Starting Materials Remains a Challenging Issue for Both Regulators and Industry; FDA DMF Assessments Show SM Information Gaps

FDA reviewers are reporting that firms producing active pharmaceutical ingredients (APIs) are not always providing adequate information on their starting material (SM) decisions or on the fate and purge of process impurities in their Type II drug master file (DMF) applications.

Reviewers must determine the adequacy of the SM designation as part of the DMF assessment – a job made more difficult if the API manufacturer does not supply the relevant information and the reviewer has to try to figure out a justification without the benefit of a deep understanding of the process.

Also an impediment are listings of impurities that include only those identified in the API specification, with very little discussion of the generation, fate, and purge of the impurities occurring upstream.

When the starting material or impurities information is missing or inadequate, the DMF completeness assessment (CA) and the subsequent approval of the abbreviated new drug applications (ANDAs) that reference them can be significantly delayed.

The issues that are surfacing around starting material designations and applying the related principles in ICH’s API guideline Q11 were explored by Office of Product Quality (OPQ) Office of New Drug Products (ONDP) Division of Lifecycle API Quality Assessment Acting Lead Ronald Michalak at the GPhA/FDA Fall Technical Conference in November in Bethesda, Maryland (provided in full below)

Michalak spoke at a track on API review on the third day of the conference.  Also discussed in the track were DMF electronic submission and completeness assessments, the business process around DMF reviews, the ICH M7 mutagenic impurity guidance and its impact on DMF reviews, and OPQ’s risk-based review process for APIs (IPQ January 26, 2016).   

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