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Since the manufacture of a starting material may often be purchased or contracted out to a supplier and because GMP applies downstream in the synthesis from this material, the correct designation of starting material is crucial. In the United States, it is usual to discuss the choice of starting materials with FDA during review of the IND (e.g., at an end-of-phase II meeting), and thus suitable commercial arrangements for sourcing the material can be put in place well in advance of the registration filing. This allows the timely manufacture of launch stock of the bulk drug substance.
For registration filings in the European Union, the 2003 Committee for Proprietary Medicinal Products (CPMP) “Guideline on the Chemistry of New Active Substances” recommends that the description of the manufacturing process should include a justification for the choice of starting material. A flow chart should be included indicating the synthetic process prior to the introduction of the starting material, as it is felt that this may be useful in evaluating the suitability of the specification. A schematic diagram is suggested as in Figure 2. The European review process has the disadvantage that the acceptability of the choice of starting material is not certain until the MAA has been reviewed.
