III. Regulatory Approach to CMC Changes
As described in 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 section VII., 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, 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.
As discussed in section V., Tools to Facilitate Changes to CCS Components, of this guidance and the guidance for industry Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency; Questions and Answers (August 2020),8 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 Quality Risk Management (June 2006) where appropriate. Whether or not a change is required to be reported to FDA, in accordance with applicable regulations,9 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).
The 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.10 DMF holders must notify affected authorized parties of any DMF changes, additions, or deletions.11 DMF holders also should provide application holders with sufficient information to determine the appropriate reporting procedure 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).12
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 section VII., References).
IV. Common Changes Related to Glass Vials and Stoppers
The tables in Appendix A 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 submission data recommendations 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.13 Changes should be supported with confirmatory14 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 tables in Appendix A necessitate a corresponding change in finished product specifications,15 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.
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 monograph16 may be necessary.
V. 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 under existing tools and capabilities to facilitate providing timely feedback, guidance, and assessment17 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 priorities18 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.
A. Risk-Based Considerations for Supplement Reporting Categories
During this public health emergency, FDA will consider requests to submit certain changes to CCS using a lower reporting category than that recommended in existing guidance if the applicants are experiencing constrained supply of CCS or components thereof, and if the relevant NDAs, ANDAs, or BLAs are related to the treatment or prevention of COVID-19 or other drugs in shortage, as appropriate. Consistent with applicable regulations and existing guidance documents related to postapproval CMC changes for drug applications 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 wishing to request a lower supplement reporting category should provide (1) their rationale,
(2) supporting information, and (3) risk-mitigation approaches, for FDA to consider whether the requested reduction in reporting category is appropriate.
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 send an email to CDER-OPQ-Inquiries@fda.hhs.gov should circumstances resulting from the COVID-19 pandemic warrant the use of atypical or flexible submission strategies as described in this section.19 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 CDER DRUG SHORTAGES (DRUGSHORTAGES@FDA.HHS.GOV) for products regulated by CDER and cbershortage@fda.hhs.gov for products regulated by CBER on those communications.
For more information, refer to the guidance for industry Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency; Questions and Answers.
B. Comparability Protocols
As explained in the draft guidance for industry Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information (April 2016),20 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).21 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 in reaction to COVID-19.
VI. Additional Resources
For additional questions about this guidance, contact CDER at CDER-OPQ- Inquiries@fda.hhs.gov, or contact the CBER office responsible for the product's regulation. The text "COVID-19 Container Closure System and Component Changes" should be included in the subject line of the email.