The QMN Weekly Bulletin

FDA Revises Draft Guidance on Protocols for CMC Changes After Approval

June 10, 2016

The FDA has a slate of new recommendations companies should follow when submitting a comparability protocol assessing changes to the chemistry, manufacturing or controls of a drug or biologic after the agency has approved its production process.

Foremost among the changes are new expectations for supporting materials that should accompany all applicable comparability protocols, including prior information justifying the production change; a summation of a risk assessment of the proposed change; data supporting the change derived from the product’s development and initial production process; research concerning the proposed change and its potential effects on product quality; and in the case of recombinant DNA-derived products, information supporting the relevance of the change.

Another change was the agency warning companies not to submit comparability protocols for changes in API suppliers or alterations that would affect a product’s approved labeling.

Tests proposed in the comparability protocol should be performed at the commercial manufacturing scale and employ a combination of routine quality controls — such as specifications and process controls. Meanwhile, nonroutine tests should provide the necessary level of detail to determine the “specific risks associated with the change to product quality.”

The document adds that increased sampling during these tests may be appropriate and all test criteria should be spelled out in the comparability protocol. The agency adds that comparative evaluations should be employed when possible, including side-by-side comparisons.

In all cases, companies should “provide scientific justification for the designs of studies, selection of the tests and analytic procedures” to ensure that they provide the necessary information.

For companies submitting multiple CMC post-approval applications at the same time, the agency issued an updated MAPP on April 19 addressing the submission process. The revised MAPP addresses so-called grouped supplements and covers NDAs, ANDAs and BLAs.

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