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Executive Summary

BIOCRAFT LABS' INADEQUATE INVESTIGATION OF FUROSEMIDE for failing in-process or finished product specifications is cited in a March 25 warning letter from FDA's Newark, N.J. district Director Matthew Lewis. "We view failure to conduct an adequate investigation of a failure of an in-process or finished product specification to be a serious deviation of drug CGMPs [current good manufacturing practices]," the warning letter says. The letter resulted from a Dec. 16-Jan. 15 inspection of Biocraft's Fairlawn, N.J. facility that uncovered numerous GMP deviations relating to the manufacture of furosemide tablets (Hoechst-Roussel's Lasix). The warning letter notes that Biocraft recalled five lots of furosemide tablets because of degradation problems. Biocraft, the letter says, "failed to conduct a formal investigation of the following, relating to furosemide 12.5 mg tablets: (a) the decision to use a new sampling method for retesting following two high blend assay results obtained for drum #2, (b) the decision to accept the retest results as an adequate demonstration for blend uniformity, and (c) the reason for the high content uniformity results obtained." Commenting on Biocraft's March 2 response to the FD-483, FDA stated that the action taken to investigate the specification failure "was not appropriate." "As we understand your firm's response," FDA noted, "the 'sampling bottle' was refilled during the resample, rather than being only 'half-full' during the original sampling." The full- bottle sample would have been mixed "to get a representative sample for assay [and] this would have tended to have an averaging effect resulting in a lowering of the value within the specification range," the agency stated. "We do not agree with the decision that your firm made in this case." The "ideal way to sample drums of bulk granulation is by use of a tier (sampling thief) with openings of the proper size to allow entry of powder equivalent to the weight of one dosage unit," the warning letter states. "The entire sample can then be weighed, dissolved to volume and assayed by the single tablet (or capsule) assay procedure." FDA recently has been publicly emphasizing that the agency considers inadequate investigations of specification failures a significant regulatory problem. FDA Division of Manufacturing and Product Quality Director Paul Vogel told the Sixteenth International GMP Conference March 16-18 that "inadequate investigation of a reported failure is a significant deviation from GMPs." Vogel noted that "most of the major enforcement actions we take involve inadequate failure investigations." The FDAer added that "until a reported failure is adequately investigated, the process may be suspect, and products derived from that process may be at risk." FDA's inspection of Biocraft also found that the company "lacked written procedures regarding in-process product storage time limitations and had [no] planned stability studies designed to validate the long term storage of granulations and other in- process materials before packaging." The agency noted that "as a result of the inspection, your firm gathered retrospective data intended to show that long term storage of the in-process materials did not adversely affect the product." Biocraft "proceeded to establish a standard operating procedure for storage times and retesting criteria," the agency noted. "We suggest that data generated under this new program be maintained not only as part of appropriate batch records but also as part of a stability validation study for these in-process materials." FDA also suggested that the firm "review such practices with all its other products and justify such long storage practices with appropriate stability studies of in-process materials. We will check such matters during future inspections." The agency agreed with Biocraft's "decision to establish a drying time specification" for furosemide. "Controlling and studying these parameters could prevent the recurrence of the [degradation] problem." FDA also noted that the product's "tray drying operation is not adequately validated." Since January, Biocraft has received approval for four generic drugs, including the first generic version of Dista's quinolone Cinobac (cinoxacin) ("The Pink Sheet" March 9, T&G-6). The approvals were the first for Biocraft in almost two years. Biocraft was notifed in mid-February that the firm's responses to GMP violations at its Waldwick, N.J. facility were satisfactory.

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