Sanofi Pasteur Vaccine Manufacturing Violations Cited In FDA Warning Letter

Sterility issues at the firm's Swiftwater, Pa. manufacturing facility should not impact supplies of the Fluzone influenza vaccine, FDA says.

Manufacturing deficiencies at Sanofi Pasteur's Swiftwater, Pa. facility are not expected to significantly impact the availability of the company's influenza vaccine, Fluzone , during the 2006-2007 flu season, according to FDA.

FDA said it continues to review the progress made by the company and noted that a loss of monovalent concentrates used to make the vaccine due to sterility issues will result in "some impact," though the result is "not expected to be significant."

The agency issued a warning letter to Sanofi-Aventis' vaccines unit June 30, citing the company for failing to correct a number of manufacturing issues associated with production of the influenza vaccine.

"The problems identified did not affect any final influenza vaccine production, and we expect that the company will be able to meet its production targets for this season," FDA Center for Biologics Evaluation & Research Deputy Director Karen Midthun said during a July 3 conference call.

"However, the warning letter reflects FDA's recognition that Sanofi Pasteur has not corrected a number of the deficiencies," she said.

In a statement, Sanofi Pasteur said it "is committed to providing our customers with vaccines of the highest purity, potency, and safety. Consistent with our commitment, we take the FDA's recent warning letter very seriously. It is important to note that none of the issues raised by the FDA compromises the safety, purity, potency, or supply of any of our products in the market."

In addition, the company said it expects to meet its goal of manufacturing approximately 50 mil. doses of the influenza vaccine for the upcoming flu season.

The warning letter comes at significant time for the agency - which was recently accused of being too lax in its enforcement - and for the flu vaccine market, where supply appears to be poised to make a full recovery from the shortages sparked by Chiron's manufacturing problems in 2004.

A report by Rep. Henry Waxman (D-Calif.) cited FDA's decision not to warn Chiron despite observing earlier deficiencies as an example of lowered enforcement standards. The letter to Sanofi Pasteur, however, allows FDA to show that it is warning companies about manufacturing problems even if they are not significant enough to impact final products.

FDA became aware of sterility failures of monovalent concentrates associated with batches of Fluzone March 31 after Sanofi Pasteur notified the agency. All of the contaminated batches were discarded, and none were used in vaccine production, FDA noted.

The agency inspected the facility April 18-28, documenting significant deviations from current good manufacturing practices associated with licensed biological products and Fluzone monovalent concentrate batches.

At the time, FDA issued a "Form 483" outlining manufacturing issues such as deficiencies with the maintenance of equipment and supplies; failure to comply with written procedures to prevent microbial contamination; failure to establish the accuracy, sensitivity, specificity and reproducibility of test methods; and failure to report events such as reports of glass in lots of the tetanus/diphtheria vaccine Decavac .

The agency also cited specific problems associated with Fluzone, including Sanofi's failure to properly investigate sterility failures of 11 Fluzone monovalent concentrate lots.

While FDA noted that Sanofi Pasteur increased non-routine surveillance monitoring to evaluate Fluzone manufacturing following the discovery, "there was no plan in place specifying the locations to be tested, sampling methods to be used and corrective actions to be assigned," according to the warning letter.

"Investigational aseptic processing simulation studies did not include pre-filtration operations and cleaning activities that are performed prior to sterile filtration of monovalent concentrate," FDA added. The agency also cited the company for failing to re-sample portions of the failed monovalent concentrate lots to determine the extent of the contaminations.

In addition, the agency pointed to several failures with Sanofi Pasteur's production and process controls and laboratory controls.

Although the company responded to FDA's "Form 483" May 19 outlining corrective action it had taken, the agency said, "We believe that your response did not provide sufficient detail to fully assess the adequacy of the corrective actions."

"FDA determined that some of the firm's corrective actions were not adequate and that a warning letter was appropriate at this time to ensure rapid action and compliance," CBER's Office of Compliance & Biologic Quality Director Mary Malarky explained.

"Although FDA is encouraged by the changes made and the lack of any additional monovalent failures during the last three months, we remain concerned both with the overall quality issues observed and with the failure to identify a conclusive route cause of the earlier failures."

FDA estimates that 100 mil. doses of influenza vaccine from all licensed manufacturers will be available for the 2006-2007 flu season.

Chiron, since acquired by Novartis, expects to produce 40 mil. doses of Fluvirin for the 2006-2007 flu season (¹ (Also see "Novartis/Chiron Deal To Close April 20" - Pink Sheet, 19 Apr, 2006.)). GlaxoSmithKline also has a U.S.-licensed influenza vaccine, Fluarix . The company filed for a BLA for an additional vaccine, FluLaval, March 23. GSK predicts it could provide a combined total of 30 mil. doses of influenza vaccine for the 2006-2007 season if FluLaval is approved (² (Also see "GSK’s Second Flu Vaccine Would Boost Capacity To 30 Mil. Doses" - Pink Sheet, 23 Mar, 2006.)).

-Jessica Merrill