WARNING LETTER FEBRUARY 9, 2011
SANOFI AVENTIS DEUTSCHLAND GmbH
1. Your firm has not established or followed appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 C.F.R. § 211.113(b)].
21 C.F.R. § 211.113(b) states that “appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed”. This includes all aseptic and sterilization processes.
For example, in June 2010, your firm failed to identify the organisms recovered from a sterility test for Apidra lot #OF100. Identification of microorganisms recovered from a sterility test is essential when conducting a sterility failure investigation. In addition, the identification of organisms is also a fundamental part of any investigation of environmental or personnel monitoring excursions.
Your firm’s failure to identify organisms recovered from a sterility test was also discussed during the December 2008 inspection.
Sanofi was observed during the December 2008 inspection and again during the most recent inspection (September 6-10, 13-16, 2010) to fail to identify microorganisms recovered from sterility tests. Any sterility test failure requires a Sterility Failure Investigation to be conducted. In addition, it remains very likely that the Investigation cannot be closed within a reasonable period of time (usually 30 calendar days) and must be transferred to a Corrective Action/Preventive Action (CAPA). To determine the root cause, the identification of the microorganisms is essential. Often, one finds that the root cause is skin flora that can readily be corrected through careful gowning as well as the use of the proper disinfectants/sporicides.
The FDA, when auditing a site it has previously audited, will evaluate all citations obtained during previous audits to assure that the Client has fulfilled its “promises” made to the Agency. In this instance, the lack of follow-up (failure to identify organisms recovered) can only be viewed as a serious omission and one that can lead to a Warning Letter.
We recognize that your firm voluntarily recalled the Apidra, Lot#0F151A, which was part of the February 2010 production campaign in which there was a significant concern regarding environmental contamination levels. We expect all procedures related to the response for an out-of-limit environmental monitoring sample or a sterility failure to include the appropriate evaluation and remedial measures, as appropriate.
Often where there exists a sterility test failure, it is caused by flora on the skin. However, in this situation, the FDA noted a “significant concern regarding environmental contamination levels” and one cannot determine if the issue was flora from the skin or environmental contamination.
All sterility testing should also contain on-going viable airborne, surface, and personnel monitoring to permit the rapid response to an out-of-limit environmental monitoring sample or sterility failure. It appears that this may not have been performed based on this Warning Letter.