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Executive Summary

FDA NARROW THERAPEUTIC RANGE SAMPLING SURVEY FOUND FIVE BATCHES from two manufacturers out of 400 samples reviewed, that did not meet official specifications, FDA Office of Compliance Director Daniel Michels told the National Association of Pharmaceutical Manufacturers' mid-year meeting in Washington, D.C. June 7. Michels noted that five batches "have been found defective, although several more remain under review." He added that "none of the defective batches has been judged to present a serious health hazard" and that the survey results "were heartening." A March recall of aminophylline tablets by Eatontown, New Jersey-based West-Ward Pharmaceutical for subpotency of the ethylenediamine component ("The Pink Sheet" May 21, T&G-14) stemmed from the sample findings. FDA's Compliance Office expects to release a report to FDA upper management and Congress on the critical dose drugs sampling effort during the week of June 18. Narrow therapeutic range drugs along with "hard to copy" drugs have being getting close attention as part of "Phase III" of the generics investigations ("The Pink Sheet" Dec. 11, p. 3). The agency has been working on a list of the hard to duplicate drugs, and is considering a sampling survey in that category as well. Michels provided an update on the generics investigations and the impact of the findings on FDA compliance policies and procedures at the meeting. Michels cited five key elements involved in "overhauling" the agency's inspectional program: more involvement of field investigational and laboratory personnel in the new drug review process; pre-approval inspections and audits of all significant drugs; regular sampling and analysis of batches of drugs used to demonstrate bioequivalence; increased level of sampling and analysis of marketed batches of drug products; and use of audits during routine surveillance inspections to monitor adherence to approved manufacturing procedures. Michels said that written field compliance programs formalizing the new procedures will be issued by September. The new procedures for consulting with district offices before applications are approved "have resulted in at least 30% more pre-approval inspections than under the previous policy," Michels noted. Explaining the agency's initiative calling for on-site pre-approval inspections for "significant" drugs, Michels said that these include "all new chemical entities, all narrow therapeutic range drugs, all drugs known to be 'hard to manufacture,' such as generic versions of Dyazide and all newly-eligible generic drugs presenting extraordinary profit potential." Michels said that FDA will "routinely" obtain samples of biobatches for testing in FDA labs in connection with these pre-approval inspections. In addition, the compliance director noted that FDA will require firms to "demonstrate the integrity" of the tested product. For example, he said, firms "should have and follow" written procedures providing for adequate documentation of the sampling, handling, shipment and storage of the biobatch samples. The documentation should include all individuals involved and the security measures to prevent authorized access to such samples before, during and after testing, Michels stated, along with a physical description of the samples. In response to the generics investigation findings, Michels explained that pre-approval batch records and validation of scale-up procedures and process changes will be two inspection focal points. The compliance office "would recommend" that firms retain records on the application batches "for the life of the ANDA," Michels said. The office is also "currently considering making changes to the record keeping requirements for such pivotal batches," he added.

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