FDA Releases Draft Guidance on CMC Postapproval Manufacturing Changes for Biologics

The FDA has issued new draft guidance on how biologic product sponsors should address postapproval changes in chemistry, manufacturing, and controls (CMC).

The draft guidance, prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and Research, provides recommendations to biologics license application (BLA) holders regarding the types of changes to an approved BLA that can be documented in annual reports. Under FDA regulation, postapproval CMC that have a minimal potential to affect product quality can be documented by BLA holders on a yearly basis, while changes that are considered major require applicants to submit and receive FDA approval of a supplement to the BLA before the affected product can be distributed. Moderate changes require a supplement to be submitted 30 days before product distribution.

The list of CMC changes to be submitted annually include:

• Components and composition (eliminations or reductions in overages from a drug-product manufacturing batch)

• Manufacturing sites (site changes for testing, labeling, and packaging; manufacture of additional products at a site; and modification of a facility)
• Manufacturing process, batch size, or equipment (mixing times, batch sizes, reduction of open-handling steps, changes among qualified sterilization chambers, and addition of identical duplicate process chains)
• Specifications (addition of tests, changes to drug substances to comply with an official test, changes to regulatory procedures, addition of tests, and improvement of acceptance criteria)
• Container closure systems (closure systems for storage of nonsterile drug substances, use of a manufacturing organization for the washing of stoppers, and changes to a crimp cap)

If the FDA determines that a CMC change that falls into one of these categories would be more appropriately categorized as a major or moderate change and therefore require a supplement, the FDA will notify the applicant and request further information.

Changes documented in annual reporting should include full descriptions, with details concerning the manufacturing sites involved, the date of the change, a cross-reference relevant to validation protocols or standard operating procedures, relevant data from studies and tests performed to assess the effect of the change on product quality, a list of products involved, and a statement that the effects of the change have been assessed.

The FDA notes that it has produced the new guidance after having observed a steady increase in the number of CMC manufacturing supplements that it has received. An annual submission of CMC changes that have a minimal potential to harm product quality could allow the agency to streamline its processes, in keeping with its current focus on efficiency and the better use of limited resources.

The FDA will accept comments on the draft guidance on docket FDA-2017-D-2802 until October 10, 2017.