When British regulators suspended the license of Chiron's manufacturing plant in Liverpool, England, in October 2004, the move caught the US Food and Drug Administration by surprise and triggered an international vaccine crisis. The FDA had inspected the plant in the past, and Chiron was slated to provide nearly half of the US vaccine supply for 2004–2005: 48 million doses of Fluvirin. Instead, the United States scrambled to find enough vaccine to protect against influenza, which kills 36,000 Americans each year. The Emeryville, Calif.-based company's stock plunged, and it reported a $22.9 million net loss in the fourth quarter of 2004.
How could things go so wrong? When they closed the plant, the UK's Medicines and Healthcare Products Regulatory Agency (MHRA) cited bacterial contamination in some lots of vaccine, and a failure to follow good manufacturing practice. GMP is a set of regulations that are meant to ensure the safety, purity, and effectiveness of drugs, medical devices, and certain other products. They regulate everything in the manufacturing process, including record keeping, equipment validation, and employee qualifications.
Companies that manufacture products in the United Kingdom must abide by GMP standards similar to or even more stringent than those in the United States. Indeed, nearly all developed countries have GMP standards comparable to those in the United States. "Today, the European and US standards are quite on the same level," says Bernard Boehm, quality commissioner for Solvay Pharmaceuticals. "The major difference ... is the national agencies' way of interpreting and handling the regulations."
The Chiron episode has led some to scrutinize not only Chiron's failings, but also those of the regulatory community. Some ask, for instance, whether the FDA adequately regulates plants outside the United States, and if other companies, especially those with overseas operations, are at risk for similar GMP problems.
The good news is that the MHRA gave Chiron the go-ahead to resume flu vaccine production in March, which was earlier than expected. This ended the company's five-month suspension and greatly increased its chances of being able to produce flu vaccine for the 2005–2006 season. The announcement caused a 6% jump in Chiron's stock. However, Chiron won't offer much insight into how its GMP problems might have been avoided in the first place. "Our current legal environment has imposed a good deal of restrictions on what we can communicate publicly," said Alison Marquiss, a Chiron spokesperson.
Plenty of industry professionals and academics, however, are willing to offer opinions on what went wrong at Chiron, and how other pharmaceutical companies can avoid similar GMP debacles in their own manufacturing operations. And some say there are lessons to be learned by the FDA as well. "A higher level of cooperation between the FDA and the regulatory agencies of the nations having FDA-licensed facilities is certainly suggested by this event," says Yusuf Chisti, a GMP compliance expert at New Zealand's Massey University.
THE STRICTER THE INSPECTORS, THE BETTER
After British authorities closed the plant, the FDA followed with its own investigation and sent a warning letter to Chiron in December 2004 that listed 20 separate problems with manufacturing and record keeping. Known in the industry as FDA Form 483, the FDA warned that the plant had failed to follow its own procedures to investigate sterility problems. For instance, bacterial contamination was found in a room that was supposed to be sterile, even after the room was fumigated. Even then, the company failed to document the impact of this sterility failure on its product. The company also failed to use proper storage temperatures for its vaccine, failed to properly follow procedures for cleaning and maintaining equipment, failed to properly review production records for accuracy, and failed to take corrective action after experiencing alerts of contamination.
Ultimately, the company found
Boehm says GMP problems often occur simply because companies do not do their homework. "Lack of knowledge about regulations, misunderstanding of regulations, (and) lack of resources to fulfill requirements" are all factors that can lead to GMP lapses, he says.
GMP problems also happen when a company is looking to cut costs, managers are looking to "streamline" operations, or a company is lulled by substandard inspections into thinking "everything is OK," says Michael Anisfeld, president of Globepharm Consulting, a Deer-field, Ill.-based firm that advises companies on GMP compliance. "Poor inspections by under-trained inspectors only make companies feel they have done sufficient (work), and that is what gives rise to GMP noncompliance problems, and that is what puts patients at risk," Anisfeld says.
Chisti believes Anisfeld's latter point may be precisely what happened in Liverpool. Chisti, who studied the FDA warning letter, concludes that the plant apparently fell into disrepair partly because the FDA failed to follow up on previous inspections that indicated problems were afoot. The scenario could happen at the manufacturing plants of other companies, he says. "The unfortunate thing was that some of these failings had been cited by the FDA from an earlier inspection, but (they) had not been satisfactorily addressed by the company," Chisti says.
The FDA knew about Chiron's contamination problems from previous inspections, according to congressional testimony from FDA Commissioner Lester Crawford. In August, Chiron informed the FDA that some lots of vaccine, equaling about 4.5 million doses, were contaminated with bacteria. But the agency apparently became aware of the severity of the problems only after British regulators suspended the Liverpool plant's license in October. This suggests there could be better communication between the FDA and regulators outside the country, Chisti says.
FDA: HOW TOUGH IS TOUGH ENOUGH?
Why would previous FDA inspections fail to either turn up or to remedy Chiron's problems? It could be that the FDA lacks the resources necessary to adhere to its own standards, especially when it comes to overseas facilities. "The British, Canadian, and Australian GMPs demand higher standards, and these countries have tougher inspection agencies," Anisfeld says. "The FDA is tough, but rests more on its reputation as 'the toughest' than on reality."
While monitoring FDA inspections for his clients, Anisfeld has witnessed first-hand how the federal agency can sometimes lack the staff or the time to conduct proper reviews. "In the past year, we have been at companies during five FDA inspections, and during each ... [we saw] a lack of trained manpower at FDA and insufficient time allocated by FDA to perform proper inspections," he says.
Boehm believes that distance and language barriers can sometimes hinder the FDA when it comes to conducting proper inspections. "There is almost no direct and quick access to [overseas] companies for the FDA for unannounced inspections, for instance, or problem-tracking," Boehm says.
Chisti concurs. "Overseas facilities are apparently inspected less frequently by the FDA than are the US facilities," he says. "A system for prioritizing which overseas facilities need FDA's more frequent attention should be useful ... based on the degree of dependence of the US market on shipments from a facility, the size of the patient population for the product, and other similar factors."
The FDA will not comment on the Chiron incident. "Questions are best answered by existing materials," says Lenore Gelb, an FDA spokesperson. The FDA 's Crawford told a congressional committee last November that his agency is modernizing its GMP rules. The rules have not been updated for 25 years, despite tremendous advancements and changes in drug manufacturing.
The new cGMP (current GMP) initiative will "build quality into the manufacturing process" and "modernize our manufacturing regulatory responsibilities," he says. Under the initiative, there will be advanced training for manufacturing investigators, in hopes this will lead to greater consistency in inspections and a quicker response to deficiencies. The FDA will also promote better communication with the firms it regulates to help manufacturers anticipate and avoid production problems "before they occur," Crawford says.
CHANGES MAY HELP
Because of the Chiron incident, Crawford says the FDA is conducting an inventory of foreign manufacturing of US-licensed products such as flu vaccine that are critical to public health. The federal agency is also completing information-sharing agreements with the European Medicines Agency, Health Canada, and Swissmedic to "help assure that legal barriers do not inhibit critical communication between these agencies and FDA."
"Among the lessons we have learned from this year's events at Chiron is the need to enhance our international regulatory collaboration and harmonization efforts," Crawford told lawmakers. Recent news reports suggest that the Bush administration's 2006 budget will call for increased inspections at flu vaccine manufacturing plants, although inspections at offshore plants that produce other drugs could be cut by 6%. The FDA may inspect overseas plants once a year, rather than every two years.
So can other companies avoid Chiron-like lapses in GMP? Experts agree that communication with the FDA or other regulatory agency is key, particularly just before, during, and after an inspection. All regulatory requirements that seem unclear should be discussed with inspectors and regulatory agencies. Experts also suggest that in light of those requirements, firms should evaluate every aspect of production including people, procedures, equipment, materials, record keeping, audits, management, and training. Sometimes, this may require hiring an in-house quality control expert.
"Attend GMP seminars and courses," Boehm says. "Transfer agency regulations into company regulations. Hire outside consultants. Join discussion groups with other companies. Learn from internal and external audits and inspections."
A thorough review of the FDA Form 483 submitted to Chiron would "be of immense value" to the quality control experts at any pharmaceutical manufacturer, Chisti says. "Companies do not need to do anything new," he says. "Rigorous compliance with the well-known [FDA] regulations is quite sufficient to prevent these kinds of problems from arising."