Although an FDA advisory committee earlier this month voted in favor of expanding the population for use of FluMist to include children under five years of age, the FDA is reserving final action on MedImmune's supplemental biologics license application (sBLA) until compliance issues at the Liverpool, UK, bulk manufacturing plant have been addressed.

The FDA issued a warning letter to the company following an inspection of the plant in March this year which uncovered serious deviations in current good manufacturing practice (cGMP). The annual inspection revealed a series of contamination problems at the facility, stemming from lack of aseptic practices by personnel, deficiencies in cleaning, validation and disinfection practices at the facility.

In addition to these downfalls, the FDA noted that the company's investigations into cases of contamination were inadequate and failed to result in preventative actions to ensure such cases did not recur.

The FDA noted the company's tendency to associate cases of contamination with the eggs used in the manufacturing process, rather than any other aspect of production at the plant such as environment of personnel. Aside from the fact that some of the microorganisms identified are commonly associated with the environment and/or water, the company still failed to implement any corrective action to control microbial contamination of the eggs or perform a review of the flock from which the eggs were obtained.

Additional criticisms of the facility came in terms of operator failures to observe proper aseptic techniques, for example leaving skin exposed or failing to sanitize or change gloves.

Cleaning and disinfection at the site were also criticized, with cases of mold noted in the warning letter, and failure on the part of the company to ensure the effectiveness of the disinfectants it was using.

"The deficiencies described in this letter are indicative of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality and purity of your components/in-process materials," the agency stated in the warning letter.

Just the latest stumbling block in FluMist's troubled history, MedImmune will now have to address all these issues before the FDA will give its final judgment on the extension to the age indication for the flu treatment to be manufactured at the site.

The company already responded to the FDA's concerns back in March at the close of the inspection, but the agency deemed the company's reply lacking, failing to provide "sufficient detail to fully assess the adequacy of the corrective actions". The company therefore has two weeks following receipt of the letter (issued by the FDA last week) to notify the agency of any additional corrective action it plans to take to address the noted violations.

With MedImmune keen to get approval for its sBLA and push ahead with plans to release the vaccine as anticipated in time for the 2007-2008 flu season, the company said it was working with the FDA to "respond promptly and thoroughly" to its concerns.

Finally receiving approval for a refrigerated version of FluMist back in January, the company managed to eliminate problems associated with the initial formulations of the product which required frozen storage. The new version is still expected to be available in time for the 2007-2008 flu season.

The FluMist product itself is a vaccine administered as a fine mist through the nose, and is indicated for the prevention of disease caused by influenza A and B viruses. Currently approved for 5 - 49 year olds, the company is aiming to extend the age indication right down to infants six months of age.