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Executive Summary

DETAILED EARLY-STAGE DRUG SYNTHESIS DESCRIPTION IN NDAs IS UNNECESSARY, Ciba-Geigy Chemical Operations Exec Richard Margerison, PhD, maintained at a July 22 Drug Information Association (DIA) workshop on the manufacturing and control requirements of the new NDA regulations. Chairman of the PMA cmte. reviewing the FDA drug substance draft guideline, Margerison maintained that "with the inclusion of 'in process controls,' it is not necessary to include [in the NDA] a very detailed description of the [synthetic] process in the early stages." Paragrarph Margerison asserted that chemical processing is not a static operation, and that continual improvements are made to the process to improve quality and the economics of the operation. "If the manufacturer is required to include a large quantity of specific details in the NDA submission," Margerison noted, "he will be obligated to file numerous supplements which will require review and prior approval by the agency. This is a time-consuming and wasteful process for the industry as well as for the agency because this effort does not contribute to the desired aims of the NDA rewrite." Margerison also objected to the level of detail requested on the fermentation process by the drug substance guideline. Much of the detail requested is of economic concern and offers no increased confidence in the quality of the drug substance, he contended. In requesting such detailed information, Margerison said, the guideline again "does not recognize that fermentation is a dynamic process and variation in concentrations of media components and processing conditions will be made on a routine basis to achieve optimum process performance." For example, Margerison noted that fermentation strains are constantly being modified by a variety of practices to find the microorganism/process set with optimum yield. Unless the species or raw materials are changed, he said, "these actions should not be considered process changes. . .which require agency notification and approval because product quality is not affected." Margerison also contended that the identification of side products and impurities in antibiotic broths and crude streams "is neither practical nor relevant" in the NDA submissions. Margerison recommended that, in general, requests in the drug substance guidelines for yields for various particular operations should be removed. Due to the nature the manufacture of the drug substance parallels, is used as a monitor for economics, and is not a reliable indication of product quality. References to yields should therefore be removed from the guidelines, Margerison contended. McNeil Analytical Development Director Richard Egan, PhD, commented at the DIA workshop on the companion NDA guideline covering final dosage forms. Egan asserted that the NDA rewrite and drug product guideline as presented will do little to expedite preparation of the chemistry, manufacturing and controls sections of the NDA, and that unless revised, "will if anything lengthen and complicate this part of the approval process." According to Egan, the new documents concentrate on facilitating the review of the submitted documentation, but not sufficiently on cost and efficiency of preparation.

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