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Executive Summary

A database on formulation and bioequivalence testing problems should be developed by FDA as a first step in liberalizing the agency's regulation of manufacturing changes, according to a general consensus reached by the agency's Generic Drugs Advisory Committee at its April 23 meeting. The committee members agreed on the need for FDA to develop a scientific database that would provide a foundation for revisions in FDA's current policies regarding process and product changes during scale-up and marketing. That database should be compiled from a review of information already housed within the agency, from additional industry submissions and targeted academic research projects, the committee recommended. Stanford University Medical Center Professor Terrence Blaschke, MD, who chaired the meeting, summarized the committee's agreement that, in redefining the agency policy, "there's an enormous amount of data that can be collected, and what's important and what's not important need to be defined, so that one can say which variables need to be controlled carefully." However, Blaschke noted, "we don't have that yet." The committee expressed support for a recommendation made by University of Maryland School of Pharmacy Associate Dean Gary Hollenbeck, PhD, that the mechanisms for putting the FDA database together should target formulation development information. The formulation information should be accumulated at FDA, Hollenbeck suggested, "either by providing incentives for the industry" to submit additional information, by tapping the information already contained in NDAs and ANDAs, or by "sponsoring research outside to collect that information." The University of Maryland and other academic institutions are in the early stages of FDA-sponsored research efforts to explore specific science issues relevant to the manufacturing review process for generic drugs. The committee also agreed with Hollenbeck that a mechanism should be created for the collection by FDA of additional information on bioequivalence test failures. "There needs to be a way for the agency to take advantage of the database that's there," Hollenbeck maintained. "Those trials that were done that didn't succeed, that weren't bioequivalent. Parts of experiments that you've already done could be collected at the agency [in order to] help establish some general theoretical principles that would guide us in setting specifications." Providing a basis for discussion at the advisory committee meeting were consensus proposals from a December workshop cosponsored by FDA and the American Association of Pharmaceutical Scientists (AAPS) on scale-up of oral solid dosage forms. The workshop was held as part of FDA's effort to improve the scientific foundation for regulating manufacturing changes. The findings at the workshop, together with input from the advisory committee, will be used by the agency to help clarify and revise its regulatory standards. The general conclusion among the FDA/AAPS workshop participants was that manufacturers should be able to make a wider variety of process, equipment and formula changes without bioequivalence testing or agency preclearance if appropriate dissolution standards are met. Reporting on the results of the workshop at the advisory committee meeting, Gordon Amidon, PhD, a pharmaceutics professor at the University of Michigan, maintained that "the fundamental issue" under consideration was the "relevance" of dissolution testing -- "when is it relevant and when can it be used as a measure of control [in order to] avoid having to do supplements or a full scale biostudy." Amidon, an advisory committee member, was part of the steering committee for the December workshop. Amidon maintained at the advisory committee meeting that a "biopharmaceutic classification of drug products" needs to be developed for agency use that would build on the workshop analysis. Under the system, Amidon explained, drugs would be classified according to their biopharmaceutics, or "absorption rate and extent," and dissolution standards for regulating manufacturing changes should be "set up on the basis of this classification." The dissolution standards would "certainly" need to include single and multiple timepoints, Amidon maintained, and the "biobatch and the scale-up batch" would need to be "fully characterized if they are going to be used in place of a bioequivalence study." Expressing support for the development of such a classification system to cut down on bioequivalence testing and submission requirements, committee members pointed to the challenge of validating the dissolution standards involved. "What we've heard from the" Office of Generic Drugs "is a sincere effort to try to minimize the requirements for bioequivalence under circumstances where there may be changes either in scale-up or post-approval changes, and Dr. Amidon is offering a potential way of studying these drugs using in vitro methods," Blaschke summarized. "The sense that I am hearing from him and from other people around the table is that this is a worthwhile approach to validate, because if it can be validated to the satisfaction of the agency. Then such tests might well serve as substitutes for in vivo bioequivalence studies." What is needed, Blaschke maintained, are "ideas about how to go about validating these things," and "some additional specific research, probably funded by FDA." FDA Office of Generic Drugs Division of Chemistry II Director Michael Beatrice reported to the committee on the efforts currently under way at his office to improve the review process for manufacturing and control information. A focal point of the Office of Generic Drugs effort has been the supplemental application process for manufacturing changes, Beatrice noted. He added that several initiatives are now under way within OGD and between generics and the compliance and field offices to evaluate and streamline the current system. As part of this reevaluation process, Beatrice explained that the generics office recently "took a snapshot in time of 100 randomly-selected supplements." The review found that over 60% of supplements filed fell into either the category of "manufacturing changes" or "control revisions," Beatrice reported. Thirty nine of the 100 supplements reviewed involved control revisions. Within this category, the addition of outside testing labs accounted for eight of the supplements; addition of new test methods, four; and deletion of in-process tests, five. Twenty three of the supplements covered manufacturing changes. New manufacturing procedures accounted for 14 of the 23 changes, and batch size increases accounted for five of the 23 manufacturing change supplements, Beatrice said. A significant number of supplements also were filed for changes in the expiration date (14), in the manufacturer/supplier (eight) and for packaging (seven). Beatrice pointed out the progress the generics office has made in reducing a "tremendous" backlog in pending supplements. "About a year ago, the Office of Generic Drugs had 1,354 supplements pending greater than 180 days, and as of today, the number is 321," he reported. While "that is quite a drop," he said, "we are not satisfied. It still needs to get better." The generics office staffer said one of the ways the generics office is considering to address the problems in the supplement review process is a "redefinition" of the code of federal regulation requirements contained in section 314.70, which address the various filing requirements for process and product changes, and/or new policy guidance on those requirements. For instance, he noted that the generics staff is currently working with the compliance and field offices on a guidance to investigators clarifying "what headquarters expects industry to comply with when a change is made." FDA Division of Chemistry I Director Rashmikant Patel, PhD, who is working on that inspection guidance, noted that a proposed draft is now being considered that would explain which process changes are considered "major," requiring supplemental clearance, and which "minor," requiring only inclusion in the firm's annual reports. In some specific cases, the proposed guide calls for liberalizing of filing requirements, Patel noted. Beatrice noted that the the Center for Drug Evaluation and Research has proposed that a "retrospective survey" be conducted of supplement information. The survey, Beatrice explained, would involve "going out and getting the opinions of the [CFR section] 314 supplementation process from both industry and FDA supervisors and try to determine where the problems are and what some good suggestions would be."

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