FDA Clarifies ICH Guideline on Selecting and Justifying Drug Manufacturing Starting Materials

Over four years after adopting an ICH guideline on manufacturing processes, the FDA has responded to industry questions on justifying starting materials for chemical entity drug substances.

The draft question and answer guidance covers the implementation of a single section of the Q11 manufacturing guideline — first developed by the International Council for Harmonisation and adopted by the FDA in 2012 — and makes recommendations for the information that should be included in marketing applications.

The guidance makes it clear that the term “starting material,” as described in the Q11 guideline, is the same as the “API starting material” referenced in the ICH’s separate Q7 guideline covering good manufacturing processes.

All principles in the Q11 guideline should be considered, instead of simply using a selection to justify starting materials. If a material does not meet all the principles, applicants should provide a rationale explaining why the material is still appropriate.

Post-approval changes to steps prior to starting materials are not explicitly covered in ICH Q11, and changes prior to starting materials should be evaluated for their impact on current and potential new impurities. Additionally, the general principles of the Q11 guideline apply independently to the selection of starting materials for linear and convergent syntheses.

The Q&A also defined the difference between a commercially available chemical and a custom synthesized chemical — the former is one sold as a commodity in a non-pharmaceutical market, while custom synthesized chemicals are generally understood to be made specifically to a drugmakers’ requirements, the document said.

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