manufacturing
Process
• Fixed
• Validation primarily based on
initial full-scale batches
• Focus on optimisation and
reproducibility
• Adjustable within design space
• Lifecycle approach to validation and, ideally,
continuous process verification
• Focus on control strategy and robustness
• Use of statistical process control methods
Process
Controls
• In-process tests primarily for
go/no go decisions
• Off-line analysis
• PAT tools utilised with appropriate feed
forward and feedback controls
• Process operations tracked and trended to
support continual improvement efforts post-
approval
Product
Specifications
• Primary means of control
• Based on batch data available
at time of registration
• Part of the overall quality control strategy
• Based on desired product performance with
relevant supportive data
Control Strategy
• Drug product quality controlled
primarily by intermediates (in-
process materials) and end
product testing
• Drug product quality ensured by risk-based
control strategy for well understood product
and process
• Quality controls shifted upstream, with the
possibility of real-time release testing or
reduced end-product testing
Lifecycle
Management
• Reactive (i.e., problem solving
and corrective action)
• Preventive action
• Continual improvement facilitated

=== PAGE 23 ===
Pharmaceutical Development

Appendix 2. Illustrative Examples

A. Use of a risk assessment tool.
For example, a cross-functional team of experts could work together to develop an
Ishikawa (fishbone) diagram that identifies potential variables which can have an
impact on the desired quality attribute.  The team could then rank the variables
based on probability, severity, and detectability using failure mode effects analysis
(FMEA) or similar tools based on prior knowledge and initial experimental data.
Design of experiments or other experimental approaches could then be used to
evaluate the impact of the higher ranked variables, to gain greater understanding of
the process, and to develop a proper control strategy.

Ishikawa Diagram

Water
Content
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame
Tablet
Drying
Granulation
Raw
Materials
Compressing
Plant
Factors
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch Penetration
Depth
Temp
RH
Air Flow
Shock Cycle
Drug
Substance
P.S.
Process Conditions
LOD
Diluents
P.S.
LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
Power
Time
Age
Tooling
Operator
Training
Analytical
Method
Sampling
Feed
Frame

=== PAGE 24 ===
Pharmaceutical Development

B. Depiction of interactions
The figure below depicts the presence or absence of interactions among  three process
parameters on the level of degradation product Y.  The figure shows a series of two-
dimensional plots showing the effect of interactions among three process parameters
(initial moisture content, temperature, mean particle size) of the drying operation of a
granulate (drug product intermediate) on degradation product Y.  The relative slopes
of the lines or curves within a plot indicate if interaction is present.  In this example,
initial moisture content and temperature are interacting; but initial moisture content
and mean particle size are not, nor are temperature and mean particle size.

0.5
1.0
1.5
%Y
Initial
moisture
content (IMC)
100°C
15%
30%
Temperature
700 µm
Mean
particle size
(d50)
1 2 3 4 5 6 7
100 µm
60°C
700 µm
100 µm
15%
30%
100°C
60°C
(d50 = 400 µm)
(Temp = 80°C)
(Temp = 80°C)
(IMC = 22.5%)
(IMC = 22.5%)
Initial Moisture
Content (%)
Temp (°C)
Mean Particle
Size (x100 µm)
0.5
1.0
1.5
%Y
0.5
1.0
1.5
%Y
(d50 = 400 µm)
0.5
1.0
1.5
%Y
Initial
moisture
content (IMC)
100°C
15%
30%
Temperature
700 µm
Mean
particle size
(d50)
1 2 3 4 5 6 7
100 µm
60°C
700 µm
100 µm
15%
30%
100°C
60°C
(d50 = 400 µm)
(Temp = 80°C)
(Temp = 80°C)
(IMC = 22.5%)
(IMC = 22.5%)
Initial Moisture
Content (%)
Temp (°C)
Mean Particle
Size (x100 µm)
0.5
1.0
1.5
%Y
0.5
1.0
1.5
%Y
(d50 = 400 µm)

=== PAGE 25 ===
Pharmaceutical Development

C. Presentations of design space

Example 1: Response graphs for dissolution are depicted as a surface plot (Figure 1a)
and a contour plot (Figure 1b). Parameters 1 and 2 are factors of a granulation
operation that affect the dissolution rate of a tablet (e.g., excipient attribute, water
amount, granule size.)

*[Figure 1a:  Response surface plot of]*

dissolution
as
a
function
of
two
parameters of a granulation operation.
Dissolution above 80% is desired.

*[Figure 1b: Contour plot of dissolution]*

from example 1a.

*[Figure 1c:  Design space for granulation]*

parameters, defined by a non-linear
combination of their ranges, that delivers
satisfactory dissolution (i.e., >80%).

*[Figure 1d: Design space for granulation]*

parameters,
defined
by
a
linear
combination of their ranges, that delivers
satisfactory dissolution (i.e., >80%).

Two examples are given of potential design spaces. In Figure 1c, the design space is
defined by a non-linear combination of parameter ranges that delivers the dissolution
critical quality attribute. In this example, the design space is expressed by the
response surface equation resolved at the limit for satisfactory response (i.e.,80%
dissolution). The acceptable range of one parameter is dependent on the value of the
other. For example:
-
If Parameter 1 has a value of 46, then Parameter 2 has a range of 0 and 1.5
-
If Parameter 2 has a value of 0.8, then Parameter 1 has a range of 43 and 54

=== PAGE 26 ===
Pharmaceutical Development

The approach in Figure 1c allows the maximum range of operation to achieve the
desired dissolution rate. In Figure 1d, the design space is defined as a smaller range,
based on a linear combination of parameters.

-
Parameter 1 has a range of 44 and 53
-
Parameter 2 has a range of 0 and 1.1

While the approach in Figure 1d is more limiting, the applicant may prefer it for
operational simplicity.

This example discusses only two parameters and thus can readily be presented
graphically. When multiple parameters are involved, the design space can be
presented for two parameters, in a manner similar to the examples shown above, at
different values (e.g., high, middle, low) within the range of the third parameter, the
fourth parameter, and so on. Alternatively, the design space can be explained
mathematically through equations describing relationships between parameters for
successful operation.

=== PAGE 27 ===
Pharmaceutical Development

Example 2:  Design space determined from the common region of successful
operating ranges for multiple CQAs. The relations of two CQAs, i.e., tablet friability
and dissolution, to two process parameters of a granulation operation are shown in
Figures 2a and 2b. Parameters 1 and 2 are factors of a granulation operation that
affect the dissolution rate of a tablet (e.g., excipient attribute, water amount, granule
size). Figure 2c shows the overlap of these regions and the maximum ranges of the
proposed design space. The applicant can elect to use the entire region as the design
space, or some subset thereof.
> 80%
75-80%
70-75%
65-70%
60-65%
> 80%
75-80%
70-75%
65-70%
60-65%

4-5%
3-4%
2-3%
< 2%
4-5%
3-4%
2-3%
< 2%

*[Figure 2a: Contour plot of dissolution as]*

a function of Parameters 1 and 2.

*[Figure 2b: Contour plot of friability as a]*

function of Parameters 1 and 2.

*[Figure 2c: Proposed design space,]*

comprised of the overlap region of
ranges
for
friability
and
or
dissolution.

=== PAGE 28 ===
Pharmaceutical Development

Example 3:  The design space for a drying operation that is dependent upon the path
of temperature and/or pressure over time.  The end point for moisture content is 1-2%.
Operating above the upper limit of the design space can cause excessive impurity
formation, while operating below the lower limit of the design space can result in
excessive particle attrition.

0%
5%
10%
15%
20%
25%
30%
35%
time (hr)
Moisture Content
Design space
lower limit
Design space
upper limit
Excessive
impurity
formation
Excessive
particle
attrition
Endpoint
criterion
{

---

### Document: ICH Q9R1 Complete (ICH)

# ICH Q9(R1) Quality Risk Management: Quality Risk Management Guideline

=== PAGE 1 ===

INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL
REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED GUIDELINE

QUALITY RISK MANAGEMENT
Q9(R1)

Final version
Adopted on 18 January 2023

This Guideline has been developed by the appropriate ICH Expert Working Group and has been
subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4
of the Process the final draft is recommended for adoption to the regulatory bodies of ICH regions.

=== PAGE 2 ===

Q9(R1)
Document History

Q9

Code
History
Date
Q9
Approval by the Steering Committee under Step 4
and recommendation for adoption to the three ICH
regulatory bodies.
9 November 2005

Revision of Q9

Code
History
Date
Q9(R1)
Endorsement by the Members of the ICH Assembly
under Step 2 and release for public consultation
(document dated 18 November 2021).
18 November
2021
Q9(R1)
Adoption by the Regulatory Members of the ICH
Assembly under Step 4.
18 January 2023

Legal notice: This document is protected by copyright and may, with the exception of the ICH
logo, be used, reproduced, incorporated into other works, adapted, modified, translated or
distributed under a public license provided that ICH's copyright in the document is acknowledged
at all times. In case of any adaption, modification or translation of the document, reasonable
steps must be taken to clearly label, demarcate or otherwise identify that changes were made to
or based on the original document.  Any impression that the adaption, modification or translation
of the original document is endorsed or sponsored by the ICH must be avoided.
The document is provided "as is" without warranty of any kind.  In no event shall the ICH or the
authors of the original document be liable for any claim, damages or other liability arising from
the use of the document.
The above-mentioned permissions do not apply to content supplied by third parties. Therefore,
for documents where the copyright vests in a third party, permission for reproduction must be
obtained from this copyright holder.

=== PAGE 3 ===

i
ICH HARMONISED GUIDELINE
QUALITY RISK MANAGEMENT
Q9(R1)
ICH Consensus Guideline

TABLE OF CONTENTS

1.
INTRODUCTION .................................................................................................................. 1
2.
SCOPE .................................................................................................................................... 2
3.
PRINCIPLES OF QUALITY RISK MANAGEMENT ...................................................... 2
4.
GENERAL QUALITY RISK MANAGEMENT PROCESS ............................................. 3
4.1.     Responsibilities ........................................................................................................................ 3
4.2.     Initiating a Quality Risk Management Process ........................................................................ 4
4.3.     Risk Assessment ....................................................................................................................... 4
4.4.     Risk Control ............................................................................................................................. 5
4.5.     Risk Communication ............................................................................................................... 5
4.6.     Risk Review ............................................................................................................................. 6
5.
RISK MANAGEMENT METHODOLOGY ....................................................................... 6
5.1      Formality in Quality Risk Management ................................................................................... 7
5.2      Risk-Based Decision-Making .................................................................................................. 8
5.3      Managing and Minimizing Subjectivity .................................................................................. 9
6.
INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND
REGULATORY OPERATIONS ..................................................................................................... 9

### 6.1 The role of Quality Risk Management in Addressing Product Availability Risks Arising from

Quality/Manufacturing Issues ........................................................................................................... 10
7.
DEFINITIONS ...................................................................................................................... 11
8.
REFERENCES ..................................................................................................................... 13
ANNEX I: QUALITY RISK MANAGEMENT METHODS AND TOOLS .............................. 15
I.1
 Basic Risk Management Facilitation Methods...................................................................... 15
I.2
 Failure Mode Effects Analysis (FMEA) ............................................................................... 15
I.3
 Failure Mode, Effects and Criticality Analysis (FMECA) .................................................... 15
I.4
 Fault Tree Analysis (FTA) ..................................................................................................... 16
I.5
 Hazard Analysis and Critical Control Points (HACCP) ....................................................... 16
I.6
 Hazard Operability Analysis (HAZOP) ................................................................................ 17

=== PAGE 4 ===
ICH Q9(R1) Guideline

I.7
 Preliminary Hazard Analysis (PHA) ..................................................................................... 17
I.8
 Risk Ranking and Filtering ................................................................................................... 17
I.9
 Supporting Statistical Tools .................................................................................................. 18
ANNEX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT ......... 19
II.1
 Quality Risk Management as Part of Integrated Quality Management ................................ 19
II.2
 Quality Risk Management as Part of Regulatory Operations ............................................... 20
II.3
 Quality Risk Management as Part of Development .............................................................. 20
II.4
 Quality Risk Management for Facilities, Equipment and Utilities ....................................... 21
II.5
 Quality Risk Management as Part of Materials Management............................................... 22
II.6
 Quality Risk Management as Part of Production .................................................................. 23
II.7
 Quality Risk Management as Part of Laboratory Control and Stability Studies................... 23
II.8
 Quality Risk Management as Part of Packaging and Labeling ............................................. 24
II.9
 Quality Risk Management as Part of Supply Chain Control ................................................ 24

=== PAGE 5 ===
ICH Q9(R1) Guideline

1. INTRODUCTION
Risk management principles are effectively utilized in many areas of business and government
including finance, insurance, occupational safety, public health, pharmacovigilance, and by
agencies regulating these industries. In the pharmaceutical sector, the principles and framework
of ICH Q9, coupled with the official ICH training material that supports this guideline, are
instrumental in enhancing the application of effective quality risk management by industry and
regulators. The importance of quality systems has been recognized in the pharmaceutical
industry and it is evident that quality risk management is a valuable component of an effective
quality system.

It is commonly understood that risk is defined as the combination of the probability of
occurrence of harm and the severity of that harm. However, achieving a shared understanding
of the application of risk management among diverse stakeholders is difficult because each
stakeholder might perceive different potential harms, place a different probability on each harm
occurring and attribute different severities to each harm. In addition, subjectivity can directly
impact the effectiveness of risk management activities and the decisions made. Therefore, it is
important that subjectivity is managed and minimized. In relation to pharmaceuticals, although
there are a variety of stakeholders, including patients and medical practitioners as well as
government and industry, the protection of the patient is of prime importance when managing
the risk to product quality and availability, when availability risks arise from
quality/manufacturing issues.

The manufacturing and use of a drug (medicinal) product, including its components,
necessarily entail some degree of risk. The risk to its quality is just one component of the overall
risk. It is important to understand that product quality is assured based on appropriate risk-
based decision-making throughout the product lifecycle, such that the attributes that are
important to the quality of the drug (medicinal) product are maintained and the product remains
safe and effective.

An effective quality risk management approach can further ensure the quality of the drug
(medicinal) product to the patient by providing a proactive means to identify and control
potential quality issues during development, manufacturing, and distribution. This includes an
appropriate application of root cause analysis that can identify and address the root cause(s)
and other causal factors (e.g., human-related) of such issues. A proactive approach to quality
risk management is beneficial, as it facilitates robust product design and continual
improvement, and it is of strategic importance in achieving an effective pharmaceutical quality
system. (See ICH Q10 for guidance in relation to an effective pharmaceutical quality system.)
Additionally, use of quality risk management can improve the decision-making if a quality
problem arises.

In the development phase and as part of validation, quality risk management is part of building
knowledge and understanding risk scenarios, so that appropriate risk control can be decided
upon for use during the commercial manufacturing phase. In this context, knowledge is used
to make informed risk-based decisions, trigger re-evaluations and stimulate continual
improvements. Effective and proactive quality risk management can enable better, more
informed and timely decisions throughout the lifecycle. This can provide regulators with
greater assurance of a company’s ability to deal with potential risks and avert problems, and
can beneficially affect the extent and level of direct regulatory oversight.

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The application of digitalization and emerging technologies in the manufacture and control of
drug (medicinal) products can lead to risk reduction, when such technologies are fit for their
intended use. However, they can also introduce other risks that may need to be controlled. The
application of quality risk management to the design, validation and technology transfer of
advanced production processes and analytical methods, advanced data analysis methods and
computerized systems is important.

The purpose of this document is to offer a systematic approach to quality risk management that
leads to better, more informed, and timely decisions. It serves as a foundation or resource
document that is independent of, yet supports, other ICH Quality documents and complements
existing quality practices, requirements, standards, and guidelines within the pharmaceutical
industry and regulatory environment. It specifically provides guidance on the principles and
some of the tools of quality risk management that can enable more effective and consistent
risk-based decisions, both by regulators and industry, regarding the quality of drug substances
and drug (medicinal) products across the product lifecycle. It is not intended to create any new
expectations beyond the current regulatory requirements.

An understanding of formality in quality risk management may lead to resources being used
more efficiently, where lower risk issues are dealt with via less formal means, freeing up
resources for managing higher risk issues and more complex problems that may require
increased levels of rigor and effort. An understanding of formality can also support risk-based
decision-making, where the level of formality that is applied may reflect the degree of
importance of the decision, as well as the level of uncertainty and complexity which may be
present.

Appropriate use of quality risk management can facilitate but does not obviate industry’s
obligation to comply with regulatory requirements and does not replace appropriate
communications between industry and regulators. Quality risk management should not be used
in a manner where decisions are made that justify a practice that would otherwise, in
accordance with regulations and/or guidance, be deemed unacceptable.

2. SCOPE
This guideline provides principles and examples of tools for quality risk management that can
be applied to different aspects of pharmaceutical quality. These aspects include development,
manufacturing, distribution, and the inspection and submission/review processes throughout
the lifecycle of drug substances, drug (medicinal) products, biological and biotechnological
products (including the use of raw materials, solvents, excipients, packaging and labeling
materials in drug (medicinal) products, biological and biotechnological products).

3. PRINCIPLES OF QUALITY RISK MANAGEMENT
Two primary principles of quality risk management are:
•
The evaluation of the risk to quality should be based on scientific knowledge and
ultimately link to the protection of the patient. (Note: Risk to quality includes situations
where product availability may be impacted, leading to potential patient harm.)
•
The level of effort, formality and documentation of the quality risk management process
should be commensurate with the level of risk.

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4. GENERAL QUALITY RISK MANAGEMENT PROCESS
Quality risk management is a systematic process for the assessment, control, communication
and review of risks to the quality of the drug (medicinal) product across the product lifecycle.
A model for quality risk management is outlined in the diagram (Figure 1). Other models could
be used. The emphasis on each component of the framework might differ from case to case but
a robust process will incorporate consideration of all the elements at a level of detail that is
commensurate with the specific risk.

*[Figure 1: Overview of a typical quality risk management process]*

Decision nodes are not shown in the diagram above because decisions can occur at any point
in the process. These decisions might be to return to the previous step and seek further
information, to adjust the risk models or even to terminate the risk management process based
upon information that supports such a decision. Note: “unacceptable” in the flowchart does not
only refer to statutory, legislative or regulatory requirements, but also to the need to revisit the
risk assessment process.

4.1. Responsibilities
Quality risk management activities are usually, but not always, undertaken by interdisciplinary
teams. When teams are formed, they should include experts from the appropriate areas (e.g.,
quality unit, product development, business development, engineering, regulatory affairs,
production operations, sales and marketing, supply chain, legal, statistics and clinical) in
addition to individuals who are knowledgeable about the quality risk management process.
Risk Assessment
Initiate
Quality Risk Management Process
Hazard Identification
Risk Analysis
Risk Evaluation
Risk Management tools
Risk Communication
Risk Control
Risk Reduction
Output / Result of the
Quality Risk Management Process
Risk Review
Risk Acceptance
unacceptable
Review Events

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Decision makers should
•
take responsibility for coordinating quality risk management across various functions and
departments of their organization;
•
assure that a quality risk management process is defined, deployed and reviewed and that
adequate resources and knowledge are available; and
•
assure that subjectivity in quality risk management activities is managed and minimized,
to facilitate scientifically robust risk-based decision-making.

4.2. Initiating a Quality Risk Management Process
Quality risk management should include systematic processes designed to coordinate, facilitate
and improve science-based decision-making with respect to risk. Possible steps used to initiate
and plan a quality risk management process might include the following:
•
Define the problem and/or risk question, including pertinent assumptions identifying the
potential for risk;
•
Assemble background information and/ or data on the potential hazard, harm or human
health impact relevant to the risk assessment;
•
Identify a leader and necessary resources;
•
Specify a timeline, deliverables and appropriate level of decision-making for the risk
management process.

4.3. Risk Assessment
Risk assessment consists of the identification of hazards and the analysis and evaluation of
risks associated with exposure to those hazards (as defined below). Quality risk assessments
begin with a well-defined problem description or risk question. When the risk in question is
well defined, an appropriate risk management tool (see examples in section 5) and the types of
information needed to address the risk question will be more readily identifiable. As an aid to
clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often
helpful:
1. What might go wrong?
2. What is the likelihood (probability) it will go wrong?
3. What are the consequences (severity)?

Hazard identification is a systematic use of information to identify hazards referring to the risk
question or problem description. Information can include historical data, theoretical analysis,
informed opinions, and the concerns of stakeholders. Hazard identification addresses the “What
might go wrong?” question, including identifying the possible consequences. This provides the
basis for further steps in the quality risk management process.

Risk analysis is the estimation of the risk associated with the identified hazards. It is the
qualitative or quantitative process of linking the likelihood of occurrence and severity of harms.
In some risk management tools, the ability to detect the harm (detectability) also factors in the
estimation of risk.

Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk
evaluations consider the strength of evidence for all three of the fundamental questions.
In doing an effective risk assessment, the robustness of the data set is important because it

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determines the quality of the output. Revealing assumptions and reasonable sources of
uncertainty will enhance confidence in this output and/or help identify its limitations.

Uncertainty is due to a combination of incomplete knowledge about a process and its expected
or unexpected variability. Typical sources of uncertainty include gaps in knowledge, gaps in
pharmaceutical science and process understanding, sources of harm (e.g., failure modes of a
process, sources of variability), and probability of detection of problems.

The output of a risk assessment is either a quantitative estimate of risk or a qualitative
description of a range of risk. When risk is expressed quantitatively, a numerical probability is
used. Alternatively, risk can be expressed using qualitative descriptors, such as “high”,
“medium”, or “low”, which should be defined in as much detail as possible. Sometimes a "risk
score" is used to further define descriptors in risk ranking. In quantitative risk assessments, a
risk estimate provides the likelihood of a specific consequence, given a set of risk-generating
circumstances. Thus, quantitative risk estimation is useful for one particular consequence at a
time. Alternatively, some risk management tools use a relative risk measure to combine
multiple levels of severity and probability into an overall estimate of relative risk. The
intermediate steps within a scoring process can sometimes employ quantitative risk estimation.

4.4. Risk Control
Risk control includes decision-making to reduce and/or accept risks. The purpose of risk
control is to reduce the risk to an acceptable level. The amount of effort used for risk control
should be proportional to the significance of the risk. Decision makers might use different
processes, including benefit-cost analysis, for understanding the optimal level of risk control.

Risk control might focus on the following questions:
1. Is the risk above an acceptable level?
2. What can be done to reduce or eliminate risks?
3. What is the appropriate balance among benefits, risks and resources?
4. Are new risks introduced as a result of the identified risks being controlled?

Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds
a specified (acceptable) level (see Fig. 1). Risk reduction might include actions taken to
mitigate the severity and probability of harm. Processes that improve the detectability of
hazards and quality risks might also be used as part of a risk control strategy. The
implementation of risk reduction measures can introduce new risks into the system or increase
the significance of other existing risks. Hence, it might be appropriate to revisit the risk
assessment to identify and evaluate any possible change in risk after implementing a risk
reduction process.

Risk acceptance is a decision to accept risk. For some types of harms, even the best quality
risk management practices might not entirely eliminate risk. In these circumstances, it might
be agreed that an appropriate quality risk management strategy has been applied and that
quality risk is reduced to a specified (acceptable) level. This (specified) acceptable level will
depend on many parameters and should be decided on a case-by-case basis.

4.5. Risk Communication
Risk communication is the sharing of information about risk and risk management between

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the decision makers and others. Parties can communicate at any stage of the risk management
process (see Fig. 1: dashed arrows). The output/result of the quality risk management process
should be appropriately communicated and documented (see Fig. 1: solid arrows).
Communications might include those among interested parties; e.g., regulators and industry,
industry and the patient, within a company, industry or regulatory authority, etc. The included
information might relate to the existence, nature, form, probability, severity, acceptability,
control, treatment, detectability or other aspects of risks to quality. Communication need not
be carried out for each and every risk acceptance. Between the industry and regulatory
authorities, communication concerning quality risk management decisions might be conducted
through existing channels as specified in regulations and guidances.

4.6. Risk Review
Risk management should be an ongoing part of the quality management process. A mechanism
to review or monitor events should be implemented.

The output/results of the risk management process should be reviewed to take into account new
knowledge and experience. Once a quality risk management process has been initiated, that
process should continue to be utilized for events that might impact the original quality risk
management decision, whether these events are planned (e.g., results of product review,
inspections, audits, change control) or unplanned (e.g., root cause from failure investigations,
recall). The frequency of any review should be based upon the level of risk. Risk review might
include reconsideration of risk acceptance decisions (section 4.4).

5. RISK MANAGEMENT METHODOLOGY
Quality risk management supports a scientific and practical approach to decision-making. It
provides documented, transparent and reproducible methods to accomplish steps of the quality
risk management process based on current knowledge about assessing the probability, severity
and sometimes detectability of the hazards, and their associated risks. While detectability may
not be a discrete factor in some quality risk management methods, detection controls are
important as they can reduce the probability of occurrence of harm.

Traditionally, risks to quality have been assessed and managed in a variety of ways (empirical
and/or internal procedures) based on, for example, compilation of observations, trends and
other information. Such approaches continue to provide useful information that might support
topics such as handling of complaints, quality defects, deviations and allocation of resources.

Additionally, the pharmaceutical industry and regulators can assess and manage risk using
recognized risk management tools and/ or internal procedures (e.g., standard operating
procedures). Below is a non-exhaustive list of some of these tools (further details in Annex 1
and section 8):
•
Basic risk management facilitation methods (flowcharts, check sheets etc.);
•
Failure Mode Effects Analysis (FMEA);
•
Failure Mode, Effects and Criticality Analysis (FMECA);
•
Fault Tree Analysis (FTA);
•
Hazard Analysis and Critical Control Points (HACCP);
•
Hazard Operability Analysis (HAZOP);
•
Preliminary Hazard Analysis (PHA);

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ICH Q9(R1) Guideline

•
Risk ranking and filtering;
•
Supporting statistical tools.

It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance
and drug (medicinal) product quality. Quality risk management methods and the supporting
statistical tools can be used in combination (e.g., Probabilistic Risk Assessment). Combined
use provides flexibility that can facilitate the application of quality risk management principles.

The degree of rigor and formality of quality risk management should reflect available
knowledge and be commensurate with the level of uncertainty, importance and complexity of
the issue to be addressed.

### 5.1 Formality in Quality Risk Management

Formality in quality risk management is not a binary concept (i.e. formal/informal); varying
degrees of formality may be applied during quality risk management activities, including when
making risk-based decisions. In this way, formality can be considered a continuum (or
spectrum), ranging from low to high.

When determining how much formality to apply to a given quality risk management activity,
certain factors may be considered. These may include, for example, the following:

•
Uncertainty: The term “uncertainty” in quality risk management means lack of knowledge
about hazards, harms and, consequently, their associated risks. The level of uncertainty
that is associated with the area being risk assessed informs how much formality may be
required to manage potential risks. Systematic approaches for acquiring, analysing, storing
and disseminating scientific information are essential for generating knowledge, which in
turn informs all quality risk management activities. Uncertainty may be reduced via
effective knowledge management, which enables accumulated and new information (both
internal and external) to be used to support risk-based decisions throughout the product
lifecycle.
•
Importance: The more important a risk-based decision may be in relation to product
quality, the higher the level of formality that should be applied, and the greater the need to
reduce the level of uncertainty associated with it.
•
Complexity: The more complex a process or subject area is to a quality risk management
activity, the higher the level of formality that should be applied to assure product quality.

Higher levels of uncertainty, importance or complexity may require more formal quality risk
management approaches to manage potential risks and to support effective risk-based decision-
making.

The overall approach for determining how much formality to apply during quality risk
management activities should be described within the quality system.  Resource constraints
should not be used to justify the use of lower levels of formality in the quality risk management
process. Risk scores, ratings and assessments should be based on an appropriate use of
evidence, science and knowledge. Regardless of how much formality is applied, the robust
management of risk is the goal of the process.

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The following may be characteristics of higher levels of formality:
•
All parts of the quality risk management process (risk assessment, risk control, risk
review and risk communication) are explicitly performed, and stand-alone quality risk
management reports or related documents which address all aspects of the process may
be generated and are documented (e.g., within the quality system).
•
Quality risk management tools, including those shown in Annex 1, are used in some or
all parts of the process.
•
A cross-functional team is assembled for the quality risk management activity.
•
Use of a facilitator, with experience and knowledge of the quality risk management
process, may be integral to a higher formality process.

The following may be characteristics of lower levels of formality:
•
One or more parts of the quality risk management process are not performed as stand-
alone activities but are addressed within other elements of the quality system which may
have risk assessment and risk control activities embedded within them.
•
Quality risk management tools might not be used in some or all parts of the process.
•
A cross-functional team might not be necessary.
•
Stand-alone quality risk management reports might not be generated. The outcome of the
quality risk management process is usually documented in the relevant parts of the
quality system.

Note: As indicated above, degrees of formality between the above higher and lower levels also
exist and may be used.

### 5.2 Risk-Based Decision-Making

Risk-based decision-making is inherent in all quality risk management activities; it provides
an essential foundation for decision makers in an organization. Effective risk-based decision-
making begins with determining the level of effort, formality and documentation that should
be applied during the quality risk management process. The decisions made from quality risk
management activities include those in relation to what hazards exist, the risks associated with
those hazards, the risk controls required, the acceptability of the residual risk after risk controls,
and also the communication and review of quality risk management activities and outputs.

As all decision-making relies on the use of knowledge, see ICH Q10 for guidance in relation
to knowledge management. It is important also to ensure the integrity of the data that are used
for risk-based decision-making.

Approaches to risk-based decision-making:

There are different processes that may be used to make risk-based decisions; these are directly
related to the level of formality that is applied during the quality risk management process.
(See Section 5.1 above for guidance on what constitutes formality in quality risk management.)

Higher levels of formality in quality risk management may require higher levels of structure in
relation to risk-based decision-making. There can be varying degrees of structure with regard
to approaches for risk-based decision-making. These degrees of structure can be considered to
be on a continuum (or spectrum). Below are descriptions of highly structured vs. less structured
processes, and for rule-based processes when making risk-based decisions:

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•
Some risk-based decision-making processes are highly structured and can involve a formal
analysis of the available options that exist before making a decision. They involve an in-
depth consideration of relevant factors associated with the available options. Such
processes might be used when there is a high degree of importance associated with the
decision, and when the level of uncertainty and/or complexity is high.
•
Other risk-based decision-making processes are less structured; here, simpler approaches
are used to arrive at decisions, and they primarily make use of existing knowledge to
support an assessment of hazards, risks and any required risk controls. Such processes
might still be used when there is a high degree of importance associated with the decision,
but the degree of uncertainty and/or complexity is lower.
•
Decisions might also be made using rule-based (or standardized) approaches, which do not
require a new risk assessment to make such decisions. This is where there are SOPs,
policies or well understood requirements in place which determine what decisions must be
made. Here, rules (or limits) may be in place which govern such decisions; these may be
based on a previously obtained understanding of the relevant risks and they usually lead
to predetermined actions and/or expected outcomes.

The above approaches to risk-based decision-making are beneficial because they address
uncertainty through the use of knowledge, facilitating informed decisions by regulators and the
pharmaceutical industry in a multitude of areas. They also help recognize where uncertainty
remains, so that appropriate risk controls (including improved detection) may be identified to
enhance understanding of those variables and further reduce the level of uncertainty.

### 5.3 Managing and Minimizing Subjectivity

Subjectivity can impact every stage of a quality risk management process, especially the
identification of hazards and the estimation of probability of occurrence and severity of harm.
It can also impact the estimation of risk reduction and the effectiveness of decisions made from
quality risk management activities.

Subjectivity can be introduced in quality risk management through differences in how risks are
assessed and in how hazards, harms and risks are perceived by different stakeholders, (e.g.,
bias). Subjectivity can also be introduced when risk questions are inadequately defined, and
when tools have poorly designed risk scoring scales.

While subjectivity cannot be completely eliminated from quality risk management activities, it
may be controlled by addressing bias and assumptions, the proper use of quality risk
management tools and maximizing the use of relevant data and sources of knowledge (see ICH
Q10, Section 1.6.1).

All participants involved with quality risk management activities should acknowledge,
anticipate, and address the potential for subjectivity.

6. INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND
REGULATORY OPERATIONS
Quality risk management is a process that supports science-based and practical decisions when
integrated into quality systems (see Annex II). As outlined in the introduction, appropriate use
of quality risk management does not obviate industry’s obligation to comply with regulatory

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ICH Q9(R1) Guideline

requirements. However, effective quality risk management can facilitate better and more
informed decisions, can provide regulators with greater assurance of a company’s ability to
deal with potential risks, and might affect the extent and level of direct regulatory oversight. In
addition, quality risk management can facilitate better use of resources by all parties.

Training of both industry and regulatory personnel in quality risk management processes
provides for greater understanding of decision-making processes and builds confidence in
quality risk management outcomes.

Quality risk management should be integrated into existing operations and documented
appropriately. Annex II provides examples of situations in which the use of the quality risk
management process might provide information that could then be used in a variety of
pharmaceutical operations. These examples are provided for illustrative purposes only and
should not be considered a definitive or exhaustive list. These examples are not intended to
create any new expectations beyond the requirements laid out in the current regulations.

Examples for industry and regulatory operations (see Annex II):
• Quality management.
Examples for industry operations and activities (see Annex II):
• Development;
• Facility, equipment and utilities;
• Materials management;
• Production;
• Laboratory control and stability testing;
• Packaging and labeling;
• Supply chain control.
Examples for regulatory operations (see Annex II):
• Inspection and assessment activities.

While regulatory decisions will continue to be taken on a regional basis, a common
understanding and application of quality risk management principles could facilitate mutual
confidence and promote more consistent decisions among regulators on the basis of the same
information. This collaboration could be important in the development of policies and
guidelines that integrate and support quality risk management practices.

### 6.1 The role of Quality Risk Management in Addressing Product Availability Risks

Arising from Quality/Manufacturing Issues
Quality/manufacturing issues, including non-compliance with Good Manufacturing Practice
(GMP), are a significant cause of product availability issues (e.g., product shortages). The
interests of patients are served by risk-based drug shortage prevention and mitigation activities
that help to proactively manage supply chain complexities and ensure availability of needed
drug (medicinal) products.

While manufacturing and supply chain diversity can be enablers of product availability,
increasingly complex supply chains lead to interdependencies that can introduce systemic
quality/manufacturing risks impacting supply chain robustness. The application of quality risk
management enables the proactive identification and implementation of preventive measures
that support product availability.

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An effective pharmaceutical quality system drives both supply chain robustness and sustainable
GMP compliance. The pharmaceutical quality system, including management responsibilities,
also uses quality risk management and knowledge management to provide an early warning
system that supports effective oversight and response to evolving quality/manufacturing risks
from the pharmaceutical company or its external partners. When risk-based drug shortage
prevention and mitigation activities are performed, the level of formality that is applied to those
activities may vary (see Section 5.1) and should be commensurate with the level of risk
associated with a loss of availability of the product(s).

Quality/manufacturing factors that can affect supply reliability, and hence product availability,
include, but are not limited to, the following:

a) Manufacturing Process Variability and State of Control:
Processes that exhibit excessive variability (e.g., process drift, non-uniformity) have capability
gaps that can result in unpredictable outputs (e.g., quality, timeliness and yield) and
consequently can adversely impact product availability. Quality risk management can help
design monitoring systems that are capable of detecting departures from a state of control and
deficiencies in manufacturing processes, so they can be investigated to address root causes.

b) Manufacturing Facilities and Equipment:
A robust facility infrastructure can facilitate reliable supply; it includes suitable equipment and
well-designed facilities for manufacturing (including packaging and testing). Robustness can
be affected by multiple factors, such as an aging facility, insufficient maintenance or an
operational design that is vulnerable to human error. Risks to supply can be reduced by
addressing these factors, as well as through the use of modern technology, such as
digitalization, automation, isolation technology, amongst others.

c) Oversight of Outsourced Activities and Suppliers:
Quality system governance includes assuring the acceptability of supply chain partners over
the product lifecycle. Approval and oversight of outsourced activities and material suppliers is
informed by risk assessments, effective knowledge management, and an effective monitoring
strategy for supply chain partner performance. A successful manufacturing partnership is
strengthened by appropriate communication and collaboration mechanisms (See Section 2.7 of
ICH Q10). When substantial variability is identified in the quality and safety of supplied
materials or in the services provided, enhanced review and monitoring activities are justified.
In some cases, it may be necessary to identify a new supply chain entity (e.g., a pre-qualified
alternative option) to perform a function.

Note that the guidance in Annex II.2, in relation to the application of quality risk management
as part of Regulatory Operations, can be useful to consider in the context of product availability
risks.

7. DEFINITIONS
Decision Maker(s):
Person(s) with the competence and authority to make appropriate and timely quality risk
management decisions.

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Detectability:
The ability to discover or determine the existence, presence, or fact of a hazard.

Harm:
Damage to health, including the damage that can occur from loss of product quality or
availability.

Hazard:
The potential source of harm (ISO/IEC Guide 51:2014).

Hazard Identification:
The systematic use of information to identify potential sources of harm (hazards) referring to
the risk question or problem description.

Product Lifecycle:
All phases in the life of the product from the initial development through marketing until the
product’s discontinuation.

Quality:
The degree to which a set of inherent properties of a product, system or process fulfills
requirements (see ICH Q6A definition specifically for “quality” of drug substance and drug
(medicinal) products.)

Quality Risk Management:
A systematic process for the assessment, control, communication and review of risks to the
quality of the drug (medicinal) product across the product lifecycle.

Quality System:
The sum of all aspects of a system that implements quality policy and ensures that quality
objectives are met.

Requirements:
The explicit or implicit needs or expectations of the patients or their surrogates (e.g., health
care professionals, regulators and legislators). In this document, “requirements” refers not only
to statutory, legislative, or regulatory requirements, but also to such needs and expectations.

Risk:
The combination of the probability of occurrence of harm and the severity of that harm
(ISO/IEC Guide 51:2014).

Risk Acceptance:
An informed decision to take a particular risk. (ISO Guide 73:2009).

Risk Analysis:
The estimation of the risk associated with the identified hazards.

Risk Assessment:
A systematic process of organizing information to support a risk decision to be made within a
risk management process. It consists of the identification of hazards and the analysis and
evaluation of risks associated with exposure to those hazards.

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Risk-Based Decision-Making:
An approach to, or a process of, making decisions that considers knowledge about risks
relevant to the decision and whether risks are at an acceptable level.

Risk Communication:
The sharing of information about risk and risk management between the decision maker and
other stakeholders.

Risk Control:
Actions implementing risk management decisions (ISO Guide 73:2009).

Risk Evaluation:
The comparison of the estimated risk to given risk criteria using a quantitative or qualitative
scale to determine the significance of the risk.

Risk Management:
The systematic application of quality management policies, procedures, and practices to the
tasks of assessing, controlling, communicating and reviewing risk.

Risk Reduction:
Actions taken to lessen the probability of occurrence of harm and the severity of that harm.

Risk Review:
Review or monitoring of output/results of the risk management process considering (if
appropriate) new knowledge and experience about the risk.

Severity:
A measure of the possible consequences of a hazard.

Stakeholder:
Any individual, group or organization that can affect, be affected by, or perceive itself to be
affected by a risk. Decision makers might also be stakeholders. For the purposes of this
guideline, the primary stakeholders are the patient, healthcare professional, regulatory
authority, and industry.

Trend:
A statistical term referring to the direction or rate of change of a variable(s).

8. REFERENCES
1. ICH Q8 Pharmaceutical Development.
2. ICH Q10 Pharmaceutical Quality System.
3. ICH Q11 Development and Manufacture of Drug Substances (Chemical Entities and
Biotechnological/Biological Entities).
4. ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management.
5. ISO/IEC Guide 73:2009 - Risk Management - Vocabulary - Guidelines for use in
Standards.
6. ISO/IEC Guide 51:2014 - Safety Aspects - Guideline for their inclusion in standards.

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ICH Q9(R1) Guideline

7. IEC 61025 - Fault Tree Analysis (FTA).
8. IEC 60812:2018 Failure modes and effects analysis (FMEA and FMECA).
9. IEC 61882:2016 - Hazard and operability studies (HAZOP studies) – Application guide.
10. ISO 14971:2019 – Medical devices - Application of risk management to medical devices.
11. ISO 7870-1:2019 - Control Charts, General guidelines.
12. ISO 7870-4:2021- Cumulative Sum Charts.
13. ISO 7870-3:2020 - Acceptance Control Charts.
14. ISO 7870-2:2013 - Shewhart Control Charts.
15. WHO Technical Report Series No 908, 2003, Annex 7 Application of Hazard Analysis
and Critical Control Point (HACCP) methodology to pharmaceuticals.
16. What is Total Quality Control?; The Japanese Way, Kaoru Ishikawa (Translated by David
J. Liu), 1985, ISBN 0139524339.
17. Failure Mode and Effect Analysis, FMEA from Theory to Execution, 2nd Edition 2003, D.
H. Stamatis, ISBN 0873895983.
18. Process Mapping by the American Productivity & Quality Center, 2002, ISBN
1928593739.
19. Parenteral Drug Association. Technical Report No. 54 Implementation of quality risk
management for pharmaceutical and biotechnology manufacturing operations. 2012.
20. Parenteral Drug Association. Points to consider for aging facilities. 2017.
21. Parenteral Drug Association. Technical Report No. 68. Risk-based approach for
prevention and management of drug shortages. 2014.
22. International Society for Pharmaceutical Engineering. Report on the ISPE Drug shortages
survey. 2013.
23. International Society for Pharmaceutical Engineering. Drug shortages prevention plan.
2014.
24. Tabersky D, Woelfle M, Ruess J, Brem S, Brombacher S. Recent regulatory trends in
pharmaceutical
manufacturing
and
their
impact
on
the
industry. CHIMIA,
2018;72(3):146-150.
25. O’Donnell K, Tobin D, Butler S, Haddad G, Kelleher D. Understanding the concept of
formality in quality risk management. J. Valid. Technol, 2020 Jun; 26(3).

=== PAGE 19 ===
ICH Q9(R1) Guideline

ANNEX I: QUALITY RISK MANAGEMENT METHODS AND TOOLS
The purpose of this annex is to provide a general overview of and references for some of the
primary tools that might be used in quality risk management by industry and regulators. The
references are included as an aid to gain more knowledge and detail about the particular tool.
This is not an exhaustive list. It is important to note that no one tool or set of tools is applicable
to every situation in which a quality risk management procedure is used.

It is neither always appropriate nor always necessary to use highly formal quality risk
management methods and tools. The use of less formal quality risk management methods and
tools can also be considered acceptable. See Section 5.1 for guidance on what constitutes
formality in quality risk management.

I.1 Basic Risk Management Facilitation Methods
Some of the simple techniques that are commonly used to structure risk management by
organizing data and facilitating decision-making are:
•
Flowcharts;
•
Check Sheets;
•
Process Mapping;
•
Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram).

I.2 Failure Mode Effects Analysis (FMEA)
FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and
their likely effect on outcomes and/or product performance. Once failure modes are established,
risk reduction can be used to eliminate, contain, reduce or control the potential failures. FMEA
relies on product and process understanding. FMEA methodically breaks down the analysis of
complex processes into manageable steps. It is a powerful tool for summarizing the important
modes of failure, factors causing these failures and the likely effects of these failures.

Potential Areas of Use(s)
FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities.
FMEA can be applied to equipment and facilities and might be used to analyze a manufacturing
operation and its effect on product or process. It identifies elements/operations within the
system that render it vulnerable. The output/ results of FMEA can be used as a basis for design
or further analysis or to guide resource deployment.

I.3 Failure Mode, Effects and Criticality Analysis (FMECA)
FMEA might be extended to incorporate an investigation of the degree of severity of the
consequences, their respective probabilities of occurrence, and their detectability, thereby
becoming a Failure Mode Effect and Criticality Analysis (FMECA; see IEC 60812). In order
for such an analysis to be performed, the product or process specifications should be
established. FMECA can identify places where additional preventive actions might be
appropriate to minimize risks.

Potential Areas of Use(s)
FMECA application in the pharmaceutical industry should mostly be utilized for failures and
risks associated with manufacturing processes; however, it is not limited to this application.

=== PAGE 20 ===
ICH Q9(R1) Guideline

The output of an FMECA is a relative risk “score” for each failure mode, which is used to rank
the modes on a relative risk basis.

I.4 Fault Tree Analysis (FTA)
The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a
product or process. This tool evaluates system (or sub-system) failures one at a time but can
combine multiple causes of failure by identifying causal chains. The results are represented
pictorially in the form of a tree of fault modes. At each level in the tree, combinations of fault
modes are described with logical operators (AND, OR, etc.). FTA relies on the experts’ process
understanding to identify causal factors.

Potential Areas of Use(s)
FTA can be used to establish the pathway to the root cause of the failure. FTA can be used to
investigate complaints or deviations in order to fully understand their root cause and to ensure
that intended improvements will fully resolve the issue and not lead to other issues (i.e. solve
one problem yet cause a different problem). Fault Tree Analysis is an effective tool for
evaluating how multiple factors affect a given issue. The output of an FTA includes a visual
representation of failure modes. It is useful both for risk assessment and in developing
monitoring programs.

I.5 Hazard Analysis and Critical Control Points (HACCP)
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability,
and safety (see WHO Technical Report Series No 908, 2003 Annex 7). It is a structured
approach that applies technical and scientific principles to analyze, evaluate, prevent, and
control the risk or adverse consequence(s) of haard(s) due to the design, development,
production, and use of products.

HACCP consists of the following seven steps:
(1)
conduct a hazard analysis and identify preventive measures for each step of the process;
(2)
determine the critical control points;
(3)
establish critical limits;
(4)
establish a system to monitor the critical control points;
(5)
establish the corrective action to be taken when monitoring indicates that the critical
control points are not in a state of control;
(6)
establish system to verify that the HACCP system is working effectively;
(7)
establish a record-keeping system.

Potential Areas of Use(s)
HACCP might be used to identify and manage risks associated with physical, chemical and
biological hazards (including microbiological contamination). HACCP is most useful when
product and process understanding is sufficiently comprehensive to support identification of
critical control points. The output of a HACCP analysis is risk management information that
facilitates monitoring of critical points not only in the manufacturing process but also in other
life cycle phases.

=== PAGE 21 ===
ICH Q9(R1) Guideline

I.6 Hazard Operability Analysis (HAZOP)
HAZOP (see IEC 61882) is based on a theory that assumes that risk events are caused by
deviations from the design or operating intentions. It is a systematic brainstorming technique
for identifying hazards using so-called “guide-words”. “Guide-words” (e.g., No, More, Other
Than, Part of, etc.) are applied to relevant parameters (e.g., contamination, temperature) to help
identify potential deviations from normal use or design intentions. It often uses a team of people
with expertise covering the design of the process or product and its application.

Potential Areas of Use(s)
HAZOP can be applied to manufacturing processes, including outsourced production and
formulation as well as the upstream suppliers, equipment and facilities for drug substances and
drug (medicinal) products. It has also been used primarily in the pharmaceutical industry for
evaluating process safety hazards. As is the case with HACCP, the output of a HAZOP analysis
is a list of critical operations for risk management. This facilitates regular monitoring of critical
points in the manufacturing process.

I.7 Preliminary Hazard Analysis (PHA)
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure
to identify future hazards, hazardous situations and events that might cause harm, as well as to
estimate their probability of occurrence for a given activity, facility, product or system. The
tool consists of: 1) the identification of the possibilities that the risk event happens, 2) the
qualitative evaluation of the extent of possible injury or damage to health that could result, 3)
a relative ranking of the hazard using a combination of severity and likelihood of occurrence,
and 4) the identification of possible remedial measures.

Potential Areas of Use(s)
PHA might be useful when analyzing existing systems or prioritizing hazards where
circumstances prevent a more extensive technique from being used. It can be used for product,
process and facility design as well as to evaluate the types of hazards for the general product
type, then the product class, and finally the specific product. PHA is most commonly used early
in the development of a project when there is little information on design details or operating
procedures; thus, it will often be a precursor to further studies. Typically, hazards identified in
the PHA are further assessed with other risk management tools such as those in this section.

I.8 Risk Ranking and Filtering
Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex
systems typically requires evaluation of multiple diverse quantitative and qualitative factors
for each risk. The tool involves breaking down a basic risk question into as many components
as needed to capture factors involved in the risk. These factors are combined into a single
relative risk score that can then be used for ranking risks. “Filters,” in the form of weighting
factors or cut-offs for risk scores, can be used to scale or fit the risk ranking to management or
policy objectives.

Potential Areas of Use(s)
Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by
regulators or industry. Risk ranking methods are particularly helpful in situations in which the
portfolio of risks and the underlying consequences to be managed are diverse and difficult to

=== PAGE 22 ===
ICH Q9(R1) Guideline

compare using a single tool. Risk ranking is useful when management needs to evaluate both
quantitatively-assessed and qualitatively-assessed risks within the same organizational
framework.

I.9 Supporting Statistical Tools
Statistical tools can support and facilitate quality risk management. They can enable effective
data assessment, aid in determining the significance of the data set(s), and facilitate more
reliable decision-making. A listing of some of the principal statistical tools commonly used in
the pharmaceutical industry is provided:
•
Control Charts, for example:
-
Acceptance Control Charts (see ISO 7870-3:2020);
-
Cumulative Sum Charts (see ISO 7870-4:2021);
-
Shewhart Control Charts (see ISO 7870-2:2013);
-
Weighted Moving Average.
•
Design of Experiments (DOE);
•
Histograms;
•
Pareto Charts;
•
Process Capability Analysis.

=== PAGE 23 ===
ICH Q9(R1) Guideline

ANNEX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT
This Annex is intended to identify potential uses of quality risk management principles and
tools by industry and regulators. However, the selection of particular risk management tools is
completely dependent upon specific facts and circumstances.

These examples are provided for illustrative purposes and only suggest potential uses of quality
risk management. This Annex is not intended to create any new expectations beyond the current
regulatory requirements.

II.1 Quality Risk Management as Part of Integrated Quality Management
Documentation
To review current interpretations and application of regulatory expectations;

To determine the desirability of and/or develop the content for SOPs, guidelines, etc.

Training and education

To determine the appropriateness of initial and/or ongoing training sessions based on
education, experience and working habits of staff, as well as on a periodic assessment of
previous training (e.g., its effectiveness);

To identify the training, experience, qualifications and physical abilities that allow personnel
to perform an operation reliably and with no adverse impact on the quality of the product.

Quality defects

To provide the basis for identifying, evaluating, and communicating the potential quality
impact of a suspected quality defect, complaint, trend, deviation, investigation, out of
specification result, etc;

To facilitate risk communications and determine appropriate action to address significant
product defects, in conjunction with regulatory authorities (e.g., recall).

Auditing/Inspection

To define the frequency and scope of audits, both internal and external, taking into account
factors such as:
•
Existing legal requirements;
•
Overall compliance status and history of the company or facility;
•
Robustness of a company’s quality risk management activities;
•
Complexity of the site;
•
Complexity of the manufacturing process;
•
Complexity of the product and its therapeutic significance;
•
Number and significance of quality defects (e.g., recall);
•
Results of previous audits/inspections;
•
Major changes of building, equipment, processes, key personnel;
•
Experience with manufacturing of a product (e.g., frequency, volume, number of

batches);

=== PAGE 24 ===
ICH Q9(R1) Guideline

•
Test results of official control laboratories.

Periodic review

To select, evaluate and interpret trend results of data within the product quality review;

To interpret monitoring data (e.g., to support an assessment of the appropriateness of
revalidation or changes in sampling).

Change management / change control

To manage changes based on knowledge and information accumulated in pharmaceutical
development and during manufacturing;

To evaluate the impact of the changes on the availability of the final product;

To evaluate the impact on product quality of changes to the facility, equipment, material,
manufacturing process or technical transfers;

To determine appropriate actions preceding the implementation of a change, e.g., additional
testing, (re)qualification, (re)validation or communication with regulators.

Continual improvement

To facilitate continual improvement in processes throughout the product lifecycle.
II.2 Quality Risk Management as Part of Regulatory Operations Inspection and
assessment activities
To assist with resource allocation including, for example, inspection planning and frequency,
and inspection and assessment intensity (see "Auditing" section in Annex II.1);

To evaluate the significance of, for example, quality defects, potential recalls and inspectional
findings;

To determine the appropriateness and type of post-inspection regulatory follow-up;

To evaluate information submitted by industry including pharmaceutical development
information;

To evaluate impact of proposed variations or changes;

To identify risks which should be communicated between inspectors and assessors to facilitate
better understanding of how risks can be or are controlled (e.g., parametric release, Process
Analytical Technology (PAT)).
II.3 Quality Risk Management as Part of Development
To design a quality product and its manufacturing process to consistently deliver the intended
performance of the product (see ICH Q8);

=== PAGE 25 ===
ICH Q9(R1) Guideline

To enhance knowledge of product performance over a wide range of material attributes (e.g.,
particle size distribution, moisture content, flow properties), processing options and process
parameters;

To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient
(API) starting materials, APIs, excipients, or packaging materials;

To establish appropriate specifications, identify critical process parameters and establish
manufacturing controls (e.g., using information from pharmaceutical development studies
regarding the clinical significance of quality attributes and the ability to control them during
processing);

To decrease variability of quality attributes:
• reduce product and material defects;
• reduce manufacturing defects.

To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up
and technology transfer;

To make use of the “design space” concept (see ICH Q8).
II.4 Quality Risk Management for Facilities, Equipment and Utilities
Design of facility / equipment

To determine appropriate zones when designing buildings and facilities, e.g.,
•
flow of material and personnel;
•
minimize contamination;
•
pest control measures;
•
prevention of mix-ups;
•
open versus closed equipment;
•
clean rooms versus isolator technologies;
•
dedicated or segregated facilities / equipment.

To determine appropriate product contact materials for equipment and containers (e.g.,
selection of stainless steel grade, gaskets, lubricants);

To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating,
ventilation and air conditioning (HVAC), water);

To determine appropriate preventive maintenance for associated equipment (e.g., inventory of
necessary spare parts).

Hygiene aspects in facilities

To protect the product from environmental hazards, including chemical, microbiological, and
physical hazards (e.g., determining appropriate clothing and gowning, hygiene concerns);

=== PAGE 26 ===
ICH Q9(R1) Guideline

To protect the environment (e.g., personnel, potential for cross-contamination) from hazards
related to the product being manufactured.

Qualification of facility/equipment/utilities

To determine the scope and extent of qualification of facilities, buildings, and production
equipment and/or laboratory instruments (including proper calibration methods).

Cleaning of equipment and environmental control

To differentiate efforts and decisions based on the intended use (e.g., multi- versus single-
purpose, batch versus continuous production);

To determine acceptable (specified) cleaning validation limits.

Calibration/preventive maintenance

To set appropriate calibration and maintenance schedules.

Computer systems and computer controlled equipment

To select the design of computer hardware and software (e.g., modular, structured, fault
tolerance);

To determine the extent of validation, e.g.,
• identification of critical performance parameters;
• selection of the requirements and design;
• code review;
• the extent of testing and test methods;
• reliability of electronic records and signatures.
II.5 Quality Risk Management as Part of Materials Management
Assessment and evaluation of suppliers and contract manufacturers

To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing,
supplier quality agreements).

Starting material

To assess differences and possible quality risks associated with variability in starting materials
(e.g., age, route of synthesis).

Use of materials

To determine whether it is appropriate to use material under quarantine (e.g., for further internal
processing);

To determine appropriateness of reprocessing, reworking, use of returned goods.

=== PAGE 27 ===
ICH Q9(R1) Guideline

Storage, logistics and distribution conditions

To assess the adequacy of arrangements to ensure maintenance of appropriate storage and
transport conditions (e.g., temperature, humidity, container design);

To determine the effect on product quality of discrepancies in storage or transport conditions
(e.g., cold chain management) in conjunction with other ICH guidelines;

To maintain infrastructure (e.g., capacity to ensure proper shipping conditions, interim storage,
handling of hazardous materials and controlled substances, customs clearance);

To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to
the supply chain).
II.6 Quality Risk Management as Part of Production
Validation

To identify the scope and extent of verification, qualification and validation activities (e.g.,
analytical methods, processes, equipment and cleaning methods);

To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation);

To distinguish between critical and non-critical process steps to facilitate design of a validation
study.

In-process sampling & testing

To evaluate the frequency and extent of in-process control testing (e.g., to justify reduced
testing under conditions of proven control);

To evaluate and justify the use of process analytical technologies (PAT) in conjunction with
parametric and real time release.

Production planning

To determine appropriate production planning (e.g., dedicated, campaign and concurrent
production process sequences).
II.7 Quality Risk Management as Part of Laboratory Control and Stability Studies
Out of specification results

To identify potential root causes and corrective actions during the investigation of out of
specification results.

Retest period / expiration date

To evaluate adequacy of storage and testing of intermediates, excipients and starting materials.

=== PAGE 28 ===
ICH Q9(R1) Guideline

II.8 Quality Risk Management as Part of Packaging and Labeling
Design of packages

To design the secondary package for the protection of primary packaged product (e.g., to ensure
product authenticity, label legibility).

Selection of container closure system

To determine the critical parameters of the container closure system.

Label controls

To design label control procedures based on the potential for mix-ups involving different
product labels, including different versions of the same label.
II.9 Quality Risk Management as Part of Supply Chain Control
With regard to product availability risks related to quality/manufacturing issues, product
lifecycle oversight of the supply chain includes maintaining current knowledge of
quality/manufacturing hazards and prioritizing efforts to manage such risks. Understanding
hazards to quality/manufacturing is critical to maintaining supply predictability. When risks are
well understood and controlled, a higher confidence in product availability can be attained.

Manufacturing Process Variation and State of Control

To decrease variability in the manufacturing process (e.g., process drift, non-uniformity) and
associated capability gaps that can result in unpredictable outputs, adversely impact quality
and consequently timeliness, yield and product availability;

To design monitoring systems that are capable of detecting departures from a state of control
and deficiencies in manufacturing processes, so they can be appropriately investigated to
determine root causes and any required risk mitigations.

Manufacturing Facilities and Equipment

To ensure that facility infrastructure and equipment are suitable and designed for robust
manufacturing (this includes packaging and testing) (see Annex II.4);

To establish facility and equipment maintenance programmes that assure reliable facility and
equipment performance;

To ensure that the operational design of equipment is not vulnerable to human error;

To obtain quality and efficiency gains through the utilization of digitalization, automation,
isolation technology, and other innovations.

Supplier Oversight and Relationships

To enhance review and monitoring activities (see Section 2.7 of ICH Q10) when substantial

=== PAGE 29 ===
ICH Q9(R1) Guideline

variability is identified in the quality and safety of supplied materials or in the services
provided.

To manage external product availability risks relating to quality/manufacturing, (e.g., from raw
material suppliers, contracted organizations, service providers, etc.)

---

### Document: Sterile Pharmaceutical Manufacturing: A Review of Barrier Isolation Technologies, Environmental Monitoring Systems, and QA/QC Validation Standards under EU GMP Annex 1 (PLS Academic Review)

# Sterile Pharmaceutical Manufacturing: A Review of Barrier Isolation Technologies, Environmental Monitoring Systems, and QA/QC Validation Standards under EU GMP Annex 1

**Author:** Priya Life Science Academic Editorial Board  
**Published:** June 2026  
**Document Classification:** Technical Report (PLS-TR-2026-001)  
**Subject Area:** Pharmaceutical Engineering, Quality Assurance, Quality Control, Sterile Processing Compliance  

---

## Abstract
Modern sterile pharmaceutical manufacturing requires a holistic contamination control strategy (CCS) to eliminate the risk of microbial and particulate contamination. With the 2023 finalization of the EU GMP Annex 1 revision, regulatory expectations have shifted from relying solely on end-product testing to active, risk-based containment and inline quality assurance. This review examines the scientific and engineering principles underpinning Restricted Access Barrier Systems (RABS) and Isolator technologies. Furthermore, it outlines the design, validation, and execution of comprehensive Environmental Monitoring (EM) programs in Grade A/B cleanrooms, emphasizing the integration of continuous viable and non-viable particulate tracking.

---

## 1. Introduction to Sterile Containment Systems
The primary vector of microbial contamination in cleanroom environments is the human operator. Standard cleanroom garments reduce, but do not eliminate, the shedding of skin flakes, hair, and respiratory droplets. Consequently, modern aseptic processing focuses on physical separation of the operator from the critical Grade A exposure zone.

Two primary technologies dominate advanced aseptic containment:
1. **Isolator Systems:** Fully sealed, pressurized enclosures that undergo automated bio-decontamination (typically using gaseous hydrogen peroxide, VHP) and are completely isolated from the surrounding room environment.
2. **Restricted Access Barrier Systems (RABS):** Enclosures that provide physical separation between the operator and the critical zone, utilizing unidirectional airflow (UDAF). RABS can be open or closed, but they allow intervention through gloveports or, under strict controls, open doors.

### Table 1: Technical Comparison of Containment Interfaces

| Parameter | Restricted Access Barrier Systems (RABS) | Isolator Systems |
| :--- | :--- | :--- |
| **Physical Isolation** | High (physical barrier with open/closed doors) | Complete (hermetically sealed, gas-tight) |
| **Surrounding Environment** | Minimum Grade B background required | Grade C or D background acceptable |
| **Decontamination Method** | Manual chemical disinfection (sporicidal agents) | Automated gaseous de-pyrogenation / VHP |
| **Transfer System** | Pass-through hatches, LAF transfer carts | Rapid Transfer Ports (RTP), isolator docks |
| **Intervention Risk** | Moderate (doors can be opened under strict controls) | Extremely Low (interventions restricted to gloveports) |

---

## 2. Aerodynamics and Air Handling in Containment
Aseptic zones require strict control over cleanroom aerodynamics. The standard for Grade A zones is unidirectional vertical airflow (UDAF) with an homogeneous air velocity of **0.45 m/s ± 20%** at the working position.

### 2.1 First Air Concept
The "First Air" concept dictates that critical aseptic manipulations (e.g., stopper insertion, vial filling) must be performed in undisturbed, HEPA-filtered air that has not previously flowed over any equipment surfaces, operators, or secondary structures. Any disruption in this laminar flow pattern introduces turbulence, eddies, and potential entrainment of particles.

### 2.2 Pressure Differentials
To maintain containment integrity, differential pressures must be established across cleanroom boundaries:
* **Positive Pressure Enclosures:** Used for non-toxic aseptic products. The aseptic core is maintained at a minimum of **+10 to +15 Pascals** relative to the adjacent background zone to prevent ingress of non-sterile air.
* **Negative Pressure Enclosures:** Employed for highly potent active pharmaceutical ingredients (HPAPIs), cytotoxic drugs, and radiopharmaceuticals. The containment zone is maintained at negative pressure to prevent toxic substance egress while ensuring aseptic protection through vertical laminar flow and dedicated exhaust HEPA filtration.

---

## 3. Environmental Monitoring (EM) Systems (QA/QC Framework)
An Environmental Monitoring (EM) program is not a tool to control contamination; rather, it is a diagnostic mechanism to validate that the cleanroom is operating in a state of control.

### 3.1 Non-Viable Airborne Particulate Monitoring
Particulate counters draw continuous air samples to detect inert particles. Under EU GMP Annex 1, the limits for non-viable particulates are strictly defined based on occupancy states ("at rest" vs. "in operation").

```
                       ISO Grade 5 / Grade A Particulate Limits
                               (Per Cubic Meter of Air)
                               
          At Rest (Static)                       In Operation (Dynamic)
                    
      ≥ 0.5 m: 3,520                        ≥ 0.5 m: 3,520        
      ≥ 5.0 m: 29                           ≥ 5.0 m: 29           
                    
```

*Note: The 2023 revision of Annex 1 reinstated the limits for ≥ 5.0 m particles in Grade A zones to detect early-warning signals of mechanical wear, macro-contamination, or air handling degradation.*

### 3.2 Viable Microbial Monitoring
Microbiological monitoring detects live, replicating microorganisms. Methods include:
* **Active Air Samplers:** Volumetric collection of air (typically 1,000 liters) onto agar plates (TSA or SDA) to quantify Colony Forming Units (CFU) per cubic meter.
* **Settle Plates:** Passive exposure of 90mm agar plates for up to 4 hours in critical Grade A areas.
* **Contact Plates:** 55mm agar plates pressed directly onto surfaces (walls, floors, equipment, gloves) to test surface sanitization efficiency.
* **Glove Prints:** Operators must perform 5-finger impressions on agar plates upon exiting Grade A zones to verify manual technique and glove integrity.

### Table 2: Microbial Contamination Limits (Recommended Action Levels)

| Grade | Active Air Sample (CFU/m³) | Settle Plates (90mm, CFU/4 hours) | Contact Plates (55mm, CFU/plate) | Glove Print (5 fingers, CFU/glove) |
| :--- | :--- | :--- | :--- | :--- |
| **Grade A** | < 1 (No growth) | < 1 (No growth) | < 1 (No growth) | < 1 (No growth) |
| **Grade B** | 10 | 5 | 5 | 5 |
| **Grade C** | 100 | 50 | 25 | N/A |
| **Grade D** | 200 | 100 | 50 | N/A |

---

## 4. Contamination Control Strategy (CCS) Validation
Validation is the documented evidence that a process, equipment, or utility consistently performs to its pre-determined specifications. Under the latest regulatory updates, validation must be structured under a comprehensive **Contamination Control Strategy (CCS)**.

### 4.1 Sterilization and Depyrogenation
* **Autoclaving (Moist Heat):** Minimum cycle of **121°C for 15 minutes** (F0 ≥ 15) to achieve a Sterility Assurance Level (SAL) of $10^{-6}$.
* **Dry Heat (Depyrogenation):** Minimum of **250°C for 30 minutes** to achieve a 3-log reduction in endotoxins.
* **Vaporized Hydrogen Peroxide (VHP):** Cycle development using biological indicators (typically *Geobacillus stearothermophilus*) to prove a 6-log reduction ($10^{-6}$) on all exposed internal surfaces.

### 4.2 Aseptic Process Simulation (Media Fills)
The ultimate validation of an aseptic processing line is the Media Fill. In this simulation, the active pharmaceutical ingredient is replaced with a sterile microbiological growth medium (e.g., Tryptic Soy Broth).
* **Scope:** The simulation must encompass all standard interventions (such as weight adjustments, line stoppage clearing, charging stopper bowls) and non-standard/emergency interventions (such as power failure restarts).
* **Acceptance Criteria:** For fill sizes under 5,000 units, any contamination is cause for concern. For runs over 10,000 units, the goal is **zero contaminated units**. Any positive unit must trigger a comprehensive investigation, root cause analysis (using fishbone/5-Why methodologies), and repeat validation runs.

---

## 5. Conclusion
Aseptic manufacturing is moving rapidly toward human-free operations. The implementation of isolators, automated transfer systems, and continuous, automated environmental monitoring represents the absolute standard for minimizing pharmaceutical risk. Achieving compliance with international regulatory bodies (FDA, EMA, HPRA) requires continuous evaluation of mechanical controls, microbiological dynamics, and documented QA/QC validation protocols.

---

## References
1. *European Commission.* (2023). EudraLex Volume 4, Annex 1: Manufacture of Sterile Medicinal Products.
2. *U.S. Food and Drug Administration (FDA).* (2004). Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice.
3. *International Society for Pharmaceutical Engineering (ISPE).* (2018). Baseline Guide Volume 3: Sterile Product Manufacturing Facilities.
4. *Parenteral Drug Association (PDA).* (2015). Technical Report No. 13: Fundamentals of an Environmental Monitoring Program.

---