FDA issues final guidance on CMC postapproval changes for annual reports

Regulatory NewsRegulatory News | 09 December 2021 |  By 

The US Food and Drug Administration (FDA) on Thursday issued a final guidance to help manufacturers of certain biological products determine which types of changes to their products should be submitted in annual reports for changes expected to have a minimal impact on product quality. The final guidance differs from the draft in providing more examples of changes that can be submitted in annual reports; however, FDA rejected calls from industry to provide a timeframe for providing notice to industry involving disagreements over a company’s designation of a change in the annual reportable category.
FDA differentiates post-approval changes into four categories: major changes requiring the submission of a prior approval supplement (PAS); moderate, requiring the filing of changes being effected-30 days supplement (CBE-30), or a CBE-0 supplement; or minor changes requiring only the filing of an annual report. Annual reports do not need to be submitted as supplements.
A draft guidance was published on 8 August 2017; the newly finalized guidance applies to biological products as defined in 21 CFR 600.3(h), but not to blood-derived products, in vitro  diagnostics, cellular and gene therapy products, or vaccines. (RELATED:  FDA Drafts Guidance on Postapproval Manufacturing Changes for Biologics, Regulatory Focus, 8 August 2017).
The document revises the draft by providing more examples of changes considered in the annual reportable category. For example, changes in testing sites that measure process-related impurities for methods that have been “successfully validated” at the new site would be considered a change subject to an annual report. So too are changes in testing sites that perform “low complexity” compendial tests, such as tests measuring pH or osmolality.
The final guidance also includes new language incorporating other International Council on Harmonisation (ICH) guidelines. “This guidance focuses on reporting mechanisms,” clarified FDA, referring firms to other ICH guidances that address change management as part of the pharmaceutical quality system, including Q9, Quality Risk Management, Q10 Pharmaceutical Quality System, and Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients.
The guidance describes how changes should be listed in annual reports. For example, a full description of the CMC change should be provided that covers the manufacturing sites or areas involved and the date the change was made, cross-references the relevant validation protocols or standard operating procedures, and includes relevant data from studies to assess the effect of the change on product quality.
The appendix lists changes that it considers having a “minimum potential” on product quality, and covers changes affecting a product’s components and composition, manufacturing site changes, manufacturing process changes, and changes to the container closure system.
Rejects industry’s suggestions to provide timeframe
The agency also did not take up Novartis’s and Biotechnology Industry Organization’s (BIO) suggestions that FDA should be held to a time frame for disagreeing with sponsors’ classification of a change in the annual reportable category. Novartis wanted FDA to provide sponsors with such notice within 60 days while BIO suggested 30 days.
Rather, the guidance specifies that “If FDA disagrees with the categorization, FDA generally intends to notify the application of the correct category and may request additional information.”
FDA also rejected Pfizer’s suggestion to add an additional category for sites that manufacture a drug substance or intermediate to the annual reportable category.
Pfizer stated that “his provision should also be applicable to facilities that manufacture drug substance or intermediate in addition to those that manufacture drug product.”
FDA final guidance on CMC changes
Comments on draft guidance


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