FDA issues final guidance on CMC postapproval changes for biologics

Regulatory NewsRegulatory News | 21 June 2021 |  By 

The US Food and Drug Administration (FDA) on Monday issued a final guidance to assist manufacturers of biological products in determining which types of changes to their products should be submitted in an annual report and which will require a prior approval supplement, the highest reporting category.
The guidance contains minor changes from a draft issued in December 2017; no reporting changes were switched from the minor to major category. Licensed biological products that are within its scope include vaccines, allergenic products, cell and gene therapy products and plasma-derived products. Products not included are whole blood products and biosimilars. Also excluded are human cells, tissues and cellular and tissue-based products (HCT/Ps) regulated solely under 42 USC 264 and regulations in 21 CFR 1271. (RELATED: CMC changes for biologics: FDA offers draft guidance, Regulatory Focus 21 December 2017)
The guidance has sections on types of reporting changes, a glossary of terms and an appendix on examples of post-approval manufacturing changes and recommended reporting categories.
Changes are categorized as either major, requiring the submission of a prior approval supplement; moderate, necessitating the filing of a changes being effected in 30 days supplement (CBE-30), or minor, requiring the filing of an annual report.
The guidance covers changes in the manufacturing process, the drug substance purification process, the starting materials and the container/closure system.
Manufacturing changes should be supported by data showing comparability of the product before and after the change. Manufacturers can use “a combination of testing, validation studies, and nonclinical or clinical studies as necessary to evaluate potential effects of the change,” according to the guidance.
A firm with a robust quality risk management system and manufacturing processes can use these strengths when submitting formal or informal risk assessments to support a post-approval manufacturing change, wrote FDA. Having a risk assessment in hand that is bolstered by a strong risk management plan “can allow the FDA to conduct a more effective assessment of the impact of a change, thereby facilitating timely review and decision."
In some cases, FDA may determine that a proposed manufacturing change will fall into a different category than the applicant has proposed. Though compliance with the distribution requirements of the new category is required, the applicant may in some cases request expedited review of a PAS.
The final guidance lays out information to be included in any supplement, as well as the requirements for an annual report. An annual report requires a detailed description of and rationale for the change and a listing of product included in the requested change. Additionally, supplements should give detail about the manufacturing site; validation protocols and data; and detailed information, including data, from studies used to evaluated effects on product quality.
The appendix includes recommended reporting categories for a number of common manufacturing changes, meant “to serve as a guide to assist applicants and the FDA to identify reportable post-approval changes and determine appropriate reporting categories,” according to the guidance. For example, a change in batch size, equipment, or growth culture requirements would require submission of a PAS; however, firms could notify FDA of minor adjustments to the volume of a fermentation step batch without other changes with an annual report.
Though FDA’s recommended reporting categories should generally be followed, firms may consult with FDA if they feel another selection would be more appropriate.
FDA said that the recommendations in the guidance “will result in a less burdensome approach for reporting changes, thereby accelerating distribution of the product made with the change. These updated recommendations are expected to promote continual improvement and innovation over the product lifecycle and minimize the risks for product shortages.”
The final guidance heeded a suggestion from the Biotechnology Industry Organization to add “intermediate” to the glossary of terms. It defines an intermediate product as “a material produced during a manufacturing process which is not the drug substance or the drug product but whose manufacture is critical to the successful production of the drug substances or the drug products. Generally, an intermediate will be quantifiable and specifications will be established to determine the successful completion of the manufacturing steps prior to continuation of the manufacturing process."
However, FDA rejected BIO’s suggestion that changes within a location should be moved from a CBE-30 change to the lower risk annual reportable category. This would include the “addition or replacement of an existing suite/room that does not affect sterility assurance or contamination/cross contamination within an approved manufacturing building.
FDA also rejected a suggestion by the Pharmaceutical Research and Manufacturers of America to expand the scope of the guidance to include recombinant proteins, therapeutic viruses, monoclonal antibodies and biosimilars of monoclonal antibodies.
FDA guidance on CMC postapproval changes
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