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By Laura O’Brien

Laura O'Brien-finalEvaluation of information related to the manufacturing process and controls for drug substances is an important part of marketing authorizations. Decisions made about the proposed starting material(s) determine what expectations apply to the quality-related information for both pre-market assessment and for post-market changes. The acceptability of the applicant’s proposed starting material also has implications for good manufacturing practices (GMPs), process validation requirements, and inspection-related activities (as outlined in ICH Q7 [PDF]). While it is recognized that ICH Q11 (PDF) provided good scientific guidance when published in 2012, differences in the interpretation of that guidance are causing problems for industry and regulators.

Implementation of ICH Q11 principles on selection of API starting materials (SMs) has been challenging based upon variations in both starting material justification packages provided to regulatory agencies and varied interpretation of data packages and expectations by regulatory reviewers. The ICH Q11 Guidance proposed a series of principles for selecting API SMs, and currently an ICH Q11 Implementation Working Group is developing a Q&A document to clarify Q11 topics including the API SM selection. Additionally, the IQ Consortium has completed three publications on API starting materials, and in Part 3 of this series it has been proactively preparing its recommendations for application of a consistent API starting material justification package that acknowledges regulatory concerns and is in alignment with ICH Q11.

The symposium Selecting a Globally Acceptable API Starting Material—Regulatory and Industry Perspectives will include regulatory and industry perspectives on considerations to select a globally acceptable API starting material. It is critical to provide regulators with sufficient information and controls both prior to and within the GMP synthesis downstream of the starting materials to justify the proposed API SM designations. Meanwhile, it is important that reviewers are able to make scientifically-justified decisions efficiently to support supply chain flexibility, cost controls, and a process for global approval and launch readiness.

We will discuss:

  1. Starting material “complexity,” the feasibility of developing general metrics to identify acceptable and risky API SM designation proposals;
  2. Expectations for a strong justification package for “advanced” API starting material designation proposals, including a thorough control strategy discussion for impurities, including stereochemical impurities and potential mutagenic impurities, within and outside of the GMP synthesis; and
  3. Quality oversight including supplier agreements and change management to communicate active systems in place that maintain a future state of oversight/control.
Laura O’Brien, Ph.D., is senior research fellow in Boehringer Ingelheim’s Global CMC Experts group. She has broad expertise in her responsibility for the scientific planning and review of documents authored by CMC Development scientists for the Quality section of regulatory submissions, from early drug development through global product registration and approval.