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Executive Summary

FDA INTERIM BATCH-SIZE POLICY CHANGED TO REFLECT INDUSTRY STANDARD in a Sept. 13 policy clarification of the agency's July 17 guidance. Noting that "industry has de facto adopted an interpretation whereby they routinely use different capacity by comparable equipment for production of demonstration batches," FDA stated that "this guide has been revised to reflect the current industry standard." The Generic Pharmaceutical Industry Association and the National Pharmaceutical Manufacturers Association and three individual companies met with the Office of Generic Drugs in late August to voice their concerns with the interim policy ("The Pink Sheet" Sept. 3, T&G-6). The major issue raised in these discussions, FDA said, was whether the demonstration test batch for bioequivalence studies "needed to be produced in the identical pieces of equipment to be used in full scale production or whether demonstration batches could be produced in equipment that was of the same design and essential operating features but of a different capacity than that proposed for full-scale production." While industry and FDA field representatives said companies routinely produced demonstration batches in comparable equipment of smaller capacity than that of full-scale production, the groups expressed concern that the requirement of "either identical equipment, or use of comparable equipment manufactured by the same equipment firm, would be a new and unduly burdensome requirement, meeting no defensibly desirable regulatory purpose," FDA explained. The revised policy states that "the production equipment used to manufacture the test batch and any alternative equipment used to produce larger scale production batches must be specifically identified and fully described in the application." The policy adds: "If different pieces of equipment are to be used to produce the full scale production lot than were used to produce the test lot, then an explanation of why and how the pieces of equipment are believed to be comparable should be provided." FDA's decision to revise the interim policy was made after the agency determined that industry has routinely used comparable equipment of different capacity to produce demonstration batches. In addition, FDA noted that "there is no evidence of a substantial or systematic problem that has been caused by the industry's adoption of this interpretation." The suggestion that full-scale equipment be used for batches undergoing bioequivalency testing seems to have emanated from the division's review chemists, and not FDA field inspectors. Noting that "FDA review chemists have long taken the position that validated full-production batches are the standard for fulfilling Current Good Manufacturing Practice (CGMP) requirements," FDA maintained that "by inference, full-production batches are also appropriate for developing data to support pending applications." While it "recognizes that there is limited supporting technical data on which to base a policy allowing for less than full size production scale test batches," FDA said that "the revised policy stated in this guide does have broad support in industry and is acceptable to the [Office of Generic Drugs]." Addressing two other issues raised by the generic industry -- actual test batch size and the type of personnel permitted to participate in test batch production -- the policy states that test batches should produce a net yield of 10% of the maximum-size production batch or 100,000 finished-dosage units, whichever is greater, and that "equipment used to produce the test batch should be operated by individuals qualified by training and experience who otherwise meet the firm's standards for personnel qualified to produce marketed pharmaceutical products in full compliance with CGMP's." In a section implementing the policy, FDA said that all applications submitted after Sept. 1, 1989 should include batches sizes outlined in the policy. However, the agency allowed that "some specific interpretations in this guide are new points and could reasonably be expected to be addressed only in newly filed applications." In addition, FDA is "prepared to consider and review, on a case-by-case basis, alternative approaches to providing evidence that data from demonstration batches, that are not full production batches and that do not meet the parameters of this guide, may be adequate to support an application for approval."

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