FDA DRAFTING GUIDANCE ON BULK PHARMACEUTICAL CHEMICAL GMP STANDARDS; AGENCY, INDUSTRY CONCERNED ABOUT FOREIGN BULK MANUFACTURER COMPLIANCE LEVELS

FDA is working on a guidance to define more clearly its standards for bulk pharmaceutical products, FDA Manufacturing and Product Quality Division Director Paul Vogel told a Sept. 27-29 Parenteral Drug Association/FDA conference in Bethesda, Md. "We have begun to draft minimum GMP requirements for bulk pharmaceutical chemicals," Vogel said, noting that the agency's "Guide to the Inspection of Bulk Pharmaceutical Chemicals" can serve in the meantime to provide "general insight into FDA's inspectional focus." The requirements may be proposed as good manufacturing practices regulations or as an industry guideline, he said. In either case, he emphasized, "the industry will be given ample opportunity to comment before anything is finalized." Vogel noted that FDA has been "increasing its focus on bulk manufacturing as part of its pre-approval as well as its normal surveillance GMP inspection programs." Some manufacturers have expressed concern that, in some cases, FDA investigators less familiar with bulk pharmaceutical chemical operations are misapplying GMP requirements intended for drug products. The Center for Drug Evaluation & Research Compliance Office has been conducting a review of recent bulk chemical inspections to help in the assessment of FDA's BPC inspection program. FDA International Programs and Technical Support Branch investigator Charles Edwards acknowledged during the PDA conference that consistency in bulk inspections "has been a problem." Some investigators, he said, "have tried to apply finished dosage standards to bulk operations, and it just doesn't work." Of particular concern to both industry and FDA is compliance at foreign bulk manufacturing sites. During an Oct. 4-5 National Pharmaceutical Alliance technical seminar in Baltimore, Lemmon Company chemist Kang Yang, PhD, said that his main concern as an assay scientist inspecting bulk product used by his company is particle size. He cited the potential for lot-to-lot variability of the bulk product to be such that "by the time we get approval and try to scale-up, the particle size difference between the pilot batch and the scale-up batch is quite different." The problem, Yang indicated, is generally with foreign suppliers. "Domestic suppliers...know the importance of consistency," he said. "If they control their processes we can generally avoid this problem. We expect the bulk producer to do their job." Yang added that one item on his "wish list" is more FDA guidance on standards for bulk drugs. FDA increasingly has been seeking to use leverage on domestic firms as a mechanism to assure compliance of foreign suppliers, particularly in relation to bulk drugs. The direction the agency is taking is indicated by a warning letter issued to Clifton, N.J.-based SST in mid-August. The letter addresses the firm's responsibility, as a domestic agent, for the handling of imported bulk nystatin. The warning letter cites findings of a June inspection indicating that the firm lacked a system "for the review, evaluation [and] follow-up of complaints and returns for quality issues, such as foreign matter and microbiological contamination found in foreign-supplied drug substance nystatin." FDA alleges in the letter that lots of nystatin returned to SST for high microbial counts were re-shipped to other dosage form manufacturers.(ITEM 150)[ EDITORS' NOTE: The September issue of "The Gold Sheet" contains an in-depth analysis of FDA's foreign inspection activities. Copies are available for $25 from F-D-C Reports, Inc. Contact Ed Picken at [phone].]