FDA has issued a final guidance document, CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports, to provide recommendations to holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) regarding the types of changes to be documented in annual reports. Specifically, the guidance describes chemistry, manufacturing, and controls (CMC) postapproval manufacturing changes that the agency has determined will likely have a minimal potential to have an adverse effect on product quality and, therefore, should be documented by applicants in an annual report.
Under 21 CFR 314.70, all postapproval CMC changes beyond the variations provided for in an approved NDA and ANDA are categorized into one of three reporting categories: major, moderate, or minor. If a change is considered to be major, an applicant must submit and receive FDA approval of a supplemental application to the NDA or ANDA before the product made with the manufacturing change is distributed (also known as a prior approval supplement (PAS)). If a change is considered to be moderate, an applicant must submit a supplement at least 30 days before the product is distributed (CBE-30 supplement) or, in some cases, submit a supplement at the time of distribution (CBE-0 supplement). If a change is considered to be minor, an applicant may proceed with the change, but must notify FDA of the change in an annual report. For any change, applicants must assess the effects of the change on product quality through appropriate studies.
“The number of CMC manufacturing supplements for NDAs and ANDAs has continued to increase over the last several years,” said FDA in the guidance. "In connection with FDA’s Pharmaceutical Product Quality Initiative and our risk-based approach to CMC review, we have evaluated the types of changes that have been submitted in CMC postapproval manufacturing supplements and determined that many of the changes being reported present low risk to the quality of the product and do not need to be submitted in supplements.”
Based on its risk-based evaluation, FDA developed a list to provide additional current recommendations to companies regarding some postapproval manufacturing changes for NDAs and ANDAs that may be considered to have a minimal potential to have an adverse effect on product quality, and, therefore, may be classified as a change to be documented in the next annual report (i.e., notification of a change after implementation) rather than in a supplement. The changes are categorized according to the type of manufacturing change. These changes are either additions or revisions to the CMC changes recommended for documentation in an annual report that were previously published in earlier guidance on changes to an approved NDA or ANDA, the SUPAC guidances, and other related guidances. The recommendations in the new guidance clarify whether submission of a supplement or documentation of the change in an annual report may be appropriate.