Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Q&A FDA

The U.S. Food and Drug Administration (FDA) recently released a draft guidance titled “Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products: Questions and Answers.” This document represents an important step in enhancing regulatory clarity for biosimilar manufacturers. In this post we delve into its key points, explore its implications, and compare it with the WHO GMP and EU GMP.

Why Did the FDA Release This Guidance?

The FDA’s rationale stems from its ongoing commitment under the Biosimilar User Fee Act (BsUFA) to streamline biosimilar development while maintaining safety and quality standards. The FDA acknowledges the complexity of postapproval changes, such as modifications in production processes, equipment, or facilities, which can significantly impact a product’s quality, safety, and efficacy. By offering these recommendations, the FDA aims to better clarify reporting requirements, reduce ambiguities, and ensure consistency in it's regulations.

A few examples of such ambiguities:

• Risk Assessment for Reporting Categories The guidance clarifies that:

  • Major changes, such as introducing new manufacturing facilities or altering drug substance production processes, require PAS submissions.

  • Moderate changes, like certain process parameter adjustments, can be reported under

    CBE-30 or CBE-0 if sufficient comparability data is provided.

  • Minor changes, like routine equipment maintenance, can be included in Annual Reports.

  • Comparability exercises should focus on critical quality attributes most impacted by the change.

  • Analytical stability testing under stress conditions may be needed for subtle manufacturing modifications, such as changes to excipient suppliers.

• Comparability Data Requirements Previously, manufacturers faced uncertainty about the extent of comparability data needed. The guidance specifies:

• Multiproduct Manufacturing Risks The guidance provides detailed recommendations for introducing biosimilars into shared facilities, addressing risks like cross-contamination and mix-ups. For example:

  • Separate manufacturing areas, strict material flows, and enhanced identity testing must be implemented, especially when manufacturing biosimilars and reference products in the same facility.

Background and Scope

This guidance is tailored for products licensed under Section 351(k) of the Public Health Service (PHS) Act, concerning biosimilars and interchangeable biosimilars. The draft guidance outlines the types of manufacturing changes that require reporting and specifies the necessary data to demonstrate that such changes do not compromise the product’s quality, safety and efficacy.

Under U.S. regulations (21 CFR 601.12), manufacturers must categorize these changes into one of three reporting tiers:

1. Prior Approval Supplement (PAS)

   For major changes with substantial potential impacts.

2. Changes Being Effected (CBE-30/CBE-0)

   For moderate changes requiring FDA notification 30 days prior to distribution.

3. Annual Reports

   For minor changes with minimal potential impact.

The guidance emphasizes conducting comparability exercises to ensure that products remain “highly similar” to their reference biologics post-change.

What Are Postapproval Manufacturing Changes?

Postapproval manufacturing changes encompass adjustments to:

• Production processes

• Quality controls

• Equipment or facilities

• Personnel

• Labeling

The guidance outlines robust requirements for validating such changes, including data on quality attributes, analytical comparability, and process validation. For example, stability testing under accelerated or stress conditions may be needed to detect subtle differences introduced by manufacturing modifications.

Comparisons with EU GMP and WHO GMP Frameworks

In the EU, postapproval changes to biosimilars follow guidelines established by the European Medicines Agency (EMA). EMA’s focus on quality variations (Type IA, IB, and II) mirrors the FDA’s tiered approach but emphasizes prior approval for more categories of changes. Similarly, the World Health Organization (WHO) provides detailed guidance on postapproval changes.

The FDA guidance aligns with international standards, such as ICH Q12, but offers additional granularity specific to the U.S. regulatory context, particularly around interchangeable biosimilars.

Approval Pathway Beyond the Draft Phase

As of now, this guidance remains in draft form, open for public comments until early 2025. Once finalized, it will supersede existing sections in earlier guidance documents, including the Q&A on biosimilar development from September 2021. To gain final approval:

1. Industry stakeholders will submit comments via the Federal Register.

2. The FDA will revise the draft based on feedback.

3. The finalized guidance will be published, representing the FDA’s official stance.

Conclusion

The FDA’s draft guidance underscores the importance of good planning and execution for postapproval manufacturing changes in biosimilars. At PCS, our GMP expertise equips clients with the insights and tools needed to meet these regulatory challenges.

For more insights on how PCS can support your biosimilar development and manufacturing strategies, feel free to contact us.