Over the years, the number of chemistry, manufacturing, and controls (CMC) postapproval drug manufacturing supplements for NDAs and ANDAs submitted to FDA has continued to increase.  These are required for “major” or “moderate” manufacturing changes:

  • Major.  If a manufacturing change is considered to be major, an applicant must submit and receive FDA approval of a prior-approval supplement (PAS) before the drug product made with the change is distributed.
  • Moderate.  If a manufacturing change is considered to be moderate, an applicant must submit a supplement at least 30 days before the drug product is distributed (a CBE-30 supplement) or, in some cases, submit a supplement at the time of distribution (a CBE-0 supplement).  “CBE” means “changes-being-effected”.

The increasing number of supplements – combined with FDA’s goal of implementing a more cooperative, efficient, and risk-based approach for regulating pharmaceutical manufacturing – has resulted in the agency examining the types of changes that historically have been submitted as CMC postapproval manufacturing supplements (PAS, CBE-30, and CBE-0).  As a result, FDA concluded that many of the changes being reported present low risk to the quality of the product and can therefore be documented in a company’s annual report (i.e., notification of a change after implementation) rather than in a supplement.

FDA began to address this issue in June 2010, when the agency issued a draft guidance for industry entitled CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports (the Annual Report guidance).  The finalized version was issued on March 4, 2014, and details the agency’s current thinking on what manufacturing changes can be submitted in an annual report, and it also adds to/revises recommendations previously published in FDA’sChanges to an Approved NDA or ANDA guidance, the Scale-up and Postapproval Changes(SUPAC) guidances, and other related guidances.

If a recommendation in the Annual Report guidance is found to be inconsistent with previously published FDA guidances, the Annual Report guidance would apply, assuming that the applicant’s proposed manufacturing change would present a minimal potential to have an adverse effect on product quality.  For changes not addressed in the Annual Report guidance, applicants should still refer to other CDER guidances, as well as Appendix B of the Annual Report guidance, to determine the appropriate reporting categories (i.e., PAS, CBE, or annual report).

The Annual Report guidance further reminds companies that in addition to properly reporting postapproval manufacturing changes, such changes must be made in compliance with current good manufacturing practice (cGMP) requirements, including:

  • establishing and following appropriate written procedures;
  • qualifying equipment as suitable for its intended use;
  • using validated test methods;
  • scientifically establishing the commercial manufacturing process; and
  • ensuring the manufacturing process’s ongoing state of control (which may include additional process validation and stability studies depending on the nature of the change).

The now final Annual Report guidance is available here