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Executive Summary

Biocraft's bulk antibiotic production methods at its Waldwick, N.J. facility have not been adequately validated, FDA charges in a Nov. 18 warning letter to the generic drug manufacturer. "Examples of failures to follow GMPs in the production of BPCs [bulk pharmaceutical chemicals] include, but are not limited to the following: Failure to establish and to follow an adequate procedure to validate the manufacturing process for amoxicillin trihydrate, ampicillin trihydrate, dicloxacillin sodium monohydrate, cloxacillin sodium monohydrate, and oxacillin sodium monohydrate bulk drug substances produced at the Waldwick plant," the warning letter says. The warning letter follows FD-483 observations made during June 29-Oct. 5 inspections of all of Biocraft's New Jersey facilities: Waldwick, Fair Lawn, Paterson, Elmwood Park and Fairfield. The letter from FDA's Newark District Office focuses on the Waldwick plant. The letter adds: "Our inspection disclosed that you have not validated any of the...drug substance chemical synthesis processes at the Waldwick site and that you have no formal [standard operating procedures] addressing the validation of your BPC processes." Biocraft said it would take all appropriate steps to respond to the letter. The company has not yet submitted a written response to the agency, but said that it would. The generic company added that it feels it will be able to satisfy FDA's concerns in a "timely manner." Biocraft said it does not believe that the agency's requests will have an impact on the sale of finished dosage form products. Biocraft has a new facility for making bulk antibiotics and pharmaceutical intermediates in Mexico, Mo. The compliance issues most likely will delay drug approvals. The letter warns that "until the violations have been corrected and verified, FDA's Center for Drug Evaluation and Research will not approve any NDAs or AADAs listing Biocraft's Waldwick facility as a source of bulk antibiotic drug substances." The recurrence of problems at Biocraft could also affect the company's options for merging with another company or being sold. Biocraft retained an investment banker to explore those options in 1992, but no agreement has been reached. Biocraft acknowledged in late October that it had received a lengthy FD-483 following inspections of its New Jersey facilities ("The Pink Sheet" Oct. 25, In Brief). At the time, the company said it planned to work with FDA to resolve all the issues. Earlier in October, Biocraft recalled 18 batches of cephradine as a result of the inspections. There have been no further recalls, nor does Biocraft expect any more. "At present, FDA expects all BPC manufacturers to be actively engaged in a validation program for their products," the warning letter states. The letter continues: "For BPC processes that have been employed for years, such as those utilized by Biocraft, companies may conduct retrospective validations based on the review and analysis of physical and analytical controls exercised over past batches and extending from starting materials through the finished bulk drug substances." "If retrospective validations are not possible or if firms lack impurity profiles for their BPCs, then the agency expects firms to temporarily cease operations and conduct prospective validations as if they were implementing new or revised manufacturing processes," the letter adds. The warning letter also cites Biocraft for "failure to establish appropriate impurity profiles for each bulk antibiotic drug substance manufactured at the Waldwick plant." The agency pointed out that "a BPC manufacturing process cannot be validated nor can changes in that process be evaluated without an awareness of the impurity profile for the product." FDA "also expects BPC manufacturers to have established or to be following a scientifically valid plan to determine limits for individual impurities and total impurities in their bulk drug substances." The agency noted that "the FD-483 observations related to finished product manufacturing operations at your Elmwood Park, Fairfield, Paterson, and Fair Lawn facilities are still under review." Biocraft previously received warning letters resulting from inspection observations in November and March 1992. The Nov. 5 letter alleged "inadequate" standard operating procedures for resampling and retesting blends at the Fairfield and Paterson facilities. The March 25 letter cited similar violations. Resolution of these problems was indicated by FDA's granting Biocraft approval last December for the first generic versions of Wyeth-Ayerst's Orudis (ketoprofen) and SmithKline Beecham's Amoxil chewable amoxicillin tabs ("The Pink Sheet" Jan. 4, T&G-6). As the warning letter indicates, Biocraft is not the only pharmaceutical company that FDA is targeting for validation of bulk manufacturing processes. Sandoz received a warning letter in June that cited a lack of specifications and acceptance criteria in validation protocols for bulk and finished dosage form products made at the company's East Hanover, N.J. facility. Penick Corp. received a warning letter in March that addressed a lack of validation of the manufacturing process for the firm's amphotericin slurry. In another June warning letter, FDA alleged that Jame Fine Chemicals' impurity evaluation was not sufficient to validate the manufacturing processes for certain drug substances. FDA has been highlighting the bulk manufacturing area as a priority for increased enforcement. Industry wants the agency to clarify its requirements, in particular, how process control and validation in bulk drug synthesis relate to requirements for finished dosage forms. In September, FDA issued a "compliance policy guide" (CPG 7132c.08) that provides the agency's approach to evaluating bulk drug process validation and impurity testing. The agency also has said it is working on a more formal policy statement on bulk drugs ("The Pink Sheet" Oct. 11, p. 14). Biocraft announced Nov. 30 that a "purported" stockholder filed suit on Nov. 29 in Newark federal court against the generic drug company and four of its officers. The suit alleges that Biocraft "made misleading statements in its June 1993 10K report to the [Securities & Exchange Commission] and its annual report to stockholders issued in July 1993 concerning the company's compliance with FDA manufacturing requirements." Biocraft declared that "not only are the allegations completely unfounded, but the degree to which the plantiff either ignores the company's prior disclosures or distorts key facts is outrageous." The company added: "We resent this attack on our integrity and will...defend this matter vigorously and take all other measures appropriate to complaints of this nature."(ITEM 150)[ EDITORS NOTE: The November issue of "The Gold Sheet" contains a detailed analysis of FDA's enforcement activities relating to BPC validation and industry's reaction. Copies are available from F-D-C Reports, Inc. Contact Ed Picken at (301) 657- 9830.]

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