By Nathan Parker, principal consultant, Parker Biopharmaceutical Consulting
In November 2023, the FDA finalized the COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers Guidance for Industry.1 While the guidance is only intended to remain in effect until Aug. 7, 2024, it contains information organized in a way that will continue to be useful even if the guidance is not further revised and extended.
Why Is FDA Just Finalizing COVID-related Guidance Now?
Throughout the COVID-19 pandemic, the FDA created guidance documents to help the pharmaceutical industry to be most effective during the unprecedented circumstances presented by the pandemic. One of the guidance documents addressed container closure system (CCS) component changes for which a draft guidance was first provided by the FDA on March 5, 2021. The guidance was created to help expedite changes in CCS necessitated by component supply constraints that have arisen due to the increased demand for vials and stoppers to produce COVID-19 vaccines and therapies.
Before the public health emergency (PHE) declaration for the COVID-19 pandemic expired, the FDA evaluated the guidance documents created during the pandemic to determine if they should expire or continue past the PHE declaration expiration.2 Through this evaluation, the FDA determined that the CCS component change guidance should remain in effect for 180 days after the PHE declaration expired and should be further revised. The CCS component change guidance was subsequently finalized in November 2023 and provided with a statement that it is to remain in effect until Aug. 7, 2024.
Summary Of The CCS Guidance
The guidance applies directly to post-approval change submissions for NDAs, ANDAs, and BLAs related to vials and stoppers for parenterally administered drug products and indicates that the FDA will consider risk-based approaches to these types of CCS changes. The risk-based approach may include adjustments to submission content and reporting categories. This is intended to allow manufacturers to make changes to a CCS more quickly if needed due to CCS component supply constraints during and after the COVID-19 pandemic. The guidance may also be useful when determining how to evaluate container closure risks for products in development.
While the guidance explicitly states that it does not apply to other types of CCS, the guidance does include tables (one table for NDA/ANDAs and one table for BLAs) with typical CCS changes, the recommended reporting category, the recommended information to support the change, and references to guidance documents that apply. The example CCS changes in the tables are more specific than the general change descriptions provided in the guidance documents referenced in the tables. As many of the change descriptions are similar to changes that could be made for CCSs other than vials and stoppers, the tables may be useful in determining how to categorize changes for those CCSs and what information should be utilized to support those changes. The body of the guidance also summarizes requirements that are applicable to many types of CCSs. As such, the guidance could be a valuable reference for many types of CCS changes even after the guidance is no longer effective.
General CCS Change Guidance
The guidance builds from and reinforces the FDA’s support of risk-based approaches in evaluating changes. Specific aspects to consider when evaluating the risks of CCS changes are addressed in the guidance and include:
- Characteristics of the product
- Properties of the container and CCS components
- Interactions of the product with the CCS over the shelf life including:
- Effect of high pH product on CCS
- Any factors that might increase the potential for glass delamination or introduction/creation of particulate matter
- Any impact related to leachable substances from CCS
- For lyophilized product, any impact from CCS on lyophilization process or the final lyophilized product
The guidance also reinforces activities that should be completed for CCS changes including:
- Assessing the effects of the proposed change and validating the effects of the change prior to distribution. This should include comparing batch data prior to and after the proposed change.
- Additional qualification or evaluation specific to unique risks for the product.
- Applicable tests and studies required by the United States Pharmacopeia (USP) to demonstrate the suitability of the glass.
- Providing complete information supporting the change in the applicable submission.
- Appropriately managing and documenting the change utilizing the company’s quality management system.
- If making multiple changes concurrently, the cumulative effect of the changes must be evaluated and the submission category for the highest risk change must be used.
- If the CCS change requires a change in finished product specifications, studies and data to support the effect of the specification change must be included in the submission.
- A supplement to change product labelling is required if changing the packaging type listed on the label.
- If a USP monograph exists for the product, the USP should be engaged to update the USP monograph.
The guidance additionally includes a discussion of comparability protocols (CPs) and encourages the use of CPs. Specifically, CPs can be used to gain the FDA’s agreement on plans for implementing post approval changes. The guidance indicates that the use of CPs can make the final submission and review process more efficient.
Requesting Lower Supplement Reporting Category
The guidance indicates that while effective (i.e., until Aug. 7, 2024), applicants may request a lower supplement reporting category than is provided in current regulations and guidance documents for glass vial and stopper related changes. The request should include:
- The rationale for the lower reporting category,
- information supporting the request, and
- risk assessment.
The above information should be provided to the appropriate FDA divisions prior to submitting a supplement with a lower reporting category. The following contact information is provided in the guidance:
- CDER Regulated Products: CDER-OPQ-Inquiries@fda.hhs.gov
- CBER Regulated Products: Contact the appropriate CBER review office
Additional contact information for products in drug shortage:
- CDER Regulated Products: DRUGSHORTAGES@FDA.HHS.GOV
- CBER Regulated Products: email@example.com
Overall Impact Of The New Guidance
The guidance directly impacts the timing for implementing changes related to glass vials and stoppers, but it also shows how the FDA is leveraging risk-based approaches to address unforeseen challenges. This guidance is another example of the FDA encouraging risk-based decision-making by demonstrating and accepting its utility within its own processes. The guidance reinforces that understanding, evaluating, and mitigating risks continues to be a cornerstone of the FDA’s guidance to the pharmaceutical industry.
- FDA Guidance for Industry, COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers Guidance for Industry, March 2021
- Federal Register Vol. 88, No. 48, Notices, March 13, 2023
About The Author:
Nathan Parker has 27 years of progressive experience in the pharmaceutical industry, including executive roles in operations and quality. With a background in chemical engineering, Nathan has supported chemical API, biologic drug substance, cell therapy, medical device, drug product, and combination product manufacturing operations. In his manufacturing and quality leadership roles, he has been able to improve the efficiency and compliance within the organizations he has led.