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Executive Summary

DUPONT MERCK CHANGING STABILITY MONITORING PROGRAM at its Manati, Puerto Rico facility to assure that drug products meet stability specifications. The stability monitoring program was cited in a Nov. 19 warning letter from FDA's San Juan District Office. The warning letter, which is the first one for DuPont Merck, results from an Oct. 12-14 inspection of the manufacturing plant in Puerto Rico. DuPont Merck said it met with FDA's San Juan office Dec. 2 to respond to the warning letter. The company said it implemented corrective actions in stability testing and quality control procedures following the inspection and prior to the issuance of the letter. FDA found these actions "favorable," DuPont Merck said. "Your stability monitoring program does not assure the products on the market meet their specifications," the warning letter claims. The letter provides an example in which follow-up actions concerning two lots of Percodan that "failed stability testing were delayed six to 11 months." One area of good manufacturing practices that FDA has been focusing on is lack of adequate follow-up on product failures. The company initiated a Class III recall on Sept. 24 of one lot of Percodan tablets in blister packs of 25 because the aspirin component did not meet stability specifications for dissolution, according to FDA's Nov. 24 "Enforcement Report" ("The Pink Sheet" Nov. 29, T&G-15). The Percodan tabs, which were made at the Manati facility, were distributed nationwide and in Puerto Rico in 5,691 boxes containing 10 blister packs. The company said the recall is "essentially complete." The Percodan recall is referred to in the warning letter. A lot of Percodan "failed dissolution testing at the six-month stability period during October 1992. No action was taken until late January 1993 when a degassification step was added to the dissolution test method." The letter continues: "The lot passed retesting by the degassification method on Jan. 30 to Feb. 6, 1993. The next dissolution test performed at the 12-month stability station during April/May 1993 failed." The agency noted that "no further testing was done. FDA was notified the lot would be recalled four months later on Sept. 24, 1993." DuPont Merck recently notified hospital pharmacists that it is discontinuing unit-dose packaging for Percodan, Percocet, Coumadin and Symmetrel ("The Pink Sheet" Nov. 8, T&G-1). "The company described the action as one its cost-cutting initiatives. Until Nov. 15, the firm was taking final orders, permitting hospitals to purchase up to a one-year supply of unit-dose packs. One lot of Percocet was found to be subpotent in a number of tests over different time periods, the warning letter says. After the last set of tests found subpotency "no further testing was done," FDA said. "Its expiry period will be over next month." "The company said there is no more product from this lot on the market. FDA noted that it received the company's Nov. 4 response to the FD-483 list of inspection observations, but that "the response does not satisfactorily address the concerns raised by the investigator." The agency stated: "You have not adequately determined the impurity profiles of raw materials. The analytical reports for [drug name purged] show an impurity peak at retention time...minutes on the HPLC assay, which has never been identified." DuPont Merck said it has addressed these concerns. The importance of thoroughly evaluating raw material impurity profiles was emphasized in FDA's "Guide to the Inspection of Bulk Pharmaceutical Chemicals" that issued in late 1991 and has been a recurring theme in recent FDA inspection actions ("The Pink Sheet" Dec. 6, p. 8). The warning letter points out past problems with follow-up of failing lab test results at DuPont Merck's facility in Wilmington, Del., which the firm said it has addressed. The letter mentions that an FD-483 issued to the Delaware facility on March 25, 1991 "noted investigations of stability test failures were initiated two years after they occurred." The FD-483 "listed patients who received subpotent drugs because of the slow follow-up. Nicardipine, the drug in question, was manufactured at your firm's facility in Aguadilla, Puerto Rico." FDA noted that "the stability monitoring was by your firm's R&D Department in Wilmington, Del."

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