Last month, FDA sent sanofi-aventis a Warning Letter describing violations of current good manufacturing practice regulations that the agency had observed during an inspection of the company’s Frankfurt am Main, Germany, facility. The inspection took place on Sept. 6–10 and 13–16, 2010.
In the letter, FDA stated that the company had not established or followed appropriate written procedures to prevent microbiological contamination of sterile drug products. As an example, FDA cited the firm’s failure to identify the organisms recovered from a sterility test for its Apidra product in June 2010. “Identification of microorganisms recovered from a sterility test is essential when conducting a sterility failure investigation,” said the letter.
In addition, the company had not established defined areas or control systems to prevent contamination or mix-ups during aseptic processing, according to FDA. The agency called the airflow velocity inside critical areas of the aseptic-processing operations of one line unacceptable. The firm’s environmental-monitoring program failed to ensure that environmental contaminants were reliably detected, added the agency. “Your practice of collecting samples from the gloves of operators, from left and right hands on alternate days, is unacceptable,” said FDA in the letter.
Finally, FDA asserted that sanofi had failed to ensure that employees had the proper training or experience for the manufacture, processing, packing, or holding of drug products. Agents observed operators executing incorrect aseptic techniques to prevent contamination while the latter were involved in cleaning operations and aseptic connections during filling.
The latest Warning Letter follows one that FDA sent sanofi-aventis in January 2011. The previous Warning Letter resulted from an inspection of the company’s Bridgewater, New Jersey, facility, which revealed a failure to comply with postmarketing adverse drug experience reporting requirements. The letter cited inadequate written procedures for the surveillance, receipt, evaluation, and reporting of adverse events; failure to submit serious and unexpected adverse drug experience reports to FDA within 15 calendar days; and failure to include all postmarketing studies in the company’s annual report to FDA. The inspection took place from Apr. 16, 2010 through May 13, 2010.
Sanofi responded to the agency’s inspectional observations, but the company’s corrective action plan did not adequately address procedural deficiencies that cause the late submission of 15-day alert and follow-up reports, according to the Warning Letter. The agency stated that sanofi’s standard operating procedures did not provide the written adverse drug experience definitions required to evaluate these experiences for the submission of individual case safety reports, including 15-day alert reports.
Sanofi’s call-center contractors used an adverse-event reporting form that failed to correctly identify the adverse outcomes required to determine the seriousness of adverse drug experiences, according to the letter. “Failure to correctly identify the outcomes of any serious adverse drug experience could lead to inaccurate data entry into your call-center database and on the MedWatch 3500A Form,” said FDA.
The agency also expressed concern that sanofi’s adverse drug experience reporting system had not been fully validated, and may have resulted in the inaccurate assessment and untimely submission of 15-day alerts. “The current application was released into production on Nov. 9, 2009, using an Interim Validation report that is still not final,” said FDA in the letter.