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FDA PROCESS VALIDATION GUIDELINES FOR DIFFERENT PRODUCT TYPES

Executive Summary

FDA PROCESS VALIDATION GUIDELINES FOR DIFFERENT PRODUCT TYPES, such as oral solid dosage forms, injectables, topicals and bulk chemicals, are being developed by the agency, Division of Manufacturing and Product Quality Director Paul Vogel told a Nonprescription Drug Manufacturers Association annual Manufacturing Controls Seminar in Philadelphia Oct. 7. FDA is also evaluating whether the current good manufacturing practice regulations (cGMPs) need to be revised to clarify process validation requirements, he said. The series of guidelines FDA is preparing will address "acceptable approaches or points-to-consider" when validating certain types of processes. Vogel explained: "It is clear that a 'one-size-fits-all' guideline is neither practical nor useful, where specificity is the objective. Therefore, we anticipate separate guidelines for different types of products like tablets/capsules, oral liquids, topicals, sterile processes and bulk chemicals." Process validation is one of a number of areas under consideration by an FDA task force currently evaluating whether the cGMP regulations need to be revised. Although FDA may "beef up" the process validation requirements, Vogel commented, the regulations will remain general in nature to provide for necessary industry flexibility and the evolution of the concepts involved. "The nature and scope of validation methodology and evaluation criteria are dependent upon numerous variables that are situational and evolve as the industry learns more about the material and process variables that influence uniformity," Vogel maintained. This complexity, he said, "explains why process validation is probably the most discussed GMP topic ever by FDA and the industry, and why it is neither possible nor practical for FDA to establish explicit 'how to' standards." On the other hand, he added, the agency believes "additional written, and more specific FDA guidance will further promote rational voluntary compliance with FDA expectations, and we have begun that effort." The compliance official emphasized that process validation will continue to be "a major focus" of FDA's inspection and enforcement programs. "Incredibly," Vogel said, the agency is still finding firms that "have never validated manufacturing processes for some finished products, or have never bothered to revalidate significantly changed processes." Vogel cited the "complacent firm, content to rely on process validation efforts conducted 10-15 years ago," as another target of FDA inspection concern. Noting that "since then, we have learned a great deal more about process validation," Vogel "challenged" firms relying on outdated validation efforts to review them in light of "current" GMP. This is "especially important," he said, where annual reviews indicate that processes may be inadequately defined or controlled. Depending on the circumstances, approaches to updating past validation efforts may include retrospective or concurrent evaluation, or "if necessary, the traditional prospective approach," Vogel said. For example, he suggested, "if the validated process bears no resemblance to the current process, we would expect validation of the new process before further shipments -- prospectively or retrospectively. On the other hand, minor process or equipment changes ('tweaks') may only require concurrent batch evaluation, albeit of validation-like intensity." While urging firms to upgrade their validation programs, Vogel cautioned against "pursuing validation merely for the sake of validation -- validating everything in site and to the 'Nth degree' -- without necessary consideration of the practicality, costs, and most importantly the 'value-added' to assuring the quality of our pharmaceuticals." He cited as an example of a misplaced validation effort, an 800-page prospective process validation report covering six production batches that his office reviewed in late September. "The report clearly demonstrated that the commercial process was reproducible, consistently delivering a product that uniformly conforms with USP specifications within each batch, and from batch to batch." The problem, Vogel explained, is that the firm "failed to consider the effect of significant differences in active ingredient particle size used in the biobatch and commercial production." New bio studies conducted by the firm "indicate that the commercial product, although uniform, is not bioequivalent, and that the very costly validation study focused on a product that cannot be marketed because of the bioequivalence problem." The compliance office staffer explained that industry will be given "ample opportunity" to comment on any proposed process validation guidelines or reg changes before FDA finalizes them. The agency will also be seeking input from its major international counterparts "in an effort to foster harmony in regulating this truly global industry," he said.
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