BY CAROLYN MATHAS
Emeryville, CA — After discovering serratia marcescens bacterial contamination in what it claims was a “limited number of lots” of its Fluvirin flu vaccine late this summer, Chiron Corp. (www.chiron.com) quarantined the approximately 46 million doses manufactured at its Liverpool facility and began an investigation into the cause of the contamination.
The rod-shaped bacteria, which found its way into a manufacturing cleanroom, is known to cause urinary tract and wound infections, and pneumonia. What makes the microbe particularly dangerous is its resistance to antibiotic treatment. The bacteria are often found growing on medical equipment, in petri dishes, saline irrigation solutions, and in other hypothetically sterile solutions.
Several regulatory bodies soon became involved in Chiron's internal investigation, including the Food and Drug Administration (FDA; www.fda.gov), and the Centers for Disease Control (CDC; www.cdc.gov).
The U.K. Medicines and Healthcare Products Regulatory Agency (MHRA; www.mhra.gov.uk), which conducted an on-site inspection in late September, suspended production in the Liverpool plant some six weeks after Chiron announced that, “In conducting final internal release procedures for our Fluvirin influenza virus vaccine, our quality systems identified a small number of lots that did not meet product sterility specifications….”
Vicky Wyatt, press officer at MHRA indicated, “The reason for the suspension of the license was because of concerns around the manufacturing process and microbial contamination of the product.” She declined to give specific details, citing manufacturing processes confidentiality.
The MHRA's position is that despite Chiron's internal investigation and testing, the process to ensure contamination-free vaccine to the U.K. was not in place.
Howard Pien, president and CEO of Chiron, called the MHRA action “disappointing and unexpected.” In a press briefing following the decision, Pien said, “When we first detected this sterility issue, we began a program that consists of retesting all of the product to establish a possible explanation as to how the issue arose in the first place—and then, eliminating all alternative explanations so that we can get to the probable root cause.”
Unlike medical devices whose parts are approved, mass-produced, and distributed, vaccines must go through a lot-release process. Lots are tested and protocols are reviewed from the testing for sterility, potency, stability, and identity of the product.
With influenza vaccines such as Fluvirin, the process takes months and requires hundreds of millions of specially raised chicken eggs. Once manufacturing and testing halted in Liverpool, there was no hope to begin the process in time to produce enough vaccine for the season.
Until the FDA was notified of the MHRA's decision to suspend production on October 5, the agency claims having no prior knowledge of the severity of the situation. “Based on the information provided in August, which included a press conference held by Chiron to provide up-to-date information based on what we were aware of, the company indicated only that they had identified lots that had some level of bacterial contamination and enacted their quarantine,” says FDA press office spokesperson Paul Richards. “It wasn't believed that any long-term affects on the Fluvirin supply would result.”
Citing disclosure by Chiron on its Web site and in open forum, the FDA claims that it had every reason to believe that the company had implemented corrective measures.
On October 15, the FDA completed its own on-site investigation of Chiron's Liverpool facility—with MHRA officials accompanying as observers—and determined that there were “…significant deficiencies in quality control and concerns regarding the test results.” Although it found that Chiron's retesting of unaffected lots showed no contamination, the FDA said it could not assure sterility of the lots.
According to the FDA spokesperson, “Each facility is inspected and a full Good Manufacturing Processes (GMP) inspection is conducted at minimum, based on resources, every other year. Every licensed facility, whether biologic or chemically derived, is inspected by the agency biannually.”
But the agency says complexities arise when FDA-licensed facilities are not within continental U.S. borders. The FDA requires that a U.S.-based company's overseas facilities meet the FDA's standards for GMP when the product they manufacture is only distributed in the U.S. But in the case of Chiron's Liverpool facility—the only Chiron facility licensed to manufacture Fluvirin—the product is distributed to more than one country, which means it must meet the regulatory standards of each of the ports of entry.
Because Chiron produces the same or equivalent product for other regions outside of the U.S., the FDA has no authority to circumvent or override another country's regulatory decisions.
Meanwhile, the FDA and MHRA will continue a cooperative effort to address concerns of Chiron's manufacturing quality. FDA Acting Commissioner Lester Crawford explains, “The decision to work cooperatively to evaluate the scope of contamination and evidence presented in Chiron's investigation report is a positive step to understand fully what is at issue, [and] will help to address any significant issues before production for 2005 begins.”