FDA Issues Draft Guidance on CMC Postapproval Changes for Annual Reports

The US Food and Drug Administration issued on June 25, 2010, a draft guidance for industry, CMC Postapproval Manufacturing Changes Reportable in Annual Reports, to provide recommendations to drug applicants about the types of changes that may be included in annual reports.

The draft guidance focuses on chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that the agency believes “present minimal potential to have adverse effects on product quality and, therefore, may be reported by applicants in an annual report,” states the document.

According to the draft guidance, the number of CMC manufacturing supplements for new and abbreviated new drug applications (NDAs and ANDAs) has increased greatly over the past few years. The agency, in line with its Pharmaceutical Product Quality Initiative and risk-based approach to CMC review, evaluated the types of changes submitted in CMC postapproval manufacturing supplements and “determined that many of the changes being reported present very low risk to the quality of the product” and therefore no longer should be submitted in supplements.  

Certain items that used to be submitted to FDA in manufacturing supplements now may be reported in annual reports, pending a final guidance document. These items include changes related to the drug product’s identity, strength, quality, purity, and potency. A specific list of changes is included in Appendix A of the draft guidance, which is broken down into the following sections: components and composition, manufacturing sites, manufacturing process, specifications, container-closure systems, and miscellaneous items. Specific changes within each section include items such as the elimination of an overage from the drug product manufacturing batch formula that was previously used to compensate for manufacturing losses, the addition of barriers to prevent routine in-process human intervention in a filling area, changes to filtration process parameters that are within currently validated parameters, the addition of a specification for excipients, the use of a contract manufacturing organization for washing a drug product stopper, and extension of expiry based on real-time stability data from pilot-scale batches.

Postapproval changes that must be reported to FDA are included in section 506A of the Federal Food, Drug, and Cosmetic Act. The agency notes in the draft guidance that if the drug applicant is submitting supplemental applications based on recommendations for CMC changes provided in FDA’s Changes to an Approved NDA or ANDA guide, the applicant should now also refer to Appendix A of this draft guidance to determine whether a particular change may now be reported in an annual report. The agency also notes in the draft guidance that applicants must continue to comply with the CGMP for Finished Pharmaceuticals regulations within 21 CFR Parts 210 and 211, and for API manufacturers, with the ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients guideline. 

Comments on the draft guidance should be submitted to FDA within 90 days, or by Sept. 23, 2010.