The British plant responsible for the recent flu vaccine shortage sent some improperly made vaccine, by mistake, to U.S. consumers three years ago, according to a 2003 government inspection report recently given to Congress.
Whether that vaccine stayed potent and sterile through its expiration date could be questioned, USA TODAY found. That was because the plant first deviated from approved manufacturing methods, then failed to document whether that would harm the vaccine's quality over time.
The report doesn't say how many doses were involved, and there's no proof the vaccine harmed anyone.
But the mistake — along with other deficiencies in vaccine production at the Liverpool plant — is likely to increase skepticism about the Food and Drug Administration's oversight of the plant and the vaccine industry.
The FDA discovered the mistakenly released vaccine during a plant inspection in mid-2003, more than a year after millions of people got flu shots for the 2001-2002 season and a month before the plant's current owner, Chiron, bought it from PowderJect Pharmaceuticals. The FDA's report became public last fall during Congress' probe of the vaccine shortage. A close examination reveals many unreported details about the plant's vaccine, most of which was for the U.S. market:
• Four out of five batches of tested vaccine made for the 2001-2002 flu season lost potency too soon.
• PowderJect managers considered — but decided against — recalling flu vaccine in 2002 because of concerns about its potency.
• Some required quality-control tests before 2003 were "simply overlooked," the company told FDA inspectors, and it didn't do others on time. In two unspecified years before 2004, the company sent the FDA test vaccine samples labeled as one kind of flu strain when they were actually another.
• Plant operators repeatedly failed to fully and properly investigate problems.
Despite these failings, the FDA largely accepted the company's word that it would correct deficiencies, even though the plant had received a bad FDA review in 1999, and was being relied upon for more of the USA's flu vaccine.
Last year, the plant's 48 million doses, half the USA's expected flu-shot supply, were scrapped after British regulators suspended the plant's license when about 8% of its vaccine turned up contaminated. British officials cited deficient manufacturing conditions. The FDA then said it couldn't be sure any of the vaccine was safe.
Chiron is upgrading the plant and hopes to provide flu shots to the United States this fall.
The story of the Liverpool plant is one of lax FDA oversight of an industry in which millions of Americans put their trust every year, FDA critics and some pharmaceutical industry experts say. If the FDA had done more to ensure plant upgrades after the 2003 inspection, this season's shortage might have been prevented, says Rep. Henry Waxman, D-Calif., an FDA critic. The FDA disputes that.
The 2003 report, which focuses on the 2001-2002 vaccine, also "raises serious questions" about the quality of vaccine the plant produced three years ago, Waxman says: "I see no clear evidence that individuals were harmed, but it is certainly a situation we do not want to repeat."
The FDA says the plant's vaccine that flu season — and in others except for 2004 — met its requirements for safety and effectiveness. No vaccine was distributed that didn't pass the manufacturer's and FDA's tests, the agency says.
But three drug-industry experts, including a former FDA investigator, who reviewed the report for USA TODAY say they cannot be sure that all the 2001-2002 vaccine met government standards. They don't think the FDA can say for certain, either. That's because the way the vaccine was made and tested was deficient in too many ways for anyone to be certain all of it met federal potency and safety standards through its expiration date, they say. None of them would have felt comfortable taking it themselves.
"I don't feel confident that the plant's vaccine was safe and effective based on its non-compliance with good manufacturing practices," says Sarah Sellers, a drug safety consultant and FDA adviser who reviewed the report.
Testing misses some problems
Testing of vaccine is just one check to ensure that it's safe and effective. But it isn't a fail-safe method, because only samples of vaccine are tested, and problems can be missed, says Denise Dion, a former 18-year FDA investigator now with consulting firm EduQuest. She also reviewed the report.
That's why regulators also check to make sure vaccines are made using good manufacturing practices, as defined by the government. Those include everything from having proven procedures to strong quality control, testing and record-keeping. Drugs made without good practices can be declared adulterated even if tests show samples are fine. Without good manufacturing practices, the World Health Organization says, it "is impossible to be sure that every unit of a medicine is of the same quality as the units ... tested in the laboratory."
In mistakenly releasing the improperly made vaccine three years ago, the plant violated good manufacturing practices, the FDA says.
"If you look at what's in FDA's own documents, it's stunning they didn't get a warning letter or something worse" after the 2003 inspection, says Gordon Richman, a former director of quality strategy for GlaxoSmithKline's manufacturing. He is now an FDA-regulatory consultant at EduQuest. He reviewed the report separately from colleague Dion.
Warning letters demand fixes under threat of further action, such as license suspension. Instead, the FDA let the plant make fixes voluntarily, Waxman says, even though its own investigators recommended official action against the plant, he says. His office reviewed several thousand pages of documents, not all of which have been released to the public. The House Committee on Government Reform, which includes Waxman, plansa hearing todayon the flu-shot shortage and future challenges.
The FDA says it allowed the plant to make voluntary fixes because it had made some corrections and planned others. In an e-mail response to USA TODAY, it also said the vaccine-making process includes safeguards, such as testing at various stages. Because of that, "violations in certain good manufacturing practices do not necessarily or routinely translate into unsafe products," it says.
The FDA declined requests for interviews with FDA officials and didn't answer all questions via e-mail. Chiron declined comment on vaccines made at the plant before it owned the plant.
Longtime supplier
The plant has provided Fluvirin flu vaccine to the USA since 1988, the FDA says. In 1999, the FDA gave the owner then, U.K.-based Medeva Pharmaceuticals, a warning letter for violating good manufacturing practices. Among the FDA's concerns: Some of the plant's partially processed vaccine contained unusuallyhigh levels of bioburden — bacteria and other microorganisms. It had to be refiltered to remove the organisms.
All flu vaccine starts out with bacteria in it because it's made using eggs, which contain bacteria. The manufacturing process is supposed to get rid of all detectable bacteria. Refiltering is discouraged because it can harm a vaccine's quality and might indicate something is wrong with the plant's system that needs to be fixed.
Medeva took issue with some of the FDA's findings but promised many fixes, FDA documents show.
In March 2001, when the FDA re-inspected the plant, PowderJect owned it. That inspection report was not made public. But the 2003 report says FDA inspectors in 2001 told plant operators that refiltering and reprocessing were not appropriate for U.S. vaccine.
Yet, when FDA investigators returned in 2003, they found just that: Batches of vaccine during the summer of 2001 had been refiltered to successfully lower bacteria levels. They were mixed with other batches to make the final vaccine.
The report says refiltered vaccine went into three lots sent to U.S. consumers. A vaccine lot typically has hundreds of thousands of doses, industry experts say.
In addition to violating FDA rules, the plant lacked sufficient data to show that the reworking didn't harm the vaccine's stability, the 2003 report indicates, which would include its ability to stay potent and sterile through its expiration date and use by consumers.
"Since there was no supporting data, it (the vaccine) may be OK but we don't know," says Lina Patel, a former Bayer AG scientist who is now a stability expert at Diosynth Biotechnology.
More.... http://www.usatoday.com/news/health/2005-02-09-vaccine-problems_x.htm
Whether that vaccine stayed potent and sterile through its expiration date could be questioned, USA TODAY found. That was because the plant first deviated from approved manufacturing methods, then failed to document whether that would harm the vaccine's quality over time.
The report doesn't say how many doses were involved, and there's no proof the vaccine harmed anyone.
But the mistake — along with other deficiencies in vaccine production at the Liverpool plant — is likely to increase skepticism about the Food and Drug Administration's oversight of the plant and the vaccine industry.
The FDA discovered the mistakenly released vaccine during a plant inspection in mid-2003, more than a year after millions of people got flu shots for the 2001-2002 season and a month before the plant's current owner, Chiron, bought it from PowderJect Pharmaceuticals. The FDA's report became public last fall during Congress' probe of the vaccine shortage. A close examination reveals many unreported details about the plant's vaccine, most of which was for the U.S. market:
• Four out of five batches of tested vaccine made for the 2001-2002 flu season lost potency too soon.
• PowderJect managers considered — but decided against — recalling flu vaccine in 2002 because of concerns about its potency.
• Some required quality-control tests before 2003 were "simply overlooked," the company told FDA inspectors, and it didn't do others on time. In two unspecified years before 2004, the company sent the FDA test vaccine samples labeled as one kind of flu strain when they were actually another.
• Plant operators repeatedly failed to fully and properly investigate problems.
Despite these failings, the FDA largely accepted the company's word that it would correct deficiencies, even though the plant had received a bad FDA review in 1999, and was being relied upon for more of the USA's flu vaccine.
Last year, the plant's 48 million doses, half the USA's expected flu-shot supply, were scrapped after British regulators suspended the plant's license when about 8% of its vaccine turned up contaminated. British officials cited deficient manufacturing conditions. The FDA then said it couldn't be sure any of the vaccine was safe.
Chiron is upgrading the plant and hopes to provide flu shots to the United States this fall.
The story of the Liverpool plant is one of lax FDA oversight of an industry in which millions of Americans put their trust every year, FDA critics and some pharmaceutical industry experts say. If the FDA had done more to ensure plant upgrades after the 2003 inspection, this season's shortage might have been prevented, says Rep. Henry Waxman, D-Calif., an FDA critic. The FDA disputes that.
The 2003 report, which focuses on the 2001-2002 vaccine, also "raises serious questions" about the quality of vaccine the plant produced three years ago, Waxman says: "I see no clear evidence that individuals were harmed, but it is certainly a situation we do not want to repeat."
The FDA says the plant's vaccine that flu season — and in others except for 2004 — met its requirements for safety and effectiveness. No vaccine was distributed that didn't pass the manufacturer's and FDA's tests, the agency says.
But three drug-industry experts, including a former FDA investigator, who reviewed the report for USA TODAY say they cannot be sure that all the 2001-2002 vaccine met government standards. They don't think the FDA can say for certain, either. That's because the way the vaccine was made and tested was deficient in too many ways for anyone to be certain all of it met federal potency and safety standards through its expiration date, they say. None of them would have felt comfortable taking it themselves.
"I don't feel confident that the plant's vaccine was safe and effective based on its non-compliance with good manufacturing practices," says Sarah Sellers, a drug safety consultant and FDA adviser who reviewed the report.
Testing misses some problems
Testing of vaccine is just one check to ensure that it's safe and effective. But it isn't a fail-safe method, because only samples of vaccine are tested, and problems can be missed, says Denise Dion, a former 18-year FDA investigator now with consulting firm EduQuest. She also reviewed the report.
That's why regulators also check to make sure vaccines are made using good manufacturing practices, as defined by the government. Those include everything from having proven procedures to strong quality control, testing and record-keeping. Drugs made without good practices can be declared adulterated even if tests show samples are fine. Without good manufacturing practices, the World Health Organization says, it "is impossible to be sure that every unit of a medicine is of the same quality as the units ... tested in the laboratory."
In mistakenly releasing the improperly made vaccine three years ago, the plant violated good manufacturing practices, the FDA says.
"If you look at what's in FDA's own documents, it's stunning they didn't get a warning letter or something worse" after the 2003 inspection, says Gordon Richman, a former director of quality strategy for GlaxoSmithKline's manufacturing. He is now an FDA-regulatory consultant at EduQuest. He reviewed the report separately from colleague Dion.
Warning letters demand fixes under threat of further action, such as license suspension. Instead, the FDA let the plant make fixes voluntarily, Waxman says, even though its own investigators recommended official action against the plant, he says. His office reviewed several thousand pages of documents, not all of which have been released to the public. The House Committee on Government Reform, which includes Waxman, plansa hearing todayon the flu-shot shortage and future challenges.
The FDA says it allowed the plant to make voluntary fixes because it had made some corrections and planned others. In an e-mail response to USA TODAY, it also said the vaccine-making process includes safeguards, such as testing at various stages. Because of that, "violations in certain good manufacturing practices do not necessarily or routinely translate into unsafe products," it says.
The FDA declined requests for interviews with FDA officials and didn't answer all questions via e-mail. Chiron declined comment on vaccines made at the plant before it owned the plant.
Longtime supplier
The plant has provided Fluvirin flu vaccine to the USA since 1988, the FDA says. In 1999, the FDA gave the owner then, U.K.-based Medeva Pharmaceuticals, a warning letter for violating good manufacturing practices. Among the FDA's concerns: Some of the plant's partially processed vaccine contained unusuallyhigh levels of bioburden — bacteria and other microorganisms. It had to be refiltered to remove the organisms.
All flu vaccine starts out with bacteria in it because it's made using eggs, which contain bacteria. The manufacturing process is supposed to get rid of all detectable bacteria. Refiltering is discouraged because it can harm a vaccine's quality and might indicate something is wrong with the plant's system that needs to be fixed.
Medeva took issue with some of the FDA's findings but promised many fixes, FDA documents show.
In March 2001, when the FDA re-inspected the plant, PowderJect owned it. That inspection report was not made public. But the 2003 report says FDA inspectors in 2001 told plant operators that refiltering and reprocessing were not appropriate for U.S. vaccine.
Yet, when FDA investigators returned in 2003, they found just that: Batches of vaccine during the summer of 2001 had been refiltered to successfully lower bacteria levels. They were mixed with other batches to make the final vaccine.
The report says refiltered vaccine went into three lots sent to U.S. consumers. A vaccine lot typically has hundreds of thousands of doses, industry experts say.
In addition to violating FDA rules, the plant lacked sufficient data to show that the reworking didn't harm the vaccine's stability, the 2003 report indicates, which would include its ability to stay potent and sterile through its expiration date and use by consumers.
"Since there was no supporting data, it (the vaccine) may be OK but we don't know," says Lina Patel, a former Bayer AG scientist who is now a stability expert at Diosynth Biotechnology.
More.... http://www.usatoday.com/news/health/2005-02-09-vaccine-problems_x.htm
