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)3Confirmatory 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
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
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)
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)
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
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
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
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
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
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
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
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
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)
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