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Executive Summary

CHASE PLANS SUPPLEMENTAL FILING FOR NIFEDIPINE DISSOLUTION TEST that is an "alternative" to the one currently used for its soft gelatin capsules. Chase said Nov. 25 that it believes the new dissolution test method superior to its current dissolution method (in vitro validation) based on favorable bioequivalence study results. Chase plans to submit the supplemental ANDA for the test method to FDA by early December. The week of Nov. 16, Chase submitted a petition to USP to use the new test. That petition includes blood level data. * Chase highlighted its intent to submit a supplemental ANDA in a Nov. 25 response to an FDA warning letter. The Nov. 3 warning letter cites the generics manufacturer for not having an adequate dissolution testing method for certain lots of nifedipine. The warning letter notes that agency inspectors discovered that a "pellicle" formed on certain nifedipine capsules that interfered "with release of the contents of the capsule." In May 1991, Chase instituted a new procedure whereby capsule components including "in- process mixes have been held and processed under [a] nitrogen blanket to prevent pellicle formation," the letter states. The warning letter, from Newark District Office Director Matthew Lewis, resulted from a Sept. 9-Oct. 1 inspection of Chase's Newark, N.J. facilities. "Our primary concern," FDA explained, "is that while you have a dissolution testing initiative" on certain lots of nifedipine capsules manufactured in May and June 1991 with a two-year expiration date, "the program does not extend to" other lots "manufactured between July 1991 and May 1992 when nitrogen sparging was initiated." The agency pointed out that Chase's dissolution testing methods yielded a "failure rate of 41%, which cannot be considered insignificant." In light of the failure rate, FDA added: "It can be predicted with a fair amount of assurance that a significant number of lots manufactured without benefit of nitrogen sparging will fail the USP dissolution test before reaching their expiration date." Lots that fail USP dissolution requirements prior to their expiration date are, by definition, adulterated drugs, the letter notes. Chase expects the supplemental ANDA filing for its new dissolution test method will satisfy FDA concerns about its present testing procedure. According to the company, FDA's Office of Generic Drugs looked at the bioequivalence data on a preliminary basis and was supportive of the plans to file a supplemental ANDA for the test method. Most other agency concerns arising from the inspection were adequately addressed in an October response to the "FDA-483" list of inspectional observations, the warning letter states. * The recent warning letter marks the second time in a year FDA has cited Chase for inadequate dissolution testing methods. In December 1991, the agency issued a warning letter for "inadequate investigation and documentation of the failure of nifedipine capsules to meet USP XXII dissolution requirements" ("The Pink Sheet" Dec. 23, 1991, T&G-14). More recently, Chase's failure to meet dissolution requirements led to a Class II recall of nifedipine gel caps initiated in September ("The Pink Sheet" Nov. 23, T&G-10).

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