April 30, 2008.
Source: Philadelphia Inqurier
Federal inspectors documented unwanted "fibers" on the stoppers of vaccine vials at Merck & Co. Inc.'s vast vaccine plant in Montgomery County.
They also found instances of contaminated children's vaccines and complaints that were not always investigated at the West Point plant.
Inspectors from the U.S. Food and Drug Administration spent 30 days at the plant between November and January and cited 49 areas of concern, including a failure to follow good manufacturing practices.
The findings are detailed in an unpublished 21-page FDA report obtained by The Inquirer under the federal Freedom of Information Act.
Independent experts who reviewed the report say it documents serious concerns in one of the country's premier vaccine plants. They suggested the problems could be a symptom of Merck's cost cutting in the face of rapid growth of its vaccine business.
"I would fault the management for not providing enough resources to do the work that needs to be done," said Scott M. Wheelwright, a biotech manufacturing expert and chief executive officer of the biotech consulting firm Strategic Manufacturing Worldwide, of Saratoga, Calif.
John T. McCubbins, who heads Merck's Global Vaccine Manufacturing and West Point Operations, disputed that assessment. He maintained that the division's employment had kept pace with vaccine production. He stressed that no contamination was found in finished vaccines and that Merck was addressing all the problems.
McCubbins stressed that Merck's own technicians - not FDA inspectors - had detected and reported most of the problems, which were found in the manufacturing process, not in vaccines themselves.
"We are absolutely confident in the quality of the product," McCubbins said.
The plant continues to operate, and the FDA has not ordered Merck to stop production or to recall any products.
The report comes as demand for Merck's vaccines is surging. The company began selling four new vaccines in 2005 and 2006, pushing up total vaccine sales from $1.1 billion in 2005 to $4.3 billion in 2007.
The West Point plant, where Merck makes most of its vaccines, has had issues before. Bulk production of varicella-related vaccine for chicken pox has been down for many months, leading to shortages. The supply of Vaqta for hepatitis A also has been disrupted.
In June 2006, the company paid $20 million in a consent decree with authorities after a chemical spill shut down recreation on the Wissahickon Creek and closed water-intake pipes on the Schuylkill.
In December 2007, the company voluntarily withdrew 1.2 million doses of the childhood vaccines PEDVAXHIB and COMVAX because executives said they could not guarantee the products' sterility.
In contrast to pills, vaccines are harder to make because they are produced by living organisms that must be grown under precise conditions and kept from contamination.
In their report, FDA inspectors criticized the company for making a manufacturing change involving the withdrawn vaccines in mid-2006 and later reversing course and citing the change as the cause for the withdrawal.
McCubbins said the recall showed the company's quality-control systems were effective. All the recent problems reflect the inherent difficulty of working with living organisms to make vaccines, he said.
"The primary driver when we get here is the quality of the products we produce," McCubbins said. Merck will resolve the agency's concerns, he said.
FDA inspectors spent a total of 30 days at the West Point plant between Nov. 26, 2007, and Jan. 17, 2008. The agency could go on to issue a warning letter and take other actions if its concerns are not addressed. The FDA declined repeated requests to comment.
The report cites cases where bulk lots of PEDVAX and ProQuad were contaminated. Unwanted "fibers" were found on the vial stoppers of MMR, the measles, mumps and rubella vaccine, among others. They were caused by "lesser quality" supplies from a vendor, the FDA report said.
The report noted defective vials had to be rejected twice to be discarded, and that one internal quality investigation went on for more than a year.
Several experts said no single finding was horrendous but that the overall pattern was troubling. "It's the sum of many small things that puts the whole operation in question," said consultant Wheelwright.
Merck is a fabled name in vaccines. It was at Merck that microbiologist Maurice Hilleman developed many of the most common childhood vaccines, which are credited with saving millions of lives.
Richard T. Clark, Merck's current chief executive, started as a quality inspector in 1972 and held several key manufacturing positions at West Point before his rise to the top.
That Merck would be having problems with FDA inspectors surprised several longtime company observers.
Sammie Young, a retired FDA deputy director, inspected the West Point plant early in his career and for many years oversaw vaccine-plant inspections for the entire agency.
"There are a lot of violations there [in the report]," Young said, after reading the report. "I'm surprised."
He said vaccine-makers were supposed to investigate vaccine lots if their use was associated with a death or a life-threatening event.
Merck failed to investigate two such cases, the FDA report said. A patient treated with the pneumococcal vaccine Pneumovax developed a half-dollar-size abscess and needed intravenous antibiotics to contain the infection. A pregnant woman who took the HPV vaccine Gardasil lost her baby, the FDA report noted. The Gardasil packaging warns against its use for pregnant women.
"I am concerned about the adverse-event reporting system," Young said. "It looks like the people didn't know when they were supposed to report. I find that hard to believe."
Wheelwright, a consultant with 25 years' experience in vaccine manufacturing, suspects that the workload could be overwhelming.
"I would not judge the plant as being out of control," he wrote in an e-mail. "There are numerous issues where they failed to comply with their own documentation and SOP [standard operating procedure] requirements. This suggests insufficient staff. There are other instances where the validation was insufficient. This also looks to me like overwork of the available crew. Sometimes in a plant where everyone feels overburdened . . . they give up trying to do everything and just try to keep their heads above water."
McCubbins disputed the criticism, saying the staff follows its procedures and investigates complaints. "There's always a level of interpretation," he said.
McCubbins said he feared the FDA report could create unwarranted "panic" about the firm's vaccines.
The plant would make changes, he said, "where we believe that the agency may have a point and often they do. Nobody's perfect."