FDA warns Merck to clean up vaccine plant
Sterility problem in 2007 forced company to recall 1.2 million vaccine doses
The Associated Press
updated 12:04 p.m. ET, Wed., April. 30, 2008
TRENTON, N.J. - The Food and Drug Administration has ordered Merck & Co. to correct numerous manufacturing deficiencies at its main vaccine plant, the latest in a string of setbacks for the drugmaker. The agency on Wednesday released a warning letter sent to Merck's chief executive, Richard T. Clark, that states FDA inspectors determined manufacturing rules are not being followed at the plant in West Point, Pa., just outside Philadelphia.
The plant, which recalled two vaccines in December over sterility problems, makes a number of children's vaccines and four for adults. The nine-page letter states FDA found "significant objectionable conditions" in the manufacture of vaccines and drug ingredients during repeated inspections from Nov. 26 to Jan. 17. In a separate posting on its Web site, the agency said it issued the warning letter because Merck's response to the FDA report sent after the inspections was "inadequate to address the serious deviations noted."
According to the heavily redacted warning letter, Merck officials didn't thoroughly investigate when vaccine batches inexplicably failed to meet specifications, even if batches had been distributed, and some combination measles-mumps-rubella shots that failed "visual inspection for critical defects" were distributed anyway. The letter also said the plant didn't have written procedures, tests or other laboratory controls to ensure "identity, strength, quality, and purity" of products. However, in the Web site posting, the FDA said it "does not believe that the issues identified will affect the safety of the vaccines" made at West Point, or their availability.
"We're committed to working with the FDA to ensure that all these issues are addressed to their full satisfaction," said Merck spokeswoman Amy Rose, who added that the company does not distribute contaminated products. "We are confident in the quality, effectiveness and safety of our medicines and vaccines," she said.
Rose said Merck would be submitting additional information to the FDA and discussing it in a meeting, which is requested in the warning letter. The letter was signed by David K. Elder, head of enforcement in the agency's Office of Regulatory Affairs. Merck shares, hammered by FDA rejecting two of its experimental drugs since Friday, initially dropped about $1 on the news, then recovered. They ended Wednesday up 90 cents, or 2.4 percent, to $38.04. The warning letter gives Merck 15 days to tell the FDA how it will correct the violations. If Merck does not comply, the letter states the FDA can take actions including suspending or revoking the
plant's manufacturing license, seizing products or seeking injunctions, such as against product shipments.
"Warning letters help achieve voluntary compliance," FDA spokeswoman Mary Long said in an e-mail response to questions from The Associated Press. "Further action can be taken in the event violations remain uncorrected and would depend on the details of a given situation." Production of two vaccines made at West Point _ PedvaxHIB, to prevent Haemophilus influenza type B, and Comvax, a combination vaccine for Haemophilus B and hepatitis B _ stopped last year and 1.2 million doses of them were recalled after a sterility problemwas discovered in October.
The plant also makes ProQuad, which protects children against measles, mumps, rubella and chickenpox; hepatitis A, hepatitis B and meningitis vaccines for children and adults; and Gardasil, to protect young women against cervical cancer.
Merck hit for plant problems
FDA cites the drug maker after Pa. plant inspections
BY ED SILVERMAN
Merck & Co. has been cited by federal regulators for numerous quality-control problems at a manufacturing plant where several important vaccines are made. The Food and Drug Administration issued two enforcement reports extensive reviews of manufacturing practices -- following inspections of a Merck plant in Pennsylvania this past summer and fall, according to documents obtained by The Star-Ledger. After the second report was compiled in November, the Merck executive incharge of vaccine operations at the West Point, Pa., plant took early retirement, according to a company memo. The FDA found Merck improperly performed procedures for sterility, testing and documentation, among other things.
They were noticed by regulators at the same time Merck bid on -- and lost -- a $428 million contract to make smallpox vaccine for the federal government. Such inspections are routine in the pharmaceutical industry, but lengthy enforcement reports aren't -- the second report was 22 pages. Ultimately, Merck could face stiff fines if enough serious violations are found over a prolonged period. Meanwhile, people familiar with the situation say production at the plant has been halted while new supervisors are trained. Between 300 and 400 people work there. This is only the latest reversal of fortunes for the Whitehouse Station drug maker, which makes some of the best-known medicines. Recently, patents expired on some big-selling drugs, its Vioxx painkiller missed sales targets and was linked to cardiovascular problems, and company officials scaled back their earnings outlook.
"Merck's had a particularly tough year. And they've got a way to go to get back on track," said Mark Ravera, an analyst at Mehta Partners, a health-care investment firm. "Something like this would not be a welcome addition to their burdens. They certainly don't need any more bad press. But the FDA has been really cracking down on everybody." Indeed, the FDA review is another example of how regulators, who have been widely criticized for the way they approve new drugs, have become stricter about enforcing manufacturing problems. In 2000, the FDA levied a large fine on American Home Products Corp. and has recently cited plants run by Schering-Plough Corp. and Eli Lilly & Co.
A Merck spokesman, Greg Reaves, declined to comment on dealings with the FDA or the departure of the vaccines executive, James Laser. Reached at home, Laser, 55, declined to comment. "I don't think there are a whole lot of dots to connect."
Reaves also insisted any supply shortages are due to "voluntary" interruptions in production, which he attributed to maintenance upgrades and changes in manufacturing practices. But he stressed that shipments are proceeding.
Among the problems the FDA found at Merck:
Timely inspections weren't performed after noticing sterility failures.
Discrepancies in the number of rejected batches weren't documented.
Spreadsheets used to determine questionable results weren't verified.
Sufficient air pressure in the building wasn't maintained properly.
The FDA typically doesn't comment on inspections that haven't yet been resolved, but an FDA source said the Merck case remains open.
Products made at Merck's Building 29, part of a huge research and manufacturing facility in West Point, include Varivax, a chicken pox vaccine; a vaccine for MMR, or measles, mumps and rubella; and vaccines for Hepatitis A and B, the spokesman confirmed. Vaccines generated only about $1 billion in sales for Merck last year out of total revenue of $21 billion. But Merck has repeatedly identified vaccines as a growth engine. For instance, the company is working on an AIDS vaccine.
"Vaccines aren't as big as Zocor," the cholesterol medication, said Hemant Shah, an independent analyst who tracks drug makers. "But it's still an important business."
Ed Silverman can be reached at firstname.lastname@example.org or at (973)
'91 Memo Warned of Mercury in Shots
By Myron Levin
Times Staff Writer
February 8, 2005
A memo from Merck & Co. shows that, nearly a decade before the first public disclosure, senior executives were concerned that infants were getting an elevated dose of mercury in vaccinations containing a widely used sterilizing agent.
The March 1991 memo, obtained by The Times, said that 6-month-old children who received their shots on schedule would get a mercury dose up to 87 times higher than guidelines for the maximum daily consumption of mercury from fish.
"When viewed in this way, the mercury load appears rather large," said the memo from Dr. Maurice R. Hilleman, an internationally renowned vaccinologist. It was written to the president of Merck's vaccine division.
The memo was prepared at a time when U.S. health authorities were aggressively expanding their immunization schedule by adding five new shots for children in their first six months. Many of these shots, as well as some previously included on the vaccine schedule, contained thimerosal, an antibacterial compound that is nearly 50% ethyl mercury, a neurotoxin.
Federal health officials disclosed for the first time in 1999 that many infants were being exposed to mercury above health guidelines through routine vaccinations. The announcement followed a review by the U.S. Food and Drug Administration that was described at the time as a first effort to assess the cumulative mercury dose.
But the Merck memo shows that at least one major manufacturer was aware of the concern much earlier.
"The key issue is whether thimerosal, in the amount given with the vaccine, does or does not constitute a safety hazard," the memo said. "However, perception of hazard may be equally important."
Merck officials would not discuss the contents of the memo, citing pending litigation.
Separately, the drug giant is trying to fend off a legal onslaught over Vioxx, the popular painkiller it introduced in 1999. The company, based in Whitehouse Station, N.J., faces hundreds of lawsuits claiming that the drug caused heart problems and that Merck concealed the risks. Merck, which in September pulled Vioxx off the market, has denied the allegations.
The legacy of thimerosal, meanwhile, also is causing problems for Merck and other drug companies.
More than 4,200 claims have been filed in a special federal tribunal, the Vaccine Injury Compensation Program, by parents asserting that their children suffered autism or other neurodevelopmental disorders from mercury in vaccines. A handful of similar claims are awaiting trial in civil courts. The plaintiffs cite various scientific studies that they say prove the dangers of thimerosal, including at the levels found in vaccines.
Thimerosal has been largely removed from pediatric vaccines in recent years in what health officials have described as a precautionary measure. (This has been accomplished as drug makers have voluntarily switched from multi-dose vials of vaccine, which require a chemical preservative like thimerosal, to single-dose containers.)
In September, Gov. Arnold Schwarzenegger signed legislation prohibiting vaccines with more than trace amounts of thimerosal from being given to babies and pregnant women. Iowa has a similar ban.
For their part, Merck and other vaccine makers, along with many government health officials and scientists, say there is no credible evidence of harm from the amounts of mercury once widely present in kids' shots. They cite a report in May by a committee of the national Institute of Medicine concluding that the evidence "favors rejection of a causal relationship" between vaccines and autism.
The seven-page Merck memo was provided to The Times by James A. Moody, a Washington lawyer who works with parent groups on vaccine safety issues. He said he obtained it from a whistle-blower whom he would not name.
The memo provides the "first hard evidence that the companies knew — or at least Merck knew — that the children were getting significantly more mercury" than the generally accepted dose, the lawyer said.
He also provided a copy to attorneys for Vera Easter, a Texas woman who blames thimerosal for the condition of her 7-year-old son, Jordan, who is autistic and mentally retarded. The Easter lawsuit is pending in U.S. District Court for the Eastern District of Texas. The defendants include Merck; rival vaccine makers GlaxoSmithKline, Aventis Pasteur Inc. and Wyeth; and thimerosal developer Eli Lilly & Co.
Easter's lawyer, Andy Waters, described the memo as "incredibly damning and incredibly significant." After receiving it in the fall, he confronted Merck lawyers about why he hadn't seen it earlier.
In a letter to Waters in October, Merck attorneys said they had in fact made available 32 boxes of records, but that the copying service hired by the plaintiffs for some reason had failed to copy several of the boxes — including the one with the Hilleman memo.
"The memo," said company spokeswoman Mary Elizabeth Blake, "was produced voluntarily by Merck in the ordinary course of discovery proceedings."
Hilleman is a former senior vice president of Merck who developed numerous vaccines for the company. A 1999 profile in the Philadelphia Inquirer said that "it is no exaggeration to assert, as many scientists do, that Maurice Hilleman has saved more lives than any other living scientist."
Hilleman, 85, currently director of the Merck Institute for Vaccinology, had officially retired and was a consultant to Merck when he wrote the '91 memo. He declined to be interviewed.
The memo was sent to Dr. Gordon Douglas, then head of Merck's vaccine division and now a consultant for the Vaccine Research Center at the National Institutes of Health. Douglas also declined to comment.
The memo stated that regulators in several countries had raised concerns about thimerosal, including in Sweden, where the chemical was being removed from vaccines.
"The public awareness has been raised by the sequential wave of experiences in Sweden including mercury exposure from additives, fish, contaminated air, bird deaths from eating mercury-treated seed grains, dental amalgam leakage, mercury allergy, etc.," the memo said.
It noted that Sweden had set a daily maximum allowance of mercury from fish of 30 micrograms for a 160-pound adult, roughly the same guideline used by the FDA. Adjusting for the body weight of infants, Hilleman calculated that babies who received their shots on schedule could get 87 times the mercury allowance.
The Swedish and FDA guidelines work out to about four-tenths of a microgram of mercury per kilogram of body weight. A stricter standard of one-tenth of a microgram per kilogram has been adopted by the Environmental Protection Agency and endorsed by the National Research Council.
These standards are based on methyl mercury, the type found in fish and airborne emissions from power plants. Though toxic, the ethyl mercury in thimerosal may be less hazardous than methyl mercury, some scientists say, because it is more quickly purged from the body.
"It appears essentially impossible, based on current information, to ascertain whether thimerosal in vaccines constitutes or does not constitute a significant addition to the normal daily input of mercury from diverse sources," the memo said.
"It is reasonable to conclude" that it should be eliminated where possible, he said, "especially where use in infants and young children is anticipated."
In the U.S., however, thimerosal continued to be added throughout the '90s to a number of widely used pediatric vaccines for hepatitis B, bacterial meningitis, diphtheria, whooping cough and tetanus.
It was added to multi-dose vials of vaccine to prevent contamination from repeated insertion of needles to extract the medicine. It was not needed in single-dose vials, but most doctors and clinics preferred to order vaccine in multi-dose containers because of the lower cost and easier storage.
The Hilleman memo said that unlike regulators in Sweden and some other countries, "the U.S. Food and Drug Administration … does not have this concern for thimerosal."
A turning point came in 1997 when Congress passed a bill ordering an FDA review of mercury ingredients in food and drugs.
Completed in 1999, the review revealed the high level of mercury exposure from pediatric vaccines and raised a furor. In e-mails later released at a congressional hearing, an FDA official said health authorities could be criticized for "being 'asleep at the switch' for decades by allowing a potentially hazardous compound to remain in many childhood vaccines, and not forcing manufacturers to exclude it from new products."
It would not have taken "rocket science" to add up the amount of exposure as the prescribed number of shots was increasing, one of the e-mails said.
While asserting that there was no proof of harm, the U.S. Public Health Service in July 1999 called on manufacturers to go mercury-free by switching to single-dose vials. Soon after, Merck introduced a mercury-free version of its hepatitis B vaccine, replacing the only thimerosal-containing vaccine it was still marketing at the time, a company spokesman said.
By 2002, thimerosal had been eliminated or reduced to trace levels in nearly all childhood vaccines. One exception is the pediatric flu vaccine made by Aventis and still sold mainly in multi-dose vials.
Blunder at Merck's biggest production site pollutes creek
By Gregory Roumeliotis
06/07/2006 - In an incident that state and federal environmental regulators are treating as “serious,” Merck released 25 gallons of a cyanide-containing chemical from its West Point facility in Pennsylvania to the sewer, killing hundreds of fish and triggering health advisories.
The compound, potassium thiocyanate, was used to scale up the production of one of Merck's experimental vaccines, but the scale-up was abandoned, and instead of discarding the material properly, operators at the vaccine research pilot plant simply poured it down the drain.