Biologics compliance

RF Quarterly | 04 October 2021 | Citation  |  PDF Link PDF

This article discusses the phases from the product development to commercialization. Biologics are subject to 21 Code of Federal Regulations in order to meet the criteria established for safety, purity, and potency. Compliance to these regulations should be built based on a quality management system and risk management to capture changes during the product development and process validation phases and prepare a product and facility for inspection readiness. Post commercialization, manufacturers must comply with FDA regulations or they could risk regulatory action letters or license revocation.
Compliance is a key part of ensuring a robust product lifecycle, starting with successful product development and approval to commercialization and postapproval monitoring. Biologics compliance follows a risk-based approach and focuses specifically on US Food and Drug Administration (FDA) requirements (Code of Federal Regulations [CFR], FDA guidances, and International Council for Harmonisation [ICH] guidelines). Biologics encompass many products, such as fractionated blood and their recombinant analogues; antitoxins; toxins; allergenic products; vaccines; oncolytic viruses; products of manipulated, cultured, or expanded human cells; and tissue therapy, gene therapy, and therapeutic serum or analogous products that aid in the prevention, treatment, or cure of disease or injuries.1
The FDA’s Center for Biologics Evaluation and Research (CBER) is responsible for ensuring biological products are safe and effective and comply with applicable laws and regulations. Biological products are licensed under Section 351 of the Public Health Service Act (PHS Act; 42 USC) and fall within the definition of a drug, found in the Food, Drug, and Cosmetic Act (FD&C Act) Section 201(g)(1). Biological products are subject to inspection under the provisions of both the PHS Act and the FD&C Act.
Biological products are subject to applicable regulations promulgated under both acts, including the current good manufacturing practice (cGMP) regulations (21 CFR Parts 210 and 211), and the biologics regulations (21 CFR Parts 600–680). In addition, human cells, tissues, and cellular- and tissue-based products regulated as biological products are subject to the registration and listing, donor eligibility, and current good tissue practice regulations in 21 CFR Part 1271. cGMP regulations apply to the manufacture of biological products under FD&C Act Section 501(a)(2)(b), and cGMP principles apply to the manufacture of biological intermediates and drug substances under the biologics regulations in 21 CFR Part 600.
Establishments also must comply with FDA-approved biologics license application (BLA) commitments and applicable standards. Biological products include a variety of indications, dosage forms, and manufacturing processes, all of critical importance in promoting and protecting the public health. To help ensure manufacturers consistently produce safe, pure, potent, and effective biological products, the FDA conducts cGMP inspections of each establishment at least biennially. Prelicense inspections (PLIs) for new biological products and preapproval inspections (PAIs) for significant changes to a BLA are performed to ensure compliance with the regulations prior to approval of a new license or significant license change.2
To provide more effective and efficient biological product regulation, the Office of Regulatory Affairs (ORA) and CBER established Team Biologics in 1997 to conduct routine and compliance follow-up cGMP inspections of biological drug product manufacturers, including blood establishments.3 Team Biologics uses ORA’s investigative skills and the Bioresearch Monitoring Program’s (BIMO) medical, scientific, and product expertise to promote and protect the public health through coordinated, integrated assessments of biologics manufacturers’ compliance status. CBER conducts PLIs and PAIs using cGMP requirements and CBER reviewer’s scientific expertise.4
This compliance program builds on knowledge gained during previous FDA inspections of biological drug and tissue industries. It reflects the objectives identified in the FDA’s Strategic Action Plan for developing and implementing new inspection approaches using a resource-efficient, risk-based approach to provide high-quality, cost-effective oversight of biological drug product manufacturing, processing, and distribution to reduce risk. 2  
The approach identifies key systems and critical elements common to biological product establishments. Most biological products covered under this compliance program were identified as critical to public health and processed aseptically. These factors help form the basis for establishing appropriate inspection coverage levels under this program.
The program also establishes two inspection levels to evaluate an establishment’s compliance with applicable cGMP regulations: Level I (Full) is a comprehensive evaluation of at least four systems; and Level II (Abbreviated) is an evaluation of one mandatory system plus one additional system on a rotating basis.4 This approach is similar in concept to that set forth in CBER’s CPG 7342.001 (Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors), which incorporates a systems-based approach covering critical elements within each system and a Level I/II inspection option.5
This quality management approach focuses on facilities’ key operating systems, and the two-tiered inspection option provides a method to focus the inspectional coverage and resources appropriate for each inspection with applicable advisory, administrative or regulatory action taken, when necessary.
Continued biennial inspections under this compliance program will:5
  • Safeguard the public health by reducing the risk of adulterated or misbranded biological products reaching the marketplace,
  • Increase communication between industry and the agency, and
  • Provide timely feedback during inspections to improve industry compliance with cGMPs
Subsequent to implementation, CBER will evaluate this inspection program annually to determine its effectiveness and assess and improve its quality.
FDA requirements for biologics licensing standards and 21 CFR 600.3 provide that biologics must be “safe, pure, and potent.” Under 21 CFR 601.20, on inspection, the production facility must demonstrate assurance the product meets these standards and complies with applicable regulations. Therefore, during the investigational new drug (IND) application stage, the manufacturer must develop processes and methods to ensure these attributes are in place before the product is licensed. These attributes are defined as follows:
  • Safety – relative freedom from harmful effect to persons affected, directly or indirectly, by a product when it is administered prudently, taking into consideration the product’s character in relation to the recipient’s condition at the time.
  • Purity – relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product; purity includes, but is not limited to, relative freedom from residual moisture or other volatile and pyrogenic substances.
  • Potency – specific product ability or capacity, as indicated by appropriate laboratory tests or adequately controlled clinical data obtained through the product’s administration in the manner intended, to effect a given result.
After BLA approval, a manufacturer receives a license to market its product in interstate commerce. The compliance and surveillance activities related to biologics licenses during the product’s lifecycle are overseen by the Office of Compliance and Biologics Quality (OCBQ). OCBQ comprises four divisions, plus additional staff within OCBQ’s Immediate Office of the Director (IOD):
  • Division of Case Management (DCM)
  • Division of Inspections and Surveillance (DIS)
  • Division of Manufacturing and Product Quality (DMPQ)
  • Division of Biological Standards and Quality Control (DBSQC)
OCBQ performs the following tasks and activities to ensure pre- and postapproval compliance.2
  • Ensure the quality of products regulated by CBER over their entire lifecycle, from premarket review and inspection to postmarket review, surveillance, inspection, outreach and compliance.
  • Monitor the quality of marketed biological products through surveillance, inspections, and compliance programs; and review, evaluate, and take appropriate compliance action, in coordination with other agency components.
  • Review and evaluate all administrative action recommendations, including suspension, revocation, denial of license, disqualification of investigators, and recommended civil and criminal actions, including seizures, injunctions, and prosecution based on findings of inspections and investigations.
  • Direct the biologic product shortages program for CBER-regulated products.
  • Direct the recall program for CBER-regulated products.
  • Direct CBER’s bioresearch monitoring program and take appropriate compliance actions, in coordination with other agency components.
  • Direct CBER’s program for Biological Product Deviation Reports (BPDRs) and reports of complications of blood collection and transfusion confirmed to be fatal.
  • Review, evaluate, and take appropriate action on manufacturing supplements submitted by manufacturers (except blood and plasma establishments), and lead preapproval and prelicense inspections supporting BLA submissions and supplements as part of the CBER managed review process.
  • Assess the compliance status of regulated establishments within CBER’s purview (compliance status checks).
  • Evaluate proposed proprietary names to avoid potential medication errors related to look-alike and sound-alike proprietary names and other mitigating factors that contribute to medication errors, such as unclear label abbreviations, acronyms, dose designations, and error-prone label and packaging design.
  • Provide consultative reviews of proposed product labeling.
  • Plan and conduct tests on biological products and conduct research to develop and improve procedures to evaluate biological products’ safety, efficacy, and purity.
  • Test biological products, in cooperation with other center components, that have been submitted for release by manufacturers, as appropriate.
  • Advise the center director and other agency officials on emerging and significant compliance issues for biological products and serve as CBER’s focal point for surveillance and enforcement policy.
  • Develop, with other CBER and agency components, biological products’ policies and compliance standards, including cGMP regulations; and ensure the uniform interpretation of standards and evaluate industry’s conformance with cGMPs in manufacturing biological products.
Preapproval compliance
CMC change control
During the IND stage, any changes to the manufacturing or testing process are submitted by filing information amendments to the IND, with sufficient data to justify the comparability or improvements related to manufacturing changes, before making the change. During product development, multiple changes are likely to arise in the manufacturing process that could impact drug product quality, safety, and efficacy. Comparability studies generally are performed to demonstrate nonclinical and clinical data generated with pre-change product are equivalent to post-change product, to facilitate further development and, ultimately, support marketing approval. An important focus while conducting comparability studies is that product quality, safety, and efficacy are not impacted and or decreased with the intended change. Comparability studies conducted during product development are influenced by factors such as the availability of validated analytical procedures and the extent of product and process knowledge, which can vary based on manufacturer experience. Due to analytical tools’ limitations in early clinical development, physicochemical and biological tests alone might not be adequate to determine comparability, and it may be necessary to bridge nonclinical and/or clinical studies.
When process changes are introduced in later development stages, and no additional clinical studies are planned to support the marketing authorization, the comparability study should be as comprehensive as that for an approved product. However, some comparability study outcomes on quality attributes still may require additional nonclinical or clinical studies.
IND safety reporting
During premarketing, expedited safety reports are required for serious and unexpected adverse experiences associated with the biological product’s use, as is the case for drugs (21 CFR 312.32). These requirements were amended in 2012 to update the definitions for safety reporting and to clarify when to submit expedited safety reports. In summary, expedited safety reporting applies to suspected adverse reactions that are both serious and unexpected and where there is a reasonable possibility of a causal relationship between the biologic and the adverse event. For other adverse events, the sponsor should collect the information and develop a process for ongoing evaluation of accumulating safety data and submitting it periodically to regulatory agencies.6
The FDA issued final regulations addressing IND safety reporting requirements in 21 CFR Part 312. A draft guidance for industry on safety assessment for IND safety reporting (December 2015) is aimed at improving the quality of safety reports submitted to by developing a systematic approach for IND safety reporting, where there is a prospective identification of anticipated serious adverse events. The guidance is most applicable to sponsors managing a drug development program with multiple studies. The guidance lays out clear definitions and standards to ensure critical safety information on investigational new drugs is reported to the FDA quickly and accurately, minimizing uninformative reports and enhancing reporting of meaningful, interpretable information.
Additional safety reporting guidance is available for specific biological products, such as those used in gene therapy clinical trials. In gene therapy trials, where there is heightened concern about the potential for delayed adverse events as a consequence of the transferred genetic material’s persistent biological activity, long-term follow-up safety studies are recommended. Adverse events associated with gene therapy trials also may need to be reported to the National Institutes of Health (NIH), through the Recombinant DNA Advisory Committee, if the trial includes NIH-funded sites.7 In August 2018, NIH released a proposal to amend the NIH guidelines to streamline the oversight for gene transfer research protocols. To that end, while NIH is reviewing the comments and proposals, no new submissions are being accepted, but these clinical studies are still under the oversight of the FDA, Institutional Review Boards (IRBs) and other relevant approvals.8
BIMO is the FDA’s compliance program for good clinical practice (GCP) and good laboratory practice (GLP) inspections during development. The program covers clinical investigators, IRBs, sponsors, contract research organization (CRO) monitors, in vivo bioequivalence laboratories and facilities, and GLP facilities. Clinical inspections focus on how sponsors ensure the validity of clinical data submitted to the FDA and the adherence of sponsors, CROs, and monitors to applicable regulations, such as adverse event reporting and article integrity from the time of manufacture until investigator receipt. To carry out these responsibilities, BIMO staff conduct preapproval data audit inspections, investigate complaints, answer questions about GCP, and help evaluate data integrity concerns.
Biological product naming
The nonproprietary or proper name for a new biological product,9 as for a drug, is determined by submitting an application and fee to the US Adopted Names Council (USANC), which is part of the American Medical Association. Sponsors should provide several selections and the naming rationale to USANC. When submitting suggested names, consideration should be given to the naming conventions used by USANC to assess submissions (i.e., use of common stems and/or syllables for existing products or product classes).10 For biologics, CBER has developed naming conventions for certain product categories, for example, cellular therapies, which must be followed to the extent possible. Under this naming convention, the nonproprietary name designated for each originator biological product, related biological product, and biosimilar product will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters.9 Thus, sponsors needing assistance may want to discuss nonproprietary name selection with CBER before submission to USANC. For well-characterized proteins, certain suffixes are standard and must be included in the nonproprietary name, for example, monoclonal antibodies use -mab as the final syllable.
The proprietary name for a new biological is approved by CBER and reviewed by OCBQ’s Advertising and Promotional Labeling Branch. Two names may be submitted, with a clear indication of the sponsor’s preference. The rationale for the choice, with summaries from marketing research studies, should be included. These studies should assess similar-sounding names and how names may be interpreted, including foreign language translations. The application also should include full descriptions of the product, therapeutic category, and/or indication and the setting for use (e.g., doctor’s office, hospital, or home). Proprietary name submissions can be made any time after phase 2, but a recommendation made before product approval will be reevaluated within 90 days of approval to ensure no new products have entered the marketplace that could give rise to confusion because of similarity in spelling or pronunciation.
Prelicense inspection
A prelicense inspection entails inspecting all facilities involved in the drug substance and drug product manufacture and testing for each biologic CBER has not yet licensed or approved. These inspections apply to the company itself and any contract sites. The inspection also can include establishments that already have one or more biologics license(s) or other product approvals. PHS Act Section 351 and FD&C Act Section 704 allow the regulatory authority to conduct inspections at any biological product manufacturing establishment.
CBER’s general policy is that a prelicense or preapproval inspection will be necessary for a BLA or supplement if any of the following criteria are met:
  • The manufacturer does not hold an active US license or, in the case of a contract manufacturer, the facility is not approved for use in manufacturing a licensed product.
  • The FDA has not inspected the establishment in the last 2 years.
  • The previous inspection revealed significant GMP deficiencies in areas related to the processes in the submission (similar processes) or systemic problems, such as quality control or quality assurance oversight.
  • The establishment is performing a significant manufacturing step, or steps, in new (unlicensed) areas using different equipment (representing a process change). This would include currently dedicated areas that have not been approved as multiproduct facilities, buildings, or areas.
  • The manufacturing process is sufficiently different (new production methods, specialized equipment or facilities) from that of other approved products produced by the establishment.
  • Other points to be considered: Differences in the process (e.g., different types of columns) or particulars (e.g., different production cell lines) that require an on-site GMP compliance determination; analytical methods that are accurate or sensitive enough to detect problems; and whether different equipment or processes are being used.
Even if the above criteria otherwise would call for an inspection, the inspection may be waived if the establishment performs only ancillary testing (testing that does not affect drug substance or drug product release) for the submission under consideration. An inspection should not be waived if the applicant receives a request to submit additional information that normally would not be submitted to a BLA or supplement.
In some cases, CBER relies on inspections to obtain validation and facility information that previously may have been submitted in the BLA, therefore, greater coordination and efficiency are required in planning and conducting inspections. However, some BLAs and supplements include manufacturing establishments that use production areas common to other licensed products, so conducting a prelicense or preapproval inspection may not be necessary. In such cases, both the director of the division with product responsibility and the director of OCBQ’s DMPQ must agree to waive an inspection, or the inspection should be scheduled according to established procedures.
Inspections for biologics are much the same as those for drugs. Systems-based inspections include review of:
  • Quality systems (e.g., change controls, deviations/investigations, training, and so on)
  • Buildings and facilities
  • Equipment cleaning and maintenance
  • Laboratory controls
In addition, the BLA’s chemistry, manufacturing, and controls (CMC) section will be compared with manufacturing site documents to establish the submission’s accuracy and integrity. Because of the complexity of biological products’ manufacturing process, the investigator is likely to spend considerably more time observing the process than is typical for small-molecule inspections. The investigator usually works with the manufacturer to schedule an appropriate time to conduct the inspection, so the entire manufacturing process can be observed. Any delay by the sponsor in this activity may delay BLA review. Another difference is the product specialist responsible for the BLA’s CMC section review generally will participate in a biologics inspection.
The regulations require annual reports, provided within 60 days after the application approval anniversary date, for products marketed under a BLA for certain situations, such as making changes to the application (21 CFR 601.12(d)); providing information on pediatric studies (21 CFR 601.28); and providing status reports on postmarket study requirements related to clinical safety, clinical efficacy, clinical pharmacology, or nonclinical toxicology (21 CFR 601.70).
The Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require additional postmarketing studies to assess known safety risks, including serious risk signals and potential serious risks associated with the drug’s use. FDAAA also gave the FDA authority to require labeling changes based on such studies’ results. FD&C Act Section 505(o)(3)(E)(ii), enacted under FDAAA, stipulates the following information be provided in the annual report for required postmarketing studies:
  • A timetable for the completion of each study;
  • Periodic reports on required studies’ status, including whether enrollment has begun, the number of participants enrolled, and whether any difficulties in completing the study have been encountered; and
  • Registration information with respect to clinical trial certification.11
In addition, FDAAA requires applicants to report on each study “otherwise undertaken by the applicant to investigate a safety issue.” The status of other postmarketing commitments (e.g., those concerning chemistry, manufacturing, production controls, and studies conducted on an applicant’s own initiative) are not required to be reported under Sections 314.81(b)(2)(vii) and 601.70.
Once a required postmarketing study commitment has been made, an annual report is due each year within 60 days after the anniversary date and must be accompanied by a completed transmittal Form FDA 2252. Sponsors must continue to report on the commitment’s progress until the postmarketing study is completed or terminated, unless the postmarketing study commitment is either no longer feasible or would no longer provide useful information (as agreed with the FDA). Failure to comply with the timetable, the periodic reporting submissions or other requirements of Section 505(o)(3)(E)(ii) will be considered a violation unless the applicant demonstrates good cause for the noncompliance (only as agreed with the FDA). Violations could result in civil penalties of up to $250,000 per violation, and the penalties can be increased (i.e., doubled) if the violation continues for more than 30 days, and can continue to double for subsequent 30-day periods.
After approval, two other types of inspections may take place: routine, periodic inspections that should occur every 2 years (biennial); and directed (for cause) inspections. CBER and ORA have built a partnership to focus resources on inspectional and compliance issues in the biologics area. To accomplish this, Team Biologics, as already mentioned, inspects licensed biological drug and device product facilities regulated by CBER. The goal of Team Biologics is to ensure biological products’ quality and safety and resolve inconsistencies quickly.
CBER oversees biologic products’ import and export to determine whether imported products, drugs and devices regulated by the center comply with the requirements of the FD&C Act, the PHS Act and the regulations promulgated under these statutes. Imported products regulated by the FDA are subject to inspection at the time of entry by the US Customs and Border Protection (CBP). Shipments found not to comply with the law are subject to detention. For imports, the FDA works with CBP to verify licensure and may perform random sampling and issue import alerts for noncompliant products. A foreign manufacturer must have a US license to import a biological product into the US. Under the FDA’s regulation procedures, licensed biologics that have been lot-released (or are exempt) by CBER may be imported into the US and may proceed through CBP without FDA examination. Entry documents for IND biologics must declare a valid, active IND number. Products in short supply also may be imported under 21 CFR 601.22. However, these products must be registered with CBER, which CBP will verify. Under 7 CFR Chapter III, overseen by the US Department of Agriculture, biological products also may require an Animal and Plant Health Inspection Service permit to enter the country if the product contains certain microbial, plant- or animal-derived materials or is otherwise a regulated product, such as a genetically engineered organism.
A licensed biologic may be exported without FDA authorization, as per an FDA guidance on export certificates (August 2002), and in accordance with FD&C Act Section 801(e) Exports or 802 Export of Certain Unapproved Products or PHS Act Section 351(h), which states a biologic is not adulterated or misbranded if it:
  • Accords to the foreign purchaser’s specifications,
  • Is not in conflict with the laws of the country to which it is intended for export,
  • Is labeled on the outside of the shipping package that it is intended for export, and
  • Is not sold or offered for sale in domestic commerce.
The FDA supplies a Certificate to Foreign Government, if requested, for the export of products that can be marketed legally in the US. It also supplies a Certificate of Exportability for the export of products that cannot be marketed legally in the US but meet FD&C Act requirements.
Import for export, per the FDA Export Reform and Enhancement Act of 1996, allows the importation of drug and device components for incorporation into a finished product that then can be exported in accordance with FD&C Act Sections 801 and 802, and PHS Act 351(h).
Postapproval changes
In accordance with FD&C Act Section 506A(b), the effect of any postapproval CMC changes on a product’s identity, strength, quality, purity, or potency, as they may relate to the product’s safety or efficacy, must be assessed.
Before distributing a product made following a change, sponsors are required to demonstrate, through appropriate validation and/or other clinical or nonclinical laboratory studies, the lack of the change’s adverse effect on identity, strength, quality, purity, or potency as they may relate to the product’s safety or effectiveness.
Sponsors should assess the change to determine the correct product reporting category:
  • Prior approval supplement (PAS) ‒ major changes that require supplement submission and approval prior to distribution of the product made using the change (21 CFR 601.12(b)). A PAS is used to report changes with substantial potential to affect a product’s identity, strength, quality, purity, or potency adversely as they may relate to the product’s safety or effectiveness. Examples would include a change in manufacturing processes or analytical methods resulting in a change of specification limits; a change to larger-scale production; major construction; a change in the stability protocol or acceptance criteria; and extension of the expiration dating period.
  • Changes being effected in 30 days (CBE-30) ‒ moderate changes (CBE-30) require a supplement to the FDA 30 days before distribution (21 CFR 601.12(c)(3)). A CBE-30 is used to report changes with moderate potential to affect a product’s identity, strength, quality, purity, or potency adversely as they may relate to the product’s safety or effectiveness. Examples would include: addition of a duplicated process chain or unit process; change in the testing site from one facility to another (e.g., from a contract laboratory to the sponsor; change from an existing contract laboratory to a new contract laboratory; change from the sponsor to a new contract laboratory).
  • Changes being effected in 0 day (CBE-0) these changes have minimal potential to affect a product’s identity, strength, quality, purity, or potency adversely as they may relate to the product’s safety or effectiveness. A CBE-0 supplement would be received by the FDA before, or concurrent with, distribution of the product made using the change. A CBE-0 typically is filed when a manufacturer wants to inform the FDA immediately, even though the change does not require FDA approval.
  • Annual report ‒ minor changes can be included in the annual report, which is submitted within 60 days of the product’s anniversary date. These are changes with minimal potential to affect a product’s identity, strength, quality, purity, or potency adversely as they may relate to the product’s safety or effectiveness. Examples would include an increase in the scale of aseptic manufacturing for finished product without a change in equipment, for example, increased number of vials filled; modifications in analytical procedures with no change in the basic test methodology or existing release specifications, provided the change is supported by validation data; and establishment of a new working cell bank derived from a previously approved master cell bank according to a standard operating procedure on file in the approved license application.
A comparability protocol is a well-defined, detailed, written plan for assessing the effect of specific CMC changes on a particular drug product’s identity, strength, quality, purity, and potency as they may relate to the product’s safety and effectiveness. A comparability protocol describes the changes it covers and specifies the tests and studies to be performed, including establishing analytical procedures and acceptance criteria to demonstrate specified CMC changes do not affect the product adversely. However, it is important to note comparability protocols are not recommended for CMC changes that cannot be evaluated definitively, require a new IND or require efficacy, safety (clinical or nonclinical), or pharmacokinetic/pharmacodynamic data to evaluate the change’s effect (e.g., certain formulation changes or clinical or nonclinical studies to qualify new impurities).
By using a comparability protocol previously reviewed by the FDA, the sponsor may be able to file certain CMC changes under a less-restrictive reporting category, for example, a change that normally would be a PAS may be allowed as a CBE-30 if it has been approved already as a comparability protocol. Although submitting a comparability protocol is not required for changes, in many cases, it will facilitate the subsequent CMC change implementation and reporting requirements, which could result in moving a product into distribution more quickly. For marketing applications or postapproval implementations, “submission of a comparability protocol in an original application or PAS allows the agency to review a description of one or more proposed CMC postapproval changes, supporting information including any analysis and risk assessment activities, a plan to implement the change(s), and, if appropriate, a proposed reduced reporting category for the change(s).”12 The comparability protocol should include a summary of the changes, description and rationale for the proposed change, supporting information and analysis, comparability protocol for the proposed change and proposed reduced reporting category.12
An FDA review committee will determine whether the changes reported in the supplement require on-site review. If the review committee determines an inspection is necessary for one or more establishments included in the supplement, the inspection(s) will be performed prior to sending the action letter for the supplement. Failure to comply with the reporting requirements outlined in 21 CFR 601.12 could result in an FDA request that all changes be submitted as a PAS. Two examples of failure to comply are the constant downgrading of changes (e.g., from a PAS to a CBE) and failing to supply sufficient information to support the changes.
Similarly, under 21 CFR 601.12(f), changes to a product package label, container label and package insert require one of the following:
  • submission of a supplement with FDA approval needed prior to product distribution, for example, the addition of superiority claims or changes based on additional preclinical and/or postmarketing clinical studies
  • submission of a supplement with product distribution allowed at the time of supplement submission (does not require a 30-day waiting period), for example, strengthening cautionary statements or instructions
  • submission of the final printed label in an Annual Report, for example, editorial changes and changes in how the product is supplied, provided there is no change in dosage form or strength
Additionally, under 21 CFR 601.12(f)(4), changes to advertising and promotional labeling must comply with the provisions of 21 CFR 314.81(b)(3)(i), which require sponsors to submit specimens of mailing pieces and any other labeling or advertising devised for a drug product’s promotion to the FDA at the time of initial dissemination of the labeling, and at the time of initial publication of the advertisement for a prescription drug product. Mailing pieces and labeling designed to contain samples of a drug product are required for the submission to be considered complete, except the drug product sample.
Postmarketing reporting requirements
Expedited postmarketing reporting requirements for serious and unexpected adverse experiences from all sources (domestic and foreign) related to biologics are similar to those for drugs and are stated in 21 CFR 600.80 and 600.81. Reporting requirements include: Postmarketing 15-day “Alert Reports,” which include reports based on scientific literature; Postmarketing 15-day Alert Report follow-ups, which also are required to be reported within 15 days of receiving new information; and periodic adverse experience reports. The reporting format for individual case study reports is the MedWatch mandatory Form FDA 3500A. However, adverse events related to vaccines must be reported on a separate form under the Vaccine Adverse Event Reporting System (VAERS). Foreign adverse experience may be reported using either Form FDA 3500A or, if preferred, a CIOMS I form. Sponsors may request waivers of the requirement to file Form FDA 3500A for nonserious, expected adverse experiences; however, the FDA does not intend to grant waivers within one year of licensure for new biological molecular entities, blood products, plasma derivatives or vaccines. For biological combination products, reports must be filed with both relevant centers. Adverse events related to vaccines also are monitored by the Centers for Disease Control. The VAERS reporting system is not linked to the vaccine injury compensation program.
Periodic adverse experience reports include serious and unexpected adverse experience summaries as well as reports of nonserious expected adverse experiences. Periodic reports are made at quarterly intervals for three years from the date of BLA issuance, and annually thereafter. The licensed manufacturer is required to submit each quarterly report within 30 days of the close of the quarter (the first quarter beginning on the date of BLA issuance) and each Annual Report within 60 days of the anniversary date.
Distribution reports for biological products, including vaccines, also are required under 21 CFR 600.81; this requirement is unique for biologics with approved BLAs. The distribution report includes the bulk, fill and label lot numbers for the total number of dosage units of each strength or potency distributed, expiration date, distribution date and quantity returned. The licensed manufacturer submits this report every six months to either CBER or CDER, as applicable. A guidance on electronic submission of lot distribution reports, issued March 2015, outlines the electronic submission requirements for lot distribution reports. The information required for the distribution reports remains the same, but electronic submission requirements now are formalized.13
Risk assessment14
Risk assessment should occur throughout a product’s lifecycle, from early potential product identification and preclinical testing, through the premarketing development process and postapproval during marketing. Premarketing risk assessment is a key step in this process, and product approval requires adequate assessment of the product’s underlying risks and benefits. The adequacy of this risk assessment is a matter of both quantity (ensuring enough patients are studied) and quality (the appropriateness of the assessments performed, appropriateness and breadth of the patient populations studied, and how results are analyzed). In reaching a final approvability decision, both existing risk information and any outstanding safety questions are considered in a product’s risk assessment and weighed against its demonstrated benefits. The fewer a product’s demonstrated benefits, the less acceptable its higher levels of demonstrated risks will be.
For postapproval risk assessment, labeling and routine reporting requirements are sufficient to mitigate risks and preserve benefits for the majority of approved products. However, in other cases, the FDA has requested additional risk minimization strategies, originally called Risk Minimization Action Plans, or RiskMAPs. FDAAA created risk evaluation and mitigation strategies (REMS). A REMS is a strategy to manage a drug or biological product’s serious safety risk, or risks, while preserving the product’s benefits. Proposed changes to approved REMS should be submitted as follows:
  • Revisions, to be submitted as “REMS Revisions,” and documented in the next annual report, or
  • REMS modifications that are categorized as either:
    • Minor, to be submitted as a CBE-30 supplement, defined as changes that may affect the risk message nominally; or
    • Major, to be submitted as a PAS, defined as changes that may substantially affect the risk message and/or substantially change REMS requirements.
The FDA also has the authority to apply a REMS retroactively and to require sponsors to submit a REMS for an already approved product.
A REMS can include a medication guide, a patient package insert, a communication plan for healthcare professionals, various elements to assure safe use (ETASU), and an implementation system. The medication guide is the most common REMS component, now required for more than 80 approved drugs.15 Medication guides are used when specific information is necessary to prevent serious adverse effects; when patient decision making should include knowledge about a serious side effect; or if patient adherence to directions for use is essential for the product’s effectiveness. The responsibility for ensuring medication guides are available to patients lies with the sponsor, not the pharmacist.
ETASU may include one or more of the following requirements:
  • Healthcare providers who prescribe the drug must have particular training or experience or be specially certified.
  • Pharmacies, practitioners, or healthcare settings dispensing the drug must be specially certified.
  • The drug is dispensed to patients only in certain healthcare settings, such as hospitals.
  • The drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results.
  • Each patient using the drug is subject to certain monitoring requirements.
  • Each patient using the drug is enrolled in a registry.
Biological product deviation reporting
Licensed biological product manufacturers are required to report events representing unexpected or unforeseeable events; or deviations from cGMPs, applicable regulations, or applicable standards or established specifications that may affect a product’s safety, purity or potency per 21 CFR 600.14. Before 2001, this was termed “error and accident” reporting. The BPDR is reported on Form FDA 3486 (the Biological Product Deviation Report Form) and must include the appropriate event type deviation code. The report must not be dated more than 45 calendar days from the date of discovery of information reasonably suggesting a reportable event has occurred. Reportable events are those that occur at the sponsor’s facility or a facility under the sponsor’s control, for example, a contract manufacturer, and include events for distributed products no longer under the sponsor’s control. Therefore, investigation procedures for an unexplained discrepancy or failure of a lot to meet any of its specifications should include provisions for timely investigation; an appropriate corrective action plan to prevent recurrence; procedures to gain control of unsuitable products in a timely manner; and appropriate disposition of all affected products (in-date and expired). All BPDRs should be submitted to OCBQ, except those for biological products transferred to CDER starting in 2003.
FDA enforcement actions
Regulatory action letters
CBER may issue several types of regulatory action letters. These letters ordinarily are issued to biological product manufacturers in an attempt to stop practices that violate the regulations and promote corrective action. Examples of regulatory action letters issued by CBER include:
  • Warning letters;
  • Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letters;
  • Untitled letters;
  • Administrative license action letters; and
  • Orders of retention, recall, destruction and cessation of manufacturing related to human cell, tissue, and cellular- and tissue-based products.
Warning letters are issued for violations of regulatory significance to achieve voluntary compliance. Significant violations are those that may lead to enforcement action if not corrected promptly and adequately. A warning letter is issued to a responsible individual or firm to establish previous notice that the agency considers one or more products, practices, processes, or other activities to be in violation of the FD&C Act, its implementing regulations and/or other federal statutes. A warning letter is one of the FDA’s principal means of achieving prompt voluntary FD&C Act compliance.
A NIDPOE letter informs the recipient clinical investigator the agency is initiating an administrative proceeding to determine whether the investigator should be disqualified from receiving investigational products pursuant to FDA regulations. Generally, the agency issues a NIDPOE letter when it believes it has evidence that the clinical investigator repeatedly or deliberately violated FDA regulations governing proper clinical study conduct involving investigational products or submitted false information to the sponsor.
An untitled letter is an initial correspondence with a sponsor citing violations that do not meet the regulatory significance threshold for a warning letter. CBER has issued untitled letters, for example, after reviewing a manufacturer’s advertising and promotional labeling; after an inspection under CBER’s BIMO program or by Team Biologics; and as a result of internet website surveillance.
Administrative license action letters include license revocation and suspension. License revocation is the cancellation of a license and withdrawal of the authorization to introduce biological products into interstate commerce. Examples of revocation grounds include FDA inability to gain access for inspection; manufacturer failure to report a change as required; product or establishment failure to conform to standards in the license or comply with cGMPs; or the product not being safe or effective or being misbranded. Except in the case of license suspension or willful violations, CBER will issue a notice of intent to revoke license letter and provide the sponsor an opportunity to demonstrate or achieve compliance before initiating revocation proceedings and issuing a license revocation letter. The licensee has 10 days to notify the FDA of its commitment to, and plans for, achieving compliance, and then has 30 days to submit a comprehensive report with rigid timetables.
License suspension is a summary action that provides for immediate withdrawal, without prior notice or a hearing, of the authorization to introduce biological products into interstate commerce when there are reasonable grounds to believe the product is a danger to public health (PHS Act Section 351). The US Department of Justice does not need to concur. All product shipping and manufacturing activities must cease until the license is reactivated.
Recalls generally are voluntary sponsor acts because the FDA has limited statutory authority to prescribe a recall. However, the National Childhood Vaccine Injury Act of 1986 amended the PHS Act to provide recall authority for biological products (42 US 262). Therefore, the FDA can order a recall if the biological product constitutes an imminent or substantial hazard to public health per PHS Act Section 351(a), or if it is considered a “dangerous” medical device per the FD&C Act. Recalls can be ordered for any reason, but if a recall is due to misbranding or adulteration, the FDA should be notified to prevent further action. Companies should work closely with the agency during a recall. There are four key stages in the recall process: discovery, planning, implementation, and termination of the recall event. Final disposition of the recalled product should be discussed with the FDA and typically involves destruction.
Judicial enforcement
The FDA’s civil and criminal enforcement actions include:
  • Seizure ‒ an action taken to remove a product from commerce because it is in violation of the law. The FDA initiates a seizure by filing a complaint with the US District Court where the product is located. A US marshal then is directed by the court to take possession, that is, seize the goods where they are found, until the matter is resolved.
  • Injunction ‒ a civil action taken against an individual or firm seeking to stop continued production or distribution of a violative product until the firm complies with FDA requirements.
  • Prosecution ‒ a criminal action taken as the result of acts prohibited in the FD&C Act that can be directed at the responsible persons in management.
Compliance and surveillance activities related to biologics licenses during the product lifecycle are overseen by CBER’s Office of Compliance and Biologics Quality. Manufacturers are required to comply with FDA’s preapproval and postapproval requirements, and noncompliance may include REMS, medication guides, or postmarketing studies. If CBER identifies areas of noncompliance, it may issue one of several types of regulatory action letters, up to and including license revocation, to stop practices found to be in violation of the regulations and to promote corrective action. CBER also has options for judicial enforcement, including seizure, injunction and prosecution, if warranted.
Acronyms and abbreviations
BIMO, Bioresearch Monitoring [program]; BLA, biologics license application; BPDR, Biological Product Deviation Report; CBE, changes being effected; CBER, Center for Biologics Evaluation and Research; CFR, Code of Federal Regulations; cGMP, current good manufacturing practice; CMC, chemistry, manufacturing, and controls; CRO, contract research organization; ETASU, elements to assure safe use; FDA, US Food and Drug Administration; FDAAA, Food and Drug Administration Amendments Act; FD&C Act, Food, Drug, and Cosmetic Act; GCP, good clinical practice; GLP, good laboratory practice; IND, investigational new drug; NIDPOE, notice of initiation of disqualification proceedings and opportunity to explain; ORA, Office of Regulatory Affairs; PAI, preapproval inspection; PHS, Public Health Service Act; PLI, prelicense inspection; REMS, risk evaluation and mitigation strategies; USANC, US Adopted Names Council; VAERS, Vaccine Adverse Event Reporting System.
About the author
Anne Marie Woodland, RAC, is currently senior vice president of regulatory affairs and quality at Replimune. She was previously vice president of regulatory affairs at uniQure and executive director of regulatory affairs at Amgen. Woodland has more than 20 years’ experience in the biopharmaceutical industry and has built regulatory and quality programs and systems that are compliant with both domestic and international requirements. She can be contacted at
Citation Woodland A. Biologics compliance. RF Quarterly. 2021;1(3):72-86. Published online October 2021.
Acknowledgment This article is based a chapter in Fundamentals of Medical Device Regulations. The full citation for the chapter is:
Woodland A. Biologics compliance. In: Fundamentals of medical device regulations [ch. 26]. 4th ed. Regulatory Affairs Professional Society; 2021: 233-44.
All references with URLs accessed 21 September 2021.
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