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Executive Summary

KV PHARMACEUTICAL's DISSOLUTION TESTING CITED IN WARNING LETTER issued by FDA on Jan. 14. The letter resulted from an Oct. 18-Dec. 2, 1991 drug master file inspection for Levsinex Timecaps (hyoscyamine sulfate). Schwarz Pharma markets Levsinex Timecaps, which is used as adjunctive therapy in the treatment of peptic ulcers. Among the GMP deficiencies, FDA found that "finished- product dissolution release-rate testing was conducted on capsule composites instead of individual capsules" of Levsinex Timecaps and "finished-product dissolution release-rate testing was performed on the capsules contents instead of the intact capsule." In its response to FDA on these items, the St. Louis contract manufacturer said that it is "commiting to assaying three bottles per dissolution test with four doses per bottle and will develop a unit dose dissolution test for the final release of this product for submission to the division of bioequivalence by Feb. 28, 1993." FDA determined that because capsule composites were tested instead of individual capsules, "uniformity and integrity of batches of the drug were not adequately established by process validation for production of the hyoscyamine sulfate time disintegration beads." KV stated that it "has agreed to repeat its process validation on three process validation batches, which will be analyzed by the revised method." The agency noted that "process validation for manufacturing processes that may cause variability in the characteristics of in- process material and the drug product, such as final blending of time release beads, did not include dissolution release rate testing as a validation protocol test criteria." The company responded that it "has incorporated into the validation protocols for Levsinex [Timecaps] the required dissolution testing of the extended-release beads at the final blend stage." In addition, "a supplement is being added to validate the upper and lower machine speed and the upper and lower fill weight." FDA also determined that "process validation for the encapsulation of the final bead blend lacked content uniformity and dissolution release rate testing as a validation protocol test criteria." KV responded that the tests "have been added to the validation protocol." The warning letter urges KV to correct not only the specific problems found in the Levsinex Timecaps preapproval inspection in a piecemeal fashion but also to address deficiencies "across the board" that agency inspectors uncovered in a series of previous inspections. The agency advised KV that "correction of these and other deficiencies should be across the board covering all applicable products." FDA reminded the firm that "you have a practice of correcting the specific deficiencies addressed by the investigators relating to a specific product but you do not follow through in correcting the deficiencies throughout the 'system' to cover all products." As an example, FDA noted, "deficiencies existed between the production of the biobatches and the full scale productions, as pointed out in inspections of May-June 1990; March-April 1991; May 1991; and August-September 1991." The summary of findings from the March-April 1991 preapproval inspection notes that "no product development reports had been prepared to establish KV's justification for claiming the drug master formula submitted for the ANDAs would produce products equivalent to the biotest and stability lots." In addition, "there were no documented reviews of all applicable R&D batches produced in order to determine if and how they supported or contradicted the formulations and procedures contained in the ANDA master formulas and biobatch records."

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