Sanofi GMP Problems Require Top-level Sit-down With FDA, But Product Impact Limited So Far

Agency’s warning letter also includes an uncommon request for a “global assessment” of operations. FDA says sterility of TheraCys lots manufactured since 2000 cannot be assured; company has halted manufacture of the bladder cancer drug and set limits on orders of its Pentacel vaccine.

FDA has requested a meeting with Sanofi’s senior management to discuss a host of manufacturing problems – from inadequate sterility testing to the nesting of birds in air units – at two of the company’s facilities.

The call for a meeting with the company is uncommon and indicates the seriousness of the violations. Among current good manufacturing practice warning letters issued in the last two-and-a-half years, FDA has asked to meet with senior management on just two occasions: in a November 2011 letter to Novartis AG regarding its Sandoz International GMBHunit’s facilities, and in a June 2010 letter to Hi-Tech Pharmacal Co. Inc. The agency also requested a meeting with Pfizer Inc. officers in a May 2010 letter concerning the company’s failures in postmarketing adverse drug experience reporting.

In its July 12 warning letter to Sanofi, FDA said the company’s deficiencies in current good manufacturing practice “are an indication of your quality control units not fulfilling their responsibility to assure the identity, strength, quality, and purity of your licensed biological drug products and intermediates.”

The letter, sent to Sanofi Senior VP Vaccines Olivier Charmeil, follows FDA inspections of Sanofi Pasteur Ltd.’s Toronto plant and Sanofi Pasteur S.A.’s plant in Marcy l’Etoile, France, in March and April. The facilities primarily manufacture vaccines.

However, all of the company’s manufacturing facilities will be impacted by FDA’s warning letter as the agency said it “expects Sanofi to undertake a comprehensive and global assessment of all of its manufacturing operations to ensure that all products conform to FDA requirements.”

That, too, is an infrequent request by the agency. FDA called for Novartis to undertake a global assessment of its manufacturing operations in its letter to the company last year (Also see "Sandoz GMP Warning Letter: Is The Problem Documentation, Or Leadership?" - Pink Sheet, 6 Dec, 2011.). And it imposed the same requirement on Merck KGAA in a December 2011 GMP warning letter and on Hospira Inc.in an April 2010 letter.

A third unusual aspect of the warning letter is that FDA released information on the manufacturing issues in advance of issuing the warning letter to the firm itself. FDA announced July 6, a week before it sent the letter, that it was working to alleviate shortage of Sanofi’s bladder cancer drug TheraCys [BCG Live (Intravesical)] in the wake of a manufacturing suspension by the firm.

Merck & Co. Inc. has more than doubled production of its bladder cancer drug TICE BCG (BCG Live) to make up for the shortfall (Also see "Sanofi TheraCys Shortage Prompts Merck To “More Than Double” Supply Of TICE BCG" - Pink Sheet, 11 Jul, 2012.).

FDA’s response to the shortfall and the development of the warning letter were almost certainly moving on parallel tracks within the agency, but the fact that FDA addressed the supply problem before formally going after the compliance one is an indication of how seriously the agency is taking drug shortages.

TheraCys, Pentacel Remediation Actions Ongoing

With regard to Sanofi’s Toronto plant itself, FDA said Sanofi had failed to establish the accuracy, sensitivity, specificity, and reproducibility of test methods. Specifically, the agency said sterility for all lots of TheraCys manufactured since the last successful BCG sterility test method validation in 2000 cannot be assured.

The revalidation of the test method conducted from March through April “failed acceptance criteria for bacteriostasis/fungistasis testing; there is no assurance that the test method is capable of detecting yeast and/or mold in the product,” FDA stated. “Further, there have been no less than 58 documented non-conformances relating to the isolation of mold within the BCG aseptic processing areas” since August 2010.

In April Sanofi temporarily stopped manufacturing TheraCys in order to renovate the Toronto facility. A Sanofi spokesperson said it made this decision after finding that the final test of the product prior to release was not performing as intended, which it determined prior to FDA’s inspection. The company forecasts that TheraCys will be available in late 2013.

Sanofi said TheraCys was the only product affected by FDA’s warning letter. In March the company started limiting the amount of Pentacel vaccine customers may order after finding that several lots were not suitable for release. Sanofi said this was unrelated to FDA’s inspection and that it expects the temporary interruption in supply will last until the first quarter of 2013.

Sanofi said Pentacel (which immunizes against diphtheria, tetanus, acellular pertusis, inactivated poliovirus and haemophilus influenza type b) could be replaced with a combination of its Daptacel (diphtheria, tetanus, acellular pertusis), Hib and polio vaccines.

Deutsche Bank AG said in an analyst note that it estimates the adverse impact on revenues from the TheraCys and Pentacel remediation actions to be roughly €20million-30million ($24million-36 million) in 2012 and €70million in 2013, the equivalent of 0.7% and 2.0% of 2011 vaccine sales.

Sanofi Disinfecting More, Investigating Equipment Alternatives

In the meantime, Sanofi is trying to fix its GMP deficiencies and is scheduling a time for Charmeil and other Sanofi executives to meet with FDA officials.

“We take their observations very seriously,” the Sanofi spokesperson stated. “We’re working with FDA to implement a series of immediate and ongoing steps to address the issues they identified in the warning letter and to further strengthen our manufacturing operations and quality oversight.”

Among other problems at the Toronto facility, FDA said the company failed to assure there was an adequate system for monitoring environmental conditions and for cleaning and disinfecting aseptic processing areas and equipment; lacked appropriate written procedures to prevent microbiological contamination of drug products; and failed to establish and follow a written testing program to assess the stability characteristics of drug products.

With regard to the latter point, the agency said that diphtheria potency, tetanus potency, and component mouse immunogenicity testing on reconstituted Pentacel was not being performed at the 12- and 18-month time points. Also, FDA said a review of stability data indicates the D-antigen test being performed on reconstituted Pentacel as the poliovirus potency test “has no approved acceptance criteria and is not a licensed test.”

In addition, FDA said the company failed to validate the performance of manufacturing processes that may be responsible for causing variability in the characteristics of in-process material; failed to validate the effectiveness of disinfectants used in the building where live Poliovirus is grown, under the actual conditions of use; and did not adequately investigate the failure of a batch or any of its components.

The agency also said Sanofi made an unapproved change to the manufacturing process for tetanus toxoid.

As for the Marcy l’Etoile facility, FDA said the company failed to thoroughly investigate any unexplained discrepancy of the failure of a batch or any of its components to meet any of its specifications and it failed to extend the investigation to other batches of the same drug product and other drug products that may have been affected.

For example, the agency noted that a conjugated haemophilus vaccine lot was found to have critical lyophilization defects that were not rejected by the semi-automated inspection process. FDA said that during Sanofi’s investigation, only lots identified as “high risk” were linked to the deviation and none of the other lots were placed on hold during the investigation.

Sanofi sent a May 15 letter to FDA responding to the inspection findings. In addition to temporarily suspending TheraCys manufacturing, the company said it would conduct a supplemental disinfectant efficacy study using mold spores of in-house isolates on various surfaces.

Among other remedial actions, Sanofi said it would increase the frequency of disinfecting the BCG facility with sporicidal agents and investigate possible short term alternatives or modifications to the current processing equipment and container closures.

Sanofi has received previous warning letters from FDA citing deficiencies at other manufacturing facilities. Last year, the agency said there were significant violations at its manufacturing facility in Frankfurt that were causing adulteration of the company’s drug products (Also see "Sanofi Lacks System To Prevent Microbial Contamination At Its German Plant, FDA Says" - Pink Sheet, 28 Feb, 2011.). And in 2006 FDA cited the company for deficiencies at its Swiftwater, Pa. plant, including failure to establish the accuracy, sensitivity, specificity and reproducibility of test methods (Also see "Sanofi Pasteur Vaccine Manufacturing Violations Cited In FDA Warning Letter" - Pink Sheet, 5 Jul, 2006.).