In today’s Federal Register (here), the FDA announced the availability of a final guidance for chemistry manufacturing and control changes (CMC) that may be reported in an annual report (AR).  CMC changes that may be submitted in an annual report are considered minor changes.  The FDA says, “This final guidance updates the draft guidance of the same title issued on August 9, 2017 (82 F  37232) in the Federal Register.  The FDA considered comments received on the draft guidance as the guidance was finalized.  Based on comments received, the FDA updated the guidance with additional manufacturing examples and made editorial changes to improve clarity.”

The guidance, titled CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports, can be found here.  The guidance notes “[E]xamples of changes that have minimal potential to have an adverse effect on product quality and therefore must be submitted in an annual report are found in 21 CFR 601.12(d).  Additionally, the FDA provides examples in the Appendix of changes that it generally considers to have a minimal potential to have an adverse effect on product quality, which are categorized according to the type of manufacturing change.”  The FDA has included an appendix of changes that supplement those described in the regulations and, therefore, the FDA suggests that the appendix in this guidance be consulted prior to making determination of the filing type and making any submission.  If the FDA disagrees with an applicant’s determination that the type of change does not comply with the regulatory listings or the appendix, they will notify the applicant upon review of the AR.

Care should be taken when close calls are made about filing type as the FDA could halt distribution, request a recall, or consider the product misbranded if the change should have clearly been submitted under another classification and may present a danger to patients.  The categories addressed in the appendix to the guidance cover the following areas:

  • Components and composition
  • Manufacturing sites (only if they meet current cGMP status and have an acceptable FDA compliance status)
  • Manufacturing process, batch size, and equipment
  • Specifications
  • Container closure system

The FDA also discusses the type of information it expects to be included to support the AR reportable change.  Please read the guidance carefully as there are specific requirements for many of the change types that must be met to qualify for submission in the AR.