Wyeth Pharmaceuticals, Madison, NJ, May 8 (San Juan, PR).

FDA inspected Wyeth's Guayama, PR-facility Nov. 7-Dec. 15, 2005, and determined the facility violated current GMP regulations in the manufacture, processing, packing and holding of the human drug products: Triphasil 21- and 28-tablets, Prempo 0.62512.5 mg- and 0.45/1.5mg-tablets, Advil (liquid gels, caplets, gel caplets), Effexor tablets, Duofeln tablets, Gestodene tablets, Caltrate 600 mg + D tablets, and Inderal LA 60 mg-tablets.

Examples of these deficiencies included failure to thoroughly investigate the unexplained discrepancies or OOS results in certain drug batches of Triphasil 21- and Triphasil 28-tablets. For example, on June 17, 2005, a stability interval assay test for Triphasil-21 50/30 mcg, 75/40 mcg and 125/30mcg detected the presence of an unknown peak at high levels. The duplicate samples confirmed the presence of the peak. On June 21, 2005, aliquots of the original sample from Triphasil 21 50/30 mcg were tested using a solvent. Also on June 21, 2005, two new samples of Triphasil-21 and Triphasil-28 were prepared and analyzed. The same unknown peaks were detected in each sample for each lot. FDA pointed out that although Wyeth's Laboratory Investigation Report--which was signed and approved on Aug. 15, 2005--concluded that the unknown peak was an artifact peak, on Nov. 15, 2005 (during FDA's inspection of the facility), the firm identified the unknown peak as caprolactam, an extractable that potentially originated from the nylon components used to pack the Triphasil drug product.

Furthermore, the agency stressed, the identity and the root cause of the peak are still unknown. Although during the inspection and in Wyeth's written response to the FDA-483 dated Dec. 23, the firm stated that the unknown was determined to be caprolactam, no evidence was provided confirming the identity or concentration of the caprolactam. Additionally, FDA noted, on Feb. 8, the firm stated the unknown peak was identified as phenol.

Additionally, FDA investigators observed 17 other examples, occurring between December 2003 and August 2005, where adequate investigations into unknown peaks were not performed. These examples involved several different products that Wyeth manufactures including Ovrette, Zebeta, Alesse, Loette, Gestodene, Duofem, Velnafaxin, Rapamune and Lo Gentrol. In each of these cases, the most probable cause assigned was external contamination, cross-contamination, contaminated glassware or human error, FDA surmised. Yet, the agency emphasized, each of these investigations failed to determine the root cause or source of the contamination, or propose any CAPAs to address future occurrence of the contamination.

The Puerto Rico-facility also was cited for failure to clean and maintain the packaging equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength and quality of the drug products. For example, consumer complaints reporting the presence of a screw and two washers found inside a bottle of Inderal LA Capsules, and other complaints reporting the presence of a foreign metal object (ejector pins from the filling/packaging line) found inside a bottle of Protonix tablets and a bottle Effexor tablets, also were received. The investigations into these incidents concluded that the equipment was not handled correctly or adequately inspected by packaging personnel. But neither Wyeth's cleaning procedures nor the line clearance inspections was able to detect that the affected equipment was missing some of its parts.

Lastly, the facility was audited for failure to adequately inspect packaging and labeling equipment prior to its use to assure that all drug products had been removed from previous operations as required; failure to submit NDA Field Alert Reports within three working days of becoming aware of information concerning significant chemical, physical or other change or deterioration in the distributed drug product as required; and, failure of Wyeth's QC unit to review production records to assure that errors had not occurred, and to fully investigate errors that did occur during the manufacturing of drug products.

FDA objected to a Dec. 23, 2005, response letter from Wyeth, because it did not explain the OOS discrepancies; and, it stated that analysis of the complaint rate revealed a stable or declining trend but failed to provide any details on the specific CAPAs that were taken to address future occurrences of such complaints. CAPA, C-H, Lab, OOS, Pak, QC/QS, Stab, Ster; Doc. 13783W

Wyeth Pharmaceuticals:

* Failed to investigate unexplained OOS discrepancies.

* Neglected to investigate inadequate packaging and labeling.

* Failed to clean packaging equipment.