Final FDA Guidance on Comparability Protocols

Recommendation
12/13 November 2025
How to implement EU-GMP Chapter 8
The U.S. Food and Drug Administration (FDA) released the final guidance on Comparability Protocols (CPs) for postapproval CMC changes. The revised guidance follows the draft version issued in April 2016.
Changes to the draft version
Among the changes are the following:
- Incorporation of the ICH Q12 principles for postapproval changes.
- Allowing API supplier changes to be made via CPs.
- Expanding the scope of the guidance to address CPs for drug master files (DMFs) and drug-device combination products (where CDER or CBER is the lead center).
The CP may be submitted as part of the original application or in a prior approval supplement (PAS).
Additionally, the guidance provides a "Questions and Answers" section on CPs in the Appendix, which covers changes to
- Formulations
- Facilities
- Processes
- Equipment
- Specifications (including Analytical Procedures)
- Packaging
- Process Analytical Technology (PAT)
- Drug-Device or Biologic-Device Combination Products
- DMFs
More information is available in FDA´s Guidance for Industry Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA.
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