The State of Michigan opened its first laboratory to manufacture vaccines and antibodies in Lansing in 1925, over 75 years ago, receiving license #99 to manufacture biological medications. On 7 July 1998, the State of Michigan approved the sale of the United States' only licensed manufacturer of anthrax vaccine to a for-profit company. The state-owned entity known as the Michigan Biologic Products Institute (MBPI) was sold effective 5 September 1998 to become BioPort Corporation. The facility's license is now listed as license #1260, with the sale of MBPI to Emergent BioSolutions Incorporated http://www.emergentbiosolutions.com.
Multiple shareholders own Emergent BioSolutions, whose headquarters remain in Lansing, Michigan. The two main companies that make up Emergent BioSolutions are Intervac, headed by William Crowe and Fuad El-Hibri, and Michigan Biologic Products Inc., which is made up of seven managers from the era when the State of Michigan owned the plant, headed by Robert Myers. The former state employees were specifically permitted by the Michigan State Legislature to bid on the sale. The legislators hoped that retaining local management as investors would help keep the plant and its 200 jobs in Michigan. Admiral William Crowe, Jr., is a former Chairman of the Joint Chiefs of Staff and the U.S. ambassador to Britain until 1997. Fuad El-Hibri, a U.S. citizen of Lebanese descent, transformed a British government plant for vaccine production into a successful private venture.
As Admiral Crowe testified to the U.S. Congress in October 1999, that the government's decision to vaccinate the Armed Forces was made after several years of internal analysis that culminated in a December 1997 decision. These events occurred well before the State of Michigan chose to sell its vaccine-production facilities to Emergent BioSolutions Incorporated.
The planning for renovations to the physical plant began in 1996. Construction began in early 1998 and was completed in May 1999. The Food and Drug Administration approved the renovations to Emergent BioSolutions' anthrax vaccine manufacturing facilities and processes January 31, 2002.
The FDA has steadily approved release of anthrax vaccine lots manufactured by Emergent BioSolutions ever since. Over the years, the State of Michigan appropriated money to upgrade and expand its existing facility in a staged fashion, as improvements in current Good Manufacturing Practices (cGMPs) were adopted by the U.S. pharmaceutical industry. In January 1993, FDA as part of a routine program inspected the anthrax vaccine manufacturing facility at Emergent BioSolutions. To improve its operations, a renovation to the Lansing facility was approved by the State of Michigan in July 1993 with funding coming in later years. The manufacturer closed the anthrax vaccine production line in January 1998 for planned renovation. Although the decision to close the facility for planned renovation was part of the manufacturer's facility improvement strategy, it was, in part, also based on a 1996 DoD assessment that concluded that the facility was inadequate to meet future production requirements. This renovation project cost $3.7 million and included upgrades of the anthrax vaccine manufacturing space along with the addition of a negative air pressure sink, a reach-in environmental chamber, and a state-of-the-art closed inoculation system.
In 1994, after Michigan authorities had approved the renovation schedule, the FDA conducted a rigorous inspection of Michigan's plasma-derivatives operation. Then, in 1995, the FDA issued a warning letter to Michigan concerning plasma operations and rabies vaccine manufacturing. After a November 1996 inspection, findings showed that corrections to the previous areas had not been completed. The FDA issued a "Notice of Intent to Revoke" (NOIR) letter in March 1997, threatening to begin a multi-step process to revoke Michigan's license to manufacture vaccines.
Michigan responded quickly to the NOIR letter, developing a strategic plan for compliance within 30 days. FDA later testified to Congress that Michigan "had made progress in achieving its compliance goals."
The FDA conducted a pre-approval inspection of the newly renovated production facility at Emergent BioSolutions in November 1999. The FDA inspection reported 30 observations to Emergent BioSolutions management that needed to be corrected as well as identified process validation steps that needed to be addressed for FDA to approve the new facility. FDA completed its approval of Emergent BioSolutions' physical renovations, as well as its extensive process-validation documentation in December 2001.
No. All lots of anthrax vaccine that have ever been released, including those used in the DoD's immunization program, met all FDA release criteria: general safety, purity, sterility, and potency. All stockpiled lots that have been used in the DoD immunization program have met DoD-mandated supplemental testing criteria and oversight of that testing has been provided by an independent DoD-contractor, Mitretek Systems, Inc.
Over the years the FDA acknowledged that the manufacturer was making progress in achieving compliance with FDA standards and regulations. FDA found no deficiencies serious enough to warrant recall of the anthrax vaccine, which is within FDA's authority. Link to FDA Enforcement Reports http://www.fda.gov/opacom/enforce.html.
Results of more recent FDA inspections of Emergent BioSolutions, both in Nov 1999 and Oct 2000, have indicated BioSolutions progress toward licensure in an environment of increasingly stringent FDA standards for process validation and for demonstrating consistency of manufacturing. FDA's actions in December 2001 and January 2002, approving all aspects of anthrax vaccine manufacture, reflect the FDA's satisfaction with Emergent BioSolutions' renovations and quality controls. FDA officials have visited Emergent BioSolutions several times since. FDA officials visit all vaccine manufacturers periodically.
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Related to Influenza and Other Vaccines with MF59 Adjuvant (which contains squalene as one component of the adjuvant):
In April 2000, the research project published its first peer-reviewed report, describing an enzyme-linked immunosorbent assay (ELISA) that could detect antibodies to squalene induced in mice. Use of squalene alone did not produce a significant amount of anti-squalene antibodies. A special chemical was needed to induce the antibodies against squalene in mice. After injecting mice with liposomes (fat globules) containing 71% squalene (710 million parts per billion), plus a second chemical called lipid A, antibodies to squalene were readily induced in mice. The validity of the method was established using positive and negative controls to preclude false positive and false-negative test results. The investigators concluded that squalene is a weak antigen (a weak inducer of antibodies). (Matyas et al., 2000).
By September 2001, researchers reported improving the assay and ensuring these tests were reproducible and sensitive enough to detect 80 ng/ml of anti-squalene antibody. The test was also reproducible from experiment to experiment (Matyas et al., 2001). The third study from this research effort, published in 2004, adapts the test described above so that it could detect anti-squalene antibodies if present in human serum. Serum from three groups of people were tested: retired employees of the U.S. Army Medical Research Institute of Infectious Diseases (average 68 years of age, 88% of whom received anthrax vaccine, mean = 26 doses per person) , civilian volunteers of similar age from Frederick, Maryland (none of whom received anthrax vaccine), and random blood donors from Fort Knox, Kentucky (vaccination status unknown), This next study indicates that anti-squalene antibodies are found in 7.5% of the vaccinated USAMRIID alumni, 15% of the unvaccinated Frederick civilians, and in 0% of the Fort Knox blood donors. The antibodies described in the previous sentence were a type of antibody called IgG. Researchers found another type of anti-squalene antibody called IgM in all three groups (37%, 32%, and 19%). The researchers found that anti-squalene antibodies are more common with increasing age (a characteristic also found in mice). The presence of anti-squalene antibodies was unrelated to anthrax vaccination status. They concluded that anti-squalene antibodies occur naturally in humans (Matyas et al., 2004).