Kansas City Star Investigation Highlights Chiron’s Vaccine Manufacturing Problems, FDA’s Knowledge

FDA regulators in 1999 were aware that contamination at Chiron's Liverpool, England, plant was "pervasive and persistent," and the agency allowed the plant to ship vaccine to the United States "despite clear departures from what the agency calls 'Good Manufacturing Practices," according to experts commissioned last week by the Kansas City Star to review FDA's 1999 inspection of the plant (McGraw, Kansas City Star, 11/7). California-based Chiron on Oct. 6 announced that the British Medicines and Healthcare Products Regulatory Agency suspended the manufacturing license of a company facility in Liverpool, England, that produces all of the flu vaccine Chiron manufactures for the United States.

As a result, Chiron will not send any flu vaccine doses to the United States for the current season. U.S. officials had expected to have about 100 million flu vaccine doses for the current flu season. France-based Aventis Pasteur will provide the United States with 56 million flu vaccine doses, and Maryland-based MedImmune will provide about three million doses of the nasal-spray flu vaccine FluMist (California Healthline, 11/1).

The FDA report reviewed by the Star was part of a lawsuit that Chiron settled earlier this year. In the suit, a woman alleged that she became paralyzed from a 1998 flu shot manufactured at the plant, which in 1999 was owned by the British firm Medeva. Chiron in mid-2003 gained control of the plant. The report shows that FDA officials in 1999 visited the plant for over one week during a biennial inspection and found 17 "problem areas," the Star reports. Inspectors found that at least 21 batches of vaccine distributed during the 1999-2000 flu season had to be filtered more than once to sterilize them.

Tests showed that before the final filtering process the vaccine contained bacteria such as E. coli and Chryseomonas luteloa, which can cause meningitis. According to the Star, testing showed that the vaccine at some points in the process had bacterial counts "hundreds of thousands of times higher than plant tolerances." According to experts commissioned by the Star -- which included a doctor specializing in virology, two pharmaceutical experts and a former industry executive -- the report showed that the plant:

• Mixed sampled vaccines with high levels of contamination with cleaner vaccine to improve test results;
  


• Did not meet FDA standards for production processes;
  


• Raised its limits for allowable contaminants, such as bacteria and toxins;
  


• Did not control air flow and other possible contamination sources;
  


• Could not produce critical documents about problems in the manufacturing process; and
  


• Did not have alarms that would alert workers to bacteria entering through the heating and cooling system.
  

Following the 1999 inspection, FDA issued a warning letter to Medeva citing "significant deviations from the acceptable standards and requirements of the Food, Drug and Cosmetic Act." FDA said that the problems could lead to license suspension. FDA issued three warning letters among the 20 vaccine manufacturers it inspected that year. The company responded in November 1999 by accepting some findings and saying FDA officials misinterpreted others. In March 2000, FDA officials said they would review the company's corrective actions during the next inspection in 2001 but noted that the agency "continues to have concerns."

The report did not identify all specific bacteria; however, there was no mention that tests detected Serratia, the bacteria found in the final step of the manufacturing process for this season's batch of flu vaccine.

The report indicated that FDA inspectors in 1997 found manufacturing problems "and that Medeva officials were in the midst of their ongoing investigation into increased contamination inside the plant," according to the Star. The FDA inspection also quoted a draft of a management report that said monitoring had begun to show an increase in contamination since about 1998. Polio vaccines manufactured at the plant in 1999 were recalled because of concerns they were contaminated with mad cow disease.

Hepatitis A vaccines being put in syringes at the plant in 2001 also were contaminated and found unusable. In 2002, routine testing of tuberculosis vaccine manufactured at the plant showed low potency levels. When Chiron purchased the plant in 2003, FDA found contamination in the flu vaccine manufacturing process, but regulators did not find significant problems with the vaccine itself. According to the Star, FDA "relied on Chiron to fix the problems, but the company reported in August that some vaccine was contaminated." FDA inspectors last month returned to the plant after the British suspension of Chiron's license.

FDA Acting Commissioner Lester Crawford said Friday in a written response that this year was the first time inspectors found contamination in the finished vaccine. Although the 1999 inspection found a problem in the final vaccine, it was a sterility failure confined to one lot manufactured the previous year, he said. Crawford said, "The most significant issues identified in 1999 were the lack of validation for its manufacturing processes, including establishing proper limits for bioburden (including bacteria) and issues related to assuring sterility in the manufacturing process."

FDA inspections in 2001 and 2003, which the agency has not yet released, show that the plant had made improvements, according to Crawford. He said, "If fully implemented, the company's plans appeared adequate to correct deficiencies." Officials of a Belgian firm that now owns Medeva did not comment. A Chiron spokesperson said, "We are taking a prospective rather than retrospective view right now with our public communications. Right now the company is focused on our remediation plan and working with (U.S. and British authorities) to get back on track for the 2005-2006 season."

Sarah Sellers, a pharmacist and former FDA adviser and consultant on pharmaceutical policy and regulation who reviewed the report for the Star, said it is likely that the 1999 and 2004 contamination problems are related. Sellers said she was surprised that FDA's warning letter did not say the company's vaccines were "adulterated" based on a strict interpretation of federal food and drug laws, an assertion that would require the FDA to pull the product from the market. Sellers noted that the plant's manufacturing process had not been certified by the company as effective since the early 1990s which could indicate lapses in earlier FDA inspections. Sellers said, "If the license was pulled and the problems dealt with in '99, we may not be facing a national public health crisis." Sellers added, "The license should have been pulled in '99 regardless of vaccine access issues. The problem was not new then, and it is not new today."

House Committee on Government Reform ranking member Henry Waxman (D-Calif.), who is helping to lead an investigation into this year's vaccine shortage, said, "To have years of warnings like this and do nothing is government malpractice. It is clear from this report that it is no unexpected accident that we have a flu vaccine shortage. The problems at the plant were systemic and known years earlier. If the government had taken strong action, the current crisis could have been avoided." David Webster, a former Aventis executive and now a biotech consultant, said, "It should have come as no surprise that there was a potential for this episode" (McGraw, Kansas City Star, 11/7).

In related news, a tracking system that public health officials implemented this year to identify increases in sales of over-the-counter medications used to treat flu symptoms could provide information about flu activity across the country, CDC Director Julie Gerberding said Sunday during the American Public Health Association's annual meeting, the AP/Houston Chronicle reports.

The federal government tracks about 80% of the sales of medications for such conditions as diarrhea and cold symptoms in an effort to learn more quickly about local outbreaks of illnesses (AP/Houston Chronicle 11/7).

According to the AP/Chronicle, tracking drug sales "may help give an earlier glimpse than waiting for hospitals to fill with the sickest patients." Texas and New York are among several states that have reported a few cases of the flu. However, many states have not recorded a single flu case, and none is reporting "widespread flu activity," the AP/Chronicle reports. CDC officials also have said they would like to track where the flu is spreading by county, which counties received flu vaccine and areas in which high-risk people did not receive the vaccination.

Gerberding said that the drug sales tracking system provides a "clue." She added, "And we don't know if it's going to be a useful clue or not. We're just learning this year." Gerberding also said that the flu season is not "getting off to a fast start." However, she said that fewer early cases of the virus do not indicate that the season will be mild. She said, "Flu is so unpredictable. I'm not making any projections, whatsoever." Gerberding also said CDC officials are "very concerned" about the threat of the avian flu virus. CDC officials are monitoring the spread of the avian flu in Asia to gauge whether the strain is evolving (AP/Houston Chronicle, 11/7).

NPR's "All Things Considered" on Friday examined CDC's data collection on flu transmission. The segment includes comments from CDC epidemiologist Lynette Brammer; Ira Longini, professor of biostatistics at Emory University; and Dr. Arnold Monto from the University of Michigan (Silberner, "All Things Considered," NPR, 11/5). The complete segment is available online in RealPlayer.