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Executive Summary

WATSON PHARMACEUTICALS PROCESS VALIDATION DRAWS WARNING LETTER from FDA's Los Angeles District Office citing deficiencies in good manufacturing practices regulations related to the firm's validation for hydrocodone 7.5 mg/acetaminophen 500 mg. Watson received approval for three strengths of the hydrocodone/acetaminophen product (the brand name drugs are Knoll's Vicodin/Ross' Lortab) on Aug. 30, 1991. "We have found your process validation to be inadequate and do not recommend approval of shipment for this product," FDA told Watson in the April 10 letter. "Introduction of this product into interstate commerce may result in regulatory action without further notice, including seizure." Watson said it already had informed FDA that it will not ship the product without approval of its process validation. Watson received 12 ANDA approvals during 1991 for five different chemical entities. The company, however, has not shipped any of the products pending approval of its process validation. The hydrocodone 7.5 mg/acetaminophen 500 mg is the first product to be inspected by FDA. The warning letter specifically questions the likelihood that the processes for the two other hydrocodone/acetaminophen strengths will be satisfactory. The 7.5 mg/300 mg strength should be "the easiest of the three products to obtain a uniform blend. Thus, we question that you were able to achieve blend uniformity in your other two products," FDA said. The warning letter follows a Feb. 17-21 inspection of the firm's Corona, Calif. facility. FDA found Watson's response to an FDA-483 inspectional observation report issued after the inspection to be "inadequate," the letter states. The warning letter cites three deviations in Watson's validation of hydrocodone/acetaminophen: "inadequate" sample procedures based on too large a sample size, use of an overly broad relative standard deviation for content uniformity testing and a lack of upper and lower assay limits for the blend samples. The letter adds that "repeat validation of...additional... tablet lots due to the high [relative standard deviation] results are not a valid assessment of the uniformity of the blend." Watson said it received the letter on April 17 and respondent to FDA by the end of the month. The firm is awaiting a reply from the agency. Watson added that it is seeking clarification from FDA about what standards are acceptable. The firm maintains that its testing is in conformity with its ANDA and with USP standards. Other 1991 approvals for Watson were two strengths of albuterol, two strengths of norethindrone and ethinyl estradiol, one strength of cyclobenzaprine and four strengths of ethynodiol diacetate and ethinyl estradiol, the first generic versions of Searle's oral contraceptive Demulen. Watson plans to market the product under the brandname Nelulen. The 1991 approvals were the first in two years for the firm. The company has not been implicated in fraud as part of the generic investigations. Watson received a regulatory letter for GMP violations found in a June 1989 inspection. According to a March 6 prospectus for an initial public offering, Watson has 25 ANDAs pending ("The Pink Sheet" March 23, T&G-8). The company is seeking up to $29 mil. in the offering, which has not yet been completed.

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