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This article was originally published in The Tan Sheet

Executive Summary

PROCESS VALIDATION GUIDELINES FOR DIFFERENT DRUG DOSAGE FORMS are being developed by FDA, Division of Manufacturing and Product Quality Director Paul Vogel told the Nonprescription Drug Manufacturers Association's annual manufacturing controls seminar in Philadelphia on Oct. 7. He noted that FDA is considering separate guidelines for solid dosage forms, injectables, topicals and bulk chemicals. FDA is also evaluating whether the current good manufacturing practices regulations (cGMPs) need to be revised to clarify process validation requirements, Vogel told NDMA. The series of guidelines will address "acceptable approaches or points-to-consider" when validating certain types of processes, Vogel said. "It is clear that a 'one-size-fits-all' guideline is neither practical nor useful, where specificity is the objective," he explained. "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 several areas under consideration by an FDA task force that is 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 observed. 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." FDA, he said, believes that written and "more specific FDA guidance will further promote rational voluntary compliance with FDA expectations, and we have begun that effort." Vogel emphasized that process validation will continue to be "a major focus" of FDA's inspection and enforcement programs. "Incredibly," 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," he noted. The "complacent firm, content to rely on process validation efforts conducted 10-15 years ago" is another target of FDA inspections, Vogel said. Noting that FDA has "learned a great deal more about process validation" over the last decade, he "challenged" firms relying on out-dated validation efforts to review them in light of "current" GMPS. 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." Vogel also 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." 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. Vogel noted that he recently returned from a meeting of the Pharmaceutical Inspection Convention (PIC) in Brussels, Belgium, where he met with his "GMP counterparts" from the major regulatory authorities in Western and Eastern Europe, Scandinavia, Canada, South Africa, Australia and Japan. "They also are enthusiastic about participating in this process," he reported. Vogel, who served as acting director of FDA's compliance office from mid-1992 to September 1993, has announced his departure from the agency. A 20-year FDA veteran, Vogel will join Westbury, N.Y.-based Lachman Consultant Services on Nov. 8. Addressing a workshop on "global validation requirements" at the NDMA meeting, Parenteral Drug Association Exec VP Edmund Fry maintained that FDA's requirements are "unevenly understood" in the U.S. and are less understood by firms overseas, where equivalent validation requirements have not been enforced. Fry contrasted the situation in the U.S., where formal written validation protocols and reports are "the usual practice" for various types of manufacturing processes, with that in Europe and Japan. In Europe, Fry said, validation is generally not approached as formally and there is less documentation and paperwork associated with process control. Fry pointed to a "residual skepticism" about the U.S. preoccupation with validation, which, he suggested, is enhanced by the "lack of definitive guidance" on U.S. requirements. He said that European firms are "only just beginning" to address the validation of non-sterile processes. In Japan, Fry said, validation concepts have only recently begun to be applied by firms that do not conduct business in the U.S. In the Japanese industry, he said, the emphasis is on quality attributes of systems and management rather than on the types of quantitative studies associated with validation in the U.S. However, Fry noted that Japan is moving toward more formal validation requirements.

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