In August 2018, the ICH Q11 Implementation Working Group (IWG) published training material in the form of a PowerPoint presentation for better clarification of ICH Q11 Questions & Answers – Selection & Justification of Starting Materials. The presentation can be found here: Q11 IWG – slide deck training material (choose “read only” option to view) . Since May 2012, when ICH Q11 reached Step 4 and was recommended for adoption in the U.S., Europe, and Japan, numerous questions arose related to clarification of what could be defined as a regulatory starting material in the manufacturing of an API/drug substance. The attempts to fit the intricacies of the science behind synthesis of APIs into the rigid boundaries of regulation have been more like the quintessential efforts of fitting a square peg into a round hole. To better address this issue, the ICH Steering Committee created a Q11 Implementation Working Group (IWG) to develop a Questions & Answers document to provide clarification on information relating to the selection and justification of starting materials. The presentation cited above was created to illustrate the general principles of a Questions & Answers document and has attempted to provide perspective regarding what could or could not be considered a starting material in the API manufacturing process by presenting a few case studies. The presentation attempts to provide a better understanding of complex topics such as why the same starting material may be acceptable for one route of manufacturing of the API and not another, how to apply the ICH M7 principles to the starting material selection, and the distinction between commercially available and custom-made starting materials.
Additionally, effort has been put into defining the term “enough” in the context of the manufacturing process of an API/drug substance. This term “enough” is used in the original Section 5.1.1 of ICH Q11, which says, “…enough of the drug substance manufacturing process should be described in the application for regulatory authorities to understand how impurities are formed in the process.” While the presentation has attempted to address the key considerations that could help determine how much is “enough,” the term still remains subjective.
This presentation is informative and will be helpful for the industry in better selecting starting materials. For innovators, who can finalize their regulatory starting materials through meetings with the Agency, this document would be beneficial in justifying their selection; however, the impact on generic sponsors of ANDAs is not very clear. The generic industry follows a model that involves referencing the API/drug substance-related information to a DMF. Many criteria for selecting the proper starting material may not be subject to the open part of the DMF and, thus, may not be clear to the drug product manufacturer when they select their API source. The redefinition of regulatory starting material is one of the roadblocks to the first cycle approval of ANDAs; thus, the ANDA holders should do their due diligence to make sure that this issue does not stand in the way of approval. At the very least, ANDA holders should make sure that there are “enough” synthetically relevant steps between the API and regulatory starting material, in addition to getting a better understanding from the DMF holders regarding the studies they may have done to determine the fate of impurities (especially potential mutagenic impurities) in their APIs.