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Executive Summary

CIBA REVAMPING VALIDATION PROCEDURES AT BASEL FACILITIES AND CONTRACTORS under an action plan developed in response to an FD- 483 issued after a June inspection of Ciba-Geigy's Summit, N.J. facility. Ciba said its action plan will cover validation of processes, equipment, cleaning, computerized systems and analytical methods. A June 16 FDA warning letter following the inspection states that where thorough investigations of unexplained discrepancies in production and control records "are called for, your firm's investigations are incomplete or lacking, not thorough." Ciba, FDA's letter says, "is not at present capable of conducting such investigations on products or batches manufactured abroad, since its information is limited to those specific products and batches shipped to the United States." Most of the products manufactured in Basel, Switzerland and by outside contractors are brought to the Summit facility for testing by the QC unit before going on the market. Ciba said it has been providing the agency with updates on its corrective actions which FDAers have deemed to be acceptable. The company is working with its parent firm in Basel and with outside contract manufacturers to ensure that discrepancies are addressed and that validation is brought up to state-of-the art. The warning letter states that "the investigation into release rate failures of Lithobid 300 mg tablets [for certain batches] did not extend to other batches; investigation of discoloration of Apresoline HCl 20 mg/ml...neither addressed the oxygen sensitivity of the product nor explored the possibility of impurities or degradation compounds in the product; investigation of discolored vials of Desferal 500 mg...did not include analysis for impurities [and] there has been no investigation of a melt-back problem in Cibacalcin in 0.5 mg Duo Syringes." Ciba is one of three major drug companies that recently received warning letters concerning problems with validation and failure investigations. The letters reflect FDA's GMP regulatory focus following the U.S. v. Barr court decision issued in February, which lends support for strengthened FDA enforcement in the QC testing area. Sandoz received a June 17 warning letter, concerning a March 30-May 7 inspection of its East Hanover, N.J. facility, which cites a 10% assay failure rate for Cafergot ("The Pink Sheet" July 5, T&G-2). FDA stated that a process that results in 10% failures is "an inadequate or invalid process." Sandoz is not commenting on the warning letter at this time. Merck was the recipient of a June 18 warning letter based on observations from a March 11-29 inspection and April 28-May 6 inspection of its West Point, Penn. facility. In the first inspection, FDA found that three lots of Prinizide tablets were distributed "although the manufacturing process had been deemed 'non-validated' in an Interim Validation Report," the warning letter states. The three lots were made after a transfer of product from Wilson, N.C. to West Point, which resulted in a change in source of lisinopril and in the equipment used in the manufacturing process. "The subsequent validation work performed at West Point was deficient in that it did not evaluate how production lots, produced after changes in raw material source, processing and manufacturing site, compare to the biobatch," FDA said. Merck said that it conducted a number of studies and the product met quality requirements. Under an action plan, Merck has updated validation procedures to require all material undergoing major process changes to be compared to a definitive biobatch, clinical material and/or previously validated material. Among observations made during the April-May inspection, "investigators observed that an investigation into dissolution failures of two batches of Sinemet CR tablets was incomplete in that it was not extended to include other, related batches," the warning letter states. Merck said that FDA's observations dealt with documentation and procedural matters, some of which stemmed from differences in interpretation of application of cGMPs. The warning letter notes that Merck submitted and discussed with FDA the action plan for correcting the deficiencies, which FDA finds "acceptable." Merck stated that "all issues in the warning letter have been resolved." FDA has increased its scrutiny of stability testing; the issue has been central to FDA's discussions with Warner-Lambert over extensive compliance problems ("The Pink Sheet" July 12, p. 3). FDA issued recent warning letters to Lilly and American Home Products that focus on stability. FDA's inspection of Lilly's Mayaquez, Puerto Rico facilities found that "the firm's stability program contains only limited results of stability on products that have been manufactured at the site for many years and stability tests are not being conducted at the scheduled times," a July 21 warning letter states. At Lilly, investigators also found that during June-August 1992 samples of water from the purified water system revealed microbial counts above established limits and that the water was used to wash equipment in the centrifugation step for bulk cephalexin monohydrate. "No investigation was conducted to determine the effect or presence of these organisms in the finished bulk product or of other lots manufactured at the same time." Lilly said that it is cooperating with FDA and that the problems do not affect the safety and efficacy of products. The company has revised procedures for testing water quality standards. FDA inspections of AHP's Whitehall Robins Division in Richmond, Va. found that "accelerated stability testing of Entozyme and Donnazyme revealed assay results below specifications at 13 weeks. Regardless, both products were given two-year expiration dates," a July 6 warning letter states. "The failure investigation regarding the accelerated stability testing of Entozyme and Donnazyme was inadequate, in that the cause of the out-of-specification results was not determined." Whitehall said it responded to the letter and is working with FDA to meet its requests.

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