Bayer receives Warning Letter for alleged deviations

The FDA has sent Bayer Schering Pharma (Germany) a Warning Letter, citing deviations from cGMP in the manufacture of nonsterile APIs. The letter follows the FDA’s inspection of Bayer’s Bergkamen (Germany) API plant in March 2009.

Bayer received a Form 483 at the end of the inspection and sent a written response to the FDA on 7 April. In its Warning Letter, the FDA acknowledged that some corrections "appear to have been completed or will soon be implemented", but said that Bayer’s response did not adequately address some deficiencies.

The FDA noted that Bayer had established procedures that allow for the averaging of out-of-specification (OOS) and within-specification analytical test results from separate samples. The company approved API batches for release to the US market based on passing, averaged assay results.

Bayer’s response to the FDA described a retrospective investigation that it had conducted of all API batches released to the US market between 2007 and 2009. The company found nine instances in which OOS results and passing results were averaged together. In all cases, Bayer concluded that no analytical errors had been identified and that the values were true OOS results. Bayer also concluded that the OOS results were within the accepted variation of the analytical method and that the quality of the batches in question was not affected.

In the Warning Letter, the FDA said it disagreed and noted that: "an assay test is used to determine potency, not method variability". The results were true OOS values, and the batches should not have been released, according to the agency. The FDA also disagreed with Bayer’s interpretation of the agency’s OOS guidance; sample results should be treated independently, said the FDA, and an OOS result should not be averaged with a passing individual result.

In addition, Bayer’s quality unit failed to maintain authority and responsibility to review and conduct investigations, according to the Warning Letter. The company did not conduct adequate investigations that included scientific justification to support conclusions and suggested appropriate corrective actions. For example, during release and stability testing of APIs, individual OOS assay results were disregarded and no OOS investigations were performed after OOS results were obtained. When OOS investigations were performed, they did not adequately determine root causes or provide for corrective action, said the FDA.

In its response, Bayer said it was revising its standard operating procedure (SOP) for handling OOS results to stress the importance of conducting and documenting OOS investigations. FDA said Bayer’s revised draft SOP appeared adequate. The agency requested a copy of the revised SOP after it has been approved.

Another violation listed in the Warning Letter was Bayer’s failure to establish and follow procedures for maintaining and cleaning equipment. The FDA noted that a part of a vessel used to produce Ethinylestradiol API was not maintained in a clean condition, even though it was in contact with the product — the letter noted that equipment had been labeled cleaned, and had been inspected and verified as cleaned. In its response, Bayer said that the operator may not have detected brown residue, but the FDA noted that Bayer had not explained or justified this conclusion.

The FDA asked Bayer for a list of all API batches shipped to the US based on an average of OOS and passing results. The agency has also asked Bayer for a report of additional corrective action that the company planned to take to correct similar violations. In addition, the FDA asked the company to explain what corrective and preventive actions it would take in other manufacturing and testing facilities that might have the same deficiencies.

www.fda.gov