Its U.K. vaccine plant has been a nightmare. Could better risk management, due diligence, regulatory oversight or new technology have led to a different outcome?
By Agnes Shanley, Editor in ChiefIntroduction
Liverpool, birthplace of the Beatles, is now also indelibly fixed in memory as the site of a pharmaceutical manufacturing fiasco, which came to light last October when British regulators halted operations at Chiron Corp.'s Fluvirin flu vaccine manufacturing plant.
The story of what went wrong at the plant is complex, one that involves not just Chiron but multiple firms and regulatory bodies. It's also a story of risk analysis and political pressure, thin profit margins, short production timeframes, misplaced optimism and bad timing.Pharmaceutical Manufacturing
has obtained uncensored copies of a 1999 FDA site inspection report and Warning Letter, as well as redacted copies of subsequent inspection reports, all of which suggest that Chiron may have inherited some serious systemic problems when it bought the Liverpool plant in 2003. Some of these problems may have been impossible for Chiron to fix given the amount of time it had to prepare for the 2004-2005 vaccine season.
In the absence of comment from Chiron or FDA, this article will discuss the lessons that drug manufacturing professionals and regulators can learn from this case, and consider its future implications for vaccine manufacturing in the U.S. Within the past few decades, regulators have continued to raise the bar for quality in a risky, low-margin business, and, since the 1970s, the number of vaccine manufacturers in the U.S. has dropped from 25 to 5. Chiron’s case has already promoted frank discussions. We can only hope that it will also lead to the decisive actions required to rebuild the U.S. vaccine supply base.
The story began last summer,
when Chiron Corp. discovered gram-negative Serratia microbes in one lot of Fluvirin vaccine manufactured at its U.K. plant. In September, inspectors from Britain’s FDA equivalent, the Medicines and Healthcare Products Regulatory Agency (MHRA), inspected the plant. They found that levels of microbial contamination there had been increasing since March, and that the levels reached in 2004 were “several orders of magnitude” higher than they had been in 2002 and 2003. Gram-negative bacteria were found in the general plant environment, in a sterilizing filtration room, in bulk and finished product.
Chiron, perhaps confident that the source of contamination lay in its upstream manufacturing operations, informed the FDA and CDC that it would be able to meet its supply schedule, only to find days later that MHRA suspended the plant’s manufacturing license. Weeks later, FDA inspectors agreed that the safety of Fluvirin made at the plant could not be guaranteed. Roughly 48 million doses of flu vaccine, nearly half the U.S. supply, could not be shipped. On December 10, FDA issued Chiron a warning letter.
Chiron has been working around the clock to resolve manufacturing issues at the plant. In December, U.K. authorities extended the license suspension, to allow the company more time to carry out remediation efforts. The suspension can be lifted at any time, once the facility demonstrates compliance. Nevertheless, the damage has been done, to Chiron itself and the security of the public health.
“I can’t say that Chiron didn’t do enough due diligence — due diligence can be extremely hard to do — or that FDA inadequately reviewed the manufacturing process,” says Jim Akers, president of Akers-Kennedy and Associates, Inc. (Kansas City, Mo.) and a specialist in aseptic processing. “Part of the problem, no doubt, reflects the continued reliance on older technologies to manufacture vaccines. Some of these technologies should have been eliminated years ago.”
Whatever their source, problems at Chiron’s Liverpool plant have had severe repercussions for the company. After committing itself to a risky market that most U.S. producers have abandoned, Chiron has had to write off $91 million in losses. Its stock price has plummeted. Chiron has also been sued by stockholders, who allege that the company covered up problems at the plant. Meanwhile, a number of opportunistic consumer class-action lawsuits have been filed across the country.
A cynic might wonder why Chiron, or any company, would choose to enter the U.S. flu vaccine market in the first place. Others might question why a savvy biotech firm would invest hundreds of millions of dollars in an old production facility with a long, documented history of systemic quality and GMP problems. “While reading the 1999 FDA inspection reports and warning letters, Chiron’s management team should have found the hairs on the backs of their necks standing up straight,” says Donald Gerson, president of the cGMP and vaccine manufacturing consulting firm Axenic, Inc. (Montebello, N.Y.).Optimistic beginnings
In May 2003, Chiron first announced its intent to buy PowderJect’s flu vaccine business; the Emeryville, Calif.-based firm was to become one of the two leading U.S. flu vaccine producers in a market that had shrunken to three suppliers in less than two decades.
One unmistakable sign of trouble was the fact that the Liverpool plant had changed hands several times in the three years before Chiron bought it: Until 1999, Medeva Pharma owned the facility. The company then sold it to Cell Tech PLC in January 2000. PowderJect bought the facility just seven months later, spending over £85 million on a new filling plant, training programs and other improvements before June 9, 2003, when Chiron officially bought PowderJect for $878 million.
|A Cursed Facility?
When owned by Medeva, the Liverpool vaccine manufacturing plant was plagued by serious quality problems. Four years ago, oral polio vaccine made at the facility was recalled when it was found that the plant might have used raw materials that could have been derived from animals infected with bovine spongiform encephalopathy (BSE) or “Mad Cow.”
In addition, in the U.K., The Observer reported that manufacturing problems in 2000 led to shortages of yellow fever and TB vaccine product from the facility.
Under Medeva’s ownership, the plant, which had also produced vaccines for TB, polio, and yellow fever was the focus of several damning FDA investigations and product recalls (see "A Cursed Facility," at right
). A 1999 FDA site inspection report and warning letter (see 1999 Documents Find Systemic Problems, below
) found 17 serious issues at the facility: Operators routinely mixed contaminated vaccine lots with cleaner ones to raise overall product cleanliness levels; equipment at the facility was not calibrated, cleaned, maintained or sanitized appropriately; and environmental monitoring was inadequate, particularly for pressurized air systems in filling rooms, but also for water. Connections and fittings were not optimized to ensure sterile conditions—a problem that regulators had also brought up to plant management in 1997.