US FDA aims to clarify reporting rules for biologics CMC changes

Biologic drug makers that tweak manufacturing processes after approval have a better idea of when and how to inform the US FDA of the changes thanks to new agency guidelines.

The US regulator issued the final guidance document last week, explaining the aim is to help biologics makers determine which reporting category is appropriate for a chemistry, manufacturing, and controls (CMC) change.

The guidance – which applies to biologics, vaccines, cell and gene therapies, plasma-derived medicines but not whole blood products, human cell or tissue-based therapies – categorizes changes as major or minor.

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In short, a minor CMC change must be shared with the FDA in an annual report, whereas biopharmaceutical manufacturers making major changes to production processes have 30 days to notify the agency.

The FDA specifies manufacturing changes be supported by data indicate the comparability of the product, explaining that companies can use “a combination of testing, validation studies, and nonclinical or clinical studies as necessary to evaluate potential effects.”

Industry input

A draft version of the guidelines was issued for industry feedback in 2017 and the final guidance incorporates a suggestion by the Biotechnology Industry Organization (BIO) that the term “intermediate” be added to the glossary.

In the guidance “intermediate” is defined 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.”

It adds that, “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.”

In contrast, the FDA rejected Pharmaceutical Research and Manufacturers of America’s (PhRMA) suggestion the guidelines also be applied to recombinant proteins, therapeutic viruses, monoclonal antibodies and biosimilars.