By Daniel Sun, MS, RAC

Senior CMC Consultant, Deputy Director of China Office, ELIQUENT Life Sciences, VP Regulatory Affairs, ELIQUENT Life Sciences

On July 24, the FDA issued final guidance: Container Closure System and Component Changes: Glass Vials and Stoppers. This guidance consolidates recommendations for reporting and implementing common changes to container closure system (CCS) components consisting of glass vials and stoppers for approved sterile drug products, including biological products administered parenterally. This guidance is applicable for the marketing stage product (i.e., NDA, ANDA, BLA).

In 2021, the FDA released a similar guidance for COVID-19: COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers, intended for use during the public health emergency, which has now expired. The new final guidance was issued because many of the recommendations set forth in the COVID-19 guidance are applicable outside the context of the Section 319 public health emergency.

Regulatory Approach to CMC Changes

According to Section 506A of the Federal Food, Drug, and Cosmetic Act (21 USC 356a), 21 CFR 314.70, 21 CFR 314.97, and 21 CFR 601.12, sponsors have the responsibility to report changes, and the reporting category depends on the risk. Changes are categorized from highest risk to lowest, and reported as: prior approval supplement (PAS), changes being effected in 30 days before (CBE30), or upon implementation (CBE0), and those notification that can be provided after implementation (annual report).

For CCS change (e.g., changes in components, composition, container type, suppliers, and manufacturers), FDA recommends a risk-based approach. Sponsors should assess risks related, but not limited, to

  • Properties of a container
  • Interaction between drug product formulation and product-contact components over the intended shelf life
  • Effect of formulation attributes such as high pH
  • 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)
  • Effect of the lyophilization process on product quality

Sponsors should also conduct applicable tests and studies outlined in United States Pharmacopeia (USP) chapters as this is the FDA recognized standard. This guidance points out several USP chapters for sponsors to consider: USP General Chapters <381> Elastomeric Closure for Injections, <660> Glass Containers Used in Pharmaceutical Packaging/Delivery Systems, <1207> Package Integrity Evaluation — Sterile Products, <1660> Evaluation of the Inner Surface Durability of Glass Containers.

In addition, FDA points out when the sponsor needs to refer to a drug master file (DMF), product-specific information is stilled needed to support changes.

Common Changes Related to Glass Vials and Stoppers

The guidance provides tables listing out examples of CCS changes and their data requirements, as well as reporting categories.

The guidance also points out that sponsors seeking to make more than one related change concurrently should address the potential risk from the cumulative effect of multiple changes.  In this case, the reporting category should be based in the highest risk change.

In addition, when introducing a new CCS component that differs from the specified CCS component type/grade in product labelling (e.g., “packaged in type 1 glass”), a supplement to change product labelling may be appropriate. When the new CCS component differs from that specified in the applicable USP monograph, appropriate engagement with USP regarding an update to the product monograph may be necessary to ensure continued compliance with the monograph.

Tools to Facilitate Changes to CCS Components

FDA suggests using appropriate tools to streamline change assessments. Some examples are provided below for sponsor’s considerations.

Risk Based Considerations for Reporting Categories:  Sponsors should consider using tools in ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management [e.g., established conditions, post-approval change management protocols (PACMPs)] to support proposals for reduced reporting categories based on an increased understanding of the risk to product quality when making a change related to the glass vial or stopper.  Sponsors should contact FDA for feedback and agreement on the proposed reporting category before submitting a supplement with a lowered reporting category.

Comparability Protocols (CP): a comparability protocol (CP) is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC post-approval change. It can be submitted as a part of an original application or as a PAS, to facilitate expeditious implementation of post-approval changes. CPs allow FDA to review a description of one or more proposed CMC post-approval changes, supporting information (including any analysis and risk assessment activities), the plan for demonstrating comparability of the post-change product to pre-change materials, and the proposed reduced reporting category for the change(s).

If the CP is approved, the changes usually can be implemented under the lower reporting category.  A CP can be used for a one-time change or be used repeatedly for a specified type of change over the product lifecycle. A CP can also cover an identical change that may affect multiple applications (grouped supplements, trans-BLA submission.)

Conclusion

Comparing with previous 2021 COVID-19 CCS guidance, this new final guidance omits all public health emergent content and regulatory flexibility during pandemic. For example, the COVID-19 CCS guidance allows sponsor could submit certain changes to CCS using a lower reporting category if the applicants are experiencing constrained supply of CCS or components thereof, and if the relevant submissions are related to the treatment or prevention of COVID-19 or other drug shortage. While in the new final guidance, FDA deleted those descriptions.

However, the general regulatory principles of two guidelines remains the same, both guidance illustrate the FDA’s expectation regarding the CCS changes and gives tables lay out all example changes and data requirement. We strongly recommend sponsors who intend to make changes to their CCS change to evaluated the expectation and requirement based on this guidance.  

Reference

FDA Guidance for Industry: Container Closure System and Component Changes: Glass Vials and Stoppers (July 2024)

FDA Guidance for Industry: COVID-19 Container Closure System and Component Changes: Glass Vials and Stoppers (March 2021)

ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management (May 2021)

FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics; Chemistry, Manufacturing, and Controls Documentation (May 1999)

FDA Guidance for Industry: Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA (October 2022)

USP General Chapters <381> Elastomeric Closure for Injections

USP <660> Glass Containers Used in Pharmaceutical Packaging/Delivery Systems

USP <1207> Package Integrity Evaluation — Sterile Products

USP <1660> Evaluation of the Inner Surface Durability of Glass Containers.