Wyeth Pharmaceuticals Cited for CGMP Violations

Noting several violations in current good manufacturing practiceregulations, the US Food and Drug Administration has issued a WarningLetter to Wyeth Pharmaceuticals's (Collegville, PA, www.wyeth.com)manufacturing facility in Puerto Rico. The site manufactures,processes, and packages dosages of the company's "Triphasil," "Prempo,""Effexor," "Duofem," "Gestodene," "Caltrate," and "Inderal" tablets, aswell as "Advil" liquid gels, caplets, and gel caplets.

The letter, resulting from a November and December 2005 inspection,details five major deficiencies:

• "failure to thoroughly investigate the unexplained discrepanciesor out-of-specification results in batches of Triphasil 21 andTriphasil 28 tablets manufactured" (21 CFR 211.192);

• "failure to clean and maintain the packaging equipment atappropriate intervals to prevent contamination that would alter thesafety, strength, quality of the drug products manufactured" (21 CFR 211.67[a]);

• "failure to adequately inspect packaging and labeling equipmentprior to its use to assure that all drug products have been removedfrom previous operations" (21 CFR 211.130[e]);

• "failure to submit NDA Field Alert Reports within three workingdays of becoming aware of information concerning any significantchemical, physical, or other change or deterioration in the distributeddrug product" (21 CFR 314.81);

• "failure of your quality control unit to review productionrecords to assure that errors have not occurred and to fullyinvestigate errors that have occurred during the manufacturing of yourdrug products" (21 CFR 211.22[a]).

Among specific concerns, the letter describes consumer complaints ofthe presence of foreign metal objects (screws, washers, ejector pins)within bottles of finished product and in-plant discovery in the fillermachine of two tablets from a previously run batch of a differentproduct, even after a complete line clearance had been performed.

Of particular moment is the extensive description of the failure toproperly identify the root cause of unknown peaks detected in Triphasilsamples tested over a period of several months. In one case, expiredsamples were used. Specifically, the investigators expressed concern"that while the investigation has been ongoing for months, the affectedlots remain in the market. In addition, there is no assurance thatother lots are not affected by the same unknown." The letter doesacknowledge, however, the company's February 2006 statement that atoxicological assessment concludes that the extractable"does not posea safety concern," a statement reiterated by company spokesman DouglasPetkus, who has pointed out that the company has recalled some lots ofTriphasil and that "there have been no reports of any impact on patientsafety and product safety."