FDA published a 14-page draft guidance, “Guidance for Industry, Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products.“ 21 CFR 314.70 and 21 CFR 601.12 require that specific post approval changes to the CMC section of the application must be submitted to FDA. A subset of changes must be approved prior to commercialization of product made implementing the changes, others are reported in either of the two types of changes-being-effected (CBE) supplements, and others are submitted in annual reports. When post-approval changes are made, two factors must be considered: impact of the change on product quality and whether the change represents a modification to the approved application. The later is the subject of this guidance, which supplements the existing collection of FDA guidance in the area of post-approval change reporting. The Federal Register announcement, published June 1, 2015 indicates that comments are due to the Agency by July 31, 2015.
The CMC section of an application addresses a variety of information including sites of manufacture, description of the manufacturing process, both in-process and API / drug product specifications, background and justifications for methods of manufacture and testing. Which of these actually constitute “regulatory commitments” has long been a topic of discussion open for multiple interpretations, even within the same company. This guidance attempts to clarify FDA’s expectations in this area. The term “established conditions” is substituted for “regulatory commitments” because of the multiple possible meanings of the later term. The guidance provides introduction (section I) and background (section II) discussion that provide context for the specific information in sections III and IV.
Section III defines what the agency means by established conditions and provides a discussion of “elements of a control strategy that may be considered established conditions.” Reference is made to ICHQ10 definition of control strategy as part of this discussion. The section identifies features of the control strategy that may generally be considered to be established conditions. Just as important, it identifies information in the submission that is not generally considered to be part of the control strategy though information in these sections are often used to define and support the control strategy. It is also clear from this section that the complexity of the product, depth of product and process understanding and knowledge and analytical capability will be considered in identifying what constitutes established conditions in the application.
Section IV provides a tabulation of the CTD sections of an application for drug substance and drug product, identifies those sections which may include established conditions and provides a non-inclusive listing of examples for these sections. Product review has always addressed the CMC section of the application though this guidance suggests that the appropriateness of the applicant proposed established conditions will be part of product review and approval. Thus, the approval of the application will also include approval of the established conditions for the CMC section of the application so the applicant and the FDA will, ideally, be aligned in this topic. It seems clear that these conditions may differ among products and manufacturers based on the firm’s knowledge of the product and manufacturing process, the depth of the firm’s risk assessments and management, and complexity of the product covered by the application. This section also addresses legacy products that do not have a clear “delineation” of established conditions. FDA “intends to develop a process” where applicants may obtain clarification of what constitutes established conditions for these products. Finally, section IV addresses how changes may be made to the approved established conditions.
Firms are advised to carefully review this draft guidance and submit comments to FDA if appropriate. The information in this guidance, when finalized, will likely require revisions to change control procedures as well as changes to Quality Agreements made with contract manufactures and contract testing laboratories.