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
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:
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:
What must be reported: Events associated with manufacturing, testing, processing, packing, labeling, storage, holding, or distribution if the event:
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:
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:
Special categories exempt from certain requirements (§§ 600.10–600.13, 610.53, 610.62):
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:
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:
Testing methods:
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:
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:
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:
Alternative label scenarios:
Section 610.61 Package Label The package label must include all information required on the container label plus:
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:
CDMO-specific considerations:
Applying these regulatory guidelines in practice? Use our free validated calculators for risk management, sampling, and environmental monitoring.