Flu Vaccine Problems Run Deep

WASHINGTON —  A Food and Drug Administration report made public Wednesday shows that bacterial contamination at Chiron Corp.’s flu vaccine plant in Britain is more widespread than previously thought, raising doubts about the company’s ability to deliver flu shots in 2005.

And the FDA disclosed during a congressional hearing into the vaccine shortage that the results of an inspection of the plant in June 2003 -- which found evidence of contamination and faulty sterilization procedures -- weren’t shared with the company until a year later, when it would have been too late to make changes to salvage this year’s batch of 50 million shots.

British health regulators shut down the Chiron plant Oct. 5 after determining that the purity of its Fluviran vaccine couldn’t be guaranteed, eliminating almost half of this country’s expected supply for the current flu season.

The FDA’s follow-up inspection of the plant in Liverpool last month found 60% of the unfinished vaccine was contaminated, with several types of bacteria and in many locations, including after the sterilization stage. The level of contamination appears to be several thousand times acceptable levels, according to people who reviewed the report.

“These problems should have been corrected and they were not,” said Deb Chakravarti, a professor at the Keck Graduate Institute of Applied Life Sciences in Claremont. “This is very serious.”

Said Geoffrey Porges, an analyst with Sanford C. Bernstein: “It is much worse than I thought. It is an antiquated facility and poorly managed. They are going to have to make material improvements.”

Porges said the odds of Emeryville, Calif.-based Chiron getting the plant in shape for the 2005 flu season were less than 50-50.

The two inspection reports released by the FDA stirred charges on Capitol Hill on Wednesday that the agency was too timid in its oversight of the plant, and thereby lost an opportunity to demand improvements that might have headed off this year’s shortage.

After its 2003 inspection, the FDA chose to work cooperatively with the British factory rather than threaten enforcement action, as had been recommended by the agency’s own inspectors.

“The documents show that FDA failed to provide effective oversight,” said Rep. Henry A. Waxman (D-Los Angeles) during a hearing of the House Government Affairs Committee. He added that if the agency had moved more aggressively after 2003, “the problems at the plant might have been avoided.”

“This is not Rogaine,” he said of the flu vaccine. “This is a product that is essential to the health of millions of Americans.”

Lester Crawford, acting commissioner of the FDA, defended the agency’s handling of the matter. He told the committee that the factory’s procedures were improving in 2003 compared with earlier years and that seeking Chiron’s cooperation, rather than threatening the company with enforcement action, was entirely appropriate.

“They in fact completed what we wanted them to do,” he said. “There was no need for a warning letter. They corrected the problem. We got the vaccine produced, and it was OK.”

The one error Crawford acknowledged was the time it took the FDA to provide Chiron with the summary of its inspection findings from June 2003. “We’ve corrected that procedure, but that was a mistake,” he said.

Howard Pien, chief executive of Chiron, told the committee Wednesday that the company was making every effort to solve the factory problems so it could be cleared to produce flu vaccine next year.

Pressed by Waxman on whether the FDA could have played a more helpful role, he demurred: “If you’re asking me to criticize our regulator, that simply isn’t something I can do, will do or shall do.”

The FDA inspection report from last month documents sloppy techniques and quality control at crucial points in the manufacturing process.

Flu vaccine consists of three strains of virus, which are grown in three separate groups of chicken eggs. The viruses are separated from the eggs, killed and filtered into batches containing a single virus strain. Then the batches are blended and sterilized to form vaccine. In the final step, the vaccine is put into vials.

Because vaccine is made from eggs, some level of contamination is expected in the early stages of production. However, the FDA report found unusually high levels early in the process, a situation that seemed to get worse as production continued. Chiron sent contaminated batches of unblended vaccine through the production process even though the bacterial levels in the vaccine exceeded accepted levels “by several orders of magnitude,” the report said.

FDA inspectors found bacteria in the filling room, where vaccine is placed into vials, which is supposed to be sterile.

Chiron tried to control the contamination last spring and inaccurately deemed its efforts a success, the FDA report said.

In May, the company fumigated the formulation suite -- the room where batches of virus are blended into vaccine -- and said the procedure knocked out a bacteria, Serratia. In fact, the FDA said, several types of bacteria, including Serratia, were later found in the room and the company took no other steps to get rid of the contamination.

In many cases, according to the report, Chiron didn’t even know what sort of bacteria it was dealing with. The FDA said that 80% of the microorganisms growing in significant parts of the factory -- the filling room, the filtration area and the formulation suite -- had not been fully identified.

The FDA said Chiron didn’t conduct regular maintenance of equipment and lacked written instructions for cleaning tanks, centrifuges and other equipment used to make vaccine.

“This is very fundamental to the cleaning process,” said Chakravarti of the Keck Graduate Institute. “It goes to the general sloppiness of the whole thing.”

Chiron’s shares rose $2.09 to $33.66 on Wednesday, a gain of nearly 7%. Analysts said investors were buoyed by upbeat remarks by committee chair Rep. Thomas M. Davis (R-Va.).

Davis said that Chiron had just ordered chicken eggs to use in vaccine production in 2005. “I am confident that Chiron will be able to produce vaccine next year,” he said.

Pien, however, was far more pessimistic in his remarks. Chiron has assigned a team of 70 employees and outside consultants to work on a remediation plan for the Liverpool factory, Pien said, adding that he personally was overseeing the project.

Restoring the company’s Liverpool license was “mission critical,” he said.

But he warned: “There can be no conclusive assurance that we will be able to meet the expectations of the FDA and [British regulators] by March 2005. Moreover, because the regulatory ... standards are ever rising we cannot say whether we will be able to meet them in the future.”