FDA Adds Additional Q&As in the Final CMC Postapproval Changes Guidance

FDA recently published the final guidance document “Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA.”  This final guidance provides recommendations to original applicants and holders of approved applications for human drugs and certain biological products on implementing chemistry, manufacturing, and controls (CMC) postapproval changes(s) through the use of a Comparability Protocol (CP).

According to the FDA, the draft guidance was published in 2016 in order to update the 2003 guidance by including current pharmaceutical quality concepts, providing more flexibility regarding filing procedures for notification of modifications to an approved CP in less burdensome reporting categories than a prior approval supplement, and adding an appendix to address commonly asked questions.  The updated final guidance now also incorporates ICH Q12 Technical and Regulatory Considerations for Pharmaceutical Product lifecycle Management.  The final guidance includes several changes that are summarized below.

Section D: Comparability Protocol for the Proposed CMC Change(s) was largely rewritten to add more detail on what the CP should describe as well as recommendations for designing the CP.  For example, the guidance now includes that the design of the CP should take into account your understanding of the product, manufacturing process, risks, control strategy that are relevant to the proposed change(s), and the intended use of the product.

To address industry comments regarding the requirement to perform tests and studies or collect and analyze data for the proposed change(s) at commercial manufacturing scale, the guidance now includes “…except where less than commercial scale is justified.”  According to the updated final guidance, it might be possible to design a CP to compare the post-change product to established quality reference standards and/or comparator products, but that it recommends reaching out to the Agency for complex products that are difficult to characterize.

FDA added examples in Section V of the guidance of modifications to an approved CP that must be submitted as an annual report.  Additional examples of modifications to an approved CP that must be submitted as either a CBE-30 or CBE-0 were also provided in the updated guidance.  In the updated guidance FDA’s clarifies that it is acceptable to submit a CBE-0 to replace or modify a characterization test or study as specified in an approved CP that provides increased assurance of the product quality.  FDA also provided additional examples as to what changes would be considered “annual reportable.”  While the clarifications appear to be minor, they can save companies significant time in the preparation of materials for FDA review.

The FDA added in Section VI that if the data does not demonstrate that the approved acceptance criteria in the CP have not been achieved or there is some other impact on product quality, applicants have a few options, including 1) withdrawal of the approved CP in a CBE-0 supplement, 2) pursue change without using a CP using applicable reporting categories established in 21 CFR 314.70 or 601.12, or 3) pursue a change using a CP by contacting FDA to discuss an appropriate course of action.

When you are ready to notify the FDA of the change(s) in the approved CP, the FDA states that you should include all of the information agreed upon in the approved CP and that the submission should update, using the ICH CTD-Q format (where applicable), the appropriate section(s) of the application to which the CMC change(s) applies.

Based on comments from Industry, the updated guidance now includes questions and answers for Manufacturing Equipment Changes, Drug-Device or Biologic-Device Combination Products, and Master Files.  The Manufacturing Process Changes section of the Appendix now includes two questions on process scale changes and a change from batch to continuous manufacturing.  FDA states that a CP can be useful for changes in manufacturing process scale (scale-up, scale-down, scale-out), and that FDA recommends including information on potential effects of changes in manufacturing scale on product quality.  Regarding a change from batch to continuous manufacturing process, the FDA states that a reporting category other than a PAS would generally not be justified.