FDA Warning Letter Asks Bayer To Fix Manufacturing Practices In German Facility

FDA says Bayer's facility in Bergkamen, Germany, is still not up to par with good manufacturing practices in the U.S.

Bayer needs to quickly address the FDA's concerns over manufacturing practices in its Bergkamen, Germany, facility, which processes ingredients intended for the U.S. market, or the drug maker could see a standstill of new drug approvals and its ingredients will be denied entry here.

The stakes are high for Bayer given that approval of its much anticipated anticoagulant Xarelto is pending at the FDA. Xarelto, which is already approved in Europe and several emerging markets, received an FDA "complete response" letter in May, but some clinicians and Wall Street analysts, nonetheless, expect it to be the first novel oral anticoagulant to enter the U.S. market.

To what extent the problems at the Bergkamen facility would affect Xarelto, specifically, is unclear. A Bayer spokeswoman says the plant makes active pharmaceutical ingredients, or APIs, that are used primarily to produce Bayer's oral contraceptives.

"Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm's compliance with current good manufacturing practices, this office may recommend withholding approval of any new applications or supplements listing your firm as an active pharmaceutical ingredient manufacturer," the agency wrote in an Aug. 5 warning letter to Bayer. FDA also threatened to deny entry of articles made by Bayer into the U.S. if manufacturing deficiencies are not corrected.

The letter was posted on FDA's Web site Sept. 15, the same day the drug maker announced senior management changes expected to take effect next year, which include replacing current chief executive Werner Wenning with Marijn Dekkers, who now heads the laboratory equipment maker Thermo Fisher Scientific. One industry analyst surmised that the shake-up is linked to disappointing results from Bayer's 2006 acquisition of Schering AG (Also see "Bayer Management Changes May Suggest Deepening Xarelto Concerns" - Pink Sheet, 15 Sep, 2009.).

Bayer first attempted to address FDA concerns in April

Bayer already made one attempt to resolve the agency's concerns with its active pharmaceutical ingredient (API) facility in Bergkamen after an early-March inspection revealed "significant deviations from the U.S. current good manufacturing practices in the manufacture of non-sterile APIs." Bayer quickly issued a written response to the agency on April 7, saying it would revise its 'out-of-specification' standard operating procedure to emphasize the importance of conducting and documenting a thorough investigation of all OOS test results.

The FDA acknowledged in its recent warning letter that "some corrections appear to have been completed or will soon be implemented. However, your response does not adequately address some of the deficiencies." The agency mainly is concerned that Bayer's procedures fail to ensure that APIs released for marketing meet established specifications.

"The company is taking this matter very seriously and is analyzing the points raised in the letter," Bayer said in a statement. "We will respond to the FDA within the agreed upon timeline of September 21, 2009."

The FDA takes issue with Bayer's allowance of averaging out-of-specification test results with those for samples that pass specification requirements. This, in turn, could result in products entering the U.S. that may not be up to par. In the warning letter, FDA asserts that it disagrees with Bayer's interpretation of the FDA OOS guidance, saying: "The hiding of an OOS result in the average is an unacceptable practice." FDA asks that Bayer treat each sample, tested individually, as an independent result and not average an out-of-specification result with a passing one.

The agency also observed that the drug maker has, on some occasions, failed to conduct follow-up investigations for out-of-specification results or has conducted investigations that "did not adequately determine root cause, or provide corrective actions to prevent recurrence."

APIs released in the market based on averaged sample results include several batches produced between 2007 and 2009 of drospirenone; ethinylestradiol and norethisterone acetate. FDA noted that an assay test - one of the measures employed by Bayer for its sample analysis- is used to determine potency, not method variability; adding to the reasons the agency said it disagrees with the drug maker's conclusion that the quality of these batches was not affected by poor manufacturing practices.

Now, the FDA is asking Bayer to include an account of corrective actions under consideration or implemented to address the OOS test result examples cited, a description of the corrective actions for each example, expected dates of completion and a more comprehensive review to ensure the revised OOS procedure's overall adequacy.

The agency also pointed out that the drug maker's Quality Unit "failed to maintain responsibility and authority to review and conduct investigations," including scientific justification to support conclusions and that "the investigations did not include proper corrective actions."

For example, the agency says some OOS results were disregarded and no investigations were conducted after obtaining individual OOS assay results during release and stability testing of the APIs, and instead these were averaged with passing results.

- Carlene Olsen ([email protected])