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Executive Summary

MARION MERRELL DOW's RIFADIN FAILURE TO MEET DISSOLUTION SPECS is the subject of Aug. 3 warning letter from FDA's Cincinnati District Office. In a May 8-26 inspection of a MMD facility in Cincinnati, FDA inspectors found that the firm's test records for the TB antibiotic "show this product fails to meet [U.S. Pharmacopoeia] test requirements for dissolution throughout the labeled shelf-life," the letter states. "Records for at least 24 ...lots examined failed to meet USP requirements for dissolution as determined in accordance with the tests and methods set forth in the USP after 23-24 months of age." Some of the Rifadin (rifampin) 300 mg hard gel capsules are still on the market "with labeled expiration dates of 36 months," FDA pointed out, and MMD's "proposed corrective actions do not address what your firm intends to do about the adulterated product" remaining on the market. Rifadin must be used with at least one other anti-TB drug. MMD is negotiating with FDA and the USP to return to a previous dissolution test method, which MMD believes is more appropriate for testing the capsules than the current method. The previous test methodology, used prior to January 1990, involves a rotation speed of 100 RPMs compared to 50 RPMs used in the current test, MMD noted. The company provided the grounds of its request for a change in the USP test in an Aug. 17 letter to FDA. FDA notes in the warning letter that MMD representatives "claim that the recurring failure with the dissolution test of the stability study samples was largely due to the inadequacy of the compendial test methodology, particularly the paddle rotation speed. By increasing the rotation speed two-fold above the current USP specifications your firm claims the dissolution problem disappeared." The agency added that "it is self-evident that a drug substance (in capsules or other dosage form) would dissolve more rapidly if it were agitated more vigorously than specified." FDA noted that "this kind of explanation does not relieve you of the obligation to conform to the current USP compendial standard, nor does it explain why your firm finds the USP method acceptable for the first 18 months of shelf life but non-acceptable thereafter." MMD "should have investigated and documented the failure from the perspective of the formulation, the manufacturing processes, and the analytical methodology before questioning the adequacy of the methodology alone," the warning letter says. "The lack of an adequate failure investigation is a significant CGMP [current good manufacturing practice] deviation."

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