Questions & Answers
Anthrax - Production Issues
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Production Issues

Questions
  1. The production facility for the anthrax vaccine, located in Lansing, Michigan, changed ownership in 1998. Who are the current owners?
  2. Did the Food and Drug Administration revoke Emergent BioSolutions' license to manufacture anthrax vaccine?
  3. The manufacturing facility owned by Emergent BioSolutions was renovated. Was this due to any findings made by the inspections by the Food & Drug Administration?
  4. There have been questions raised about the anthrax vaccine due to the results of the FDA inspections over the past few years. Are there reasons to be concerned about the inspection results?
  5. Is there a connection between deficiencies found in the 20 February 1998 FDA Inspection Report and the fact that MBPI suspended anthrax vaccine production?
  6. Given the nature of the problems identified by the FDA in their inspection of the Michigan Biological Products Institute (now BioPort) in 1996, what safeguards did DoD take to assure that the anthrax vaccine is safe and effective?
  7. Emergent BioSolutions recently received a full go-ahead from FDA. What did it take to earn this FDA approval?
  8. Since 1970, has anthrax vaccine been subject to additional FDA evaluation or testing?
  9. What is required before releasing the anthrax vaccine into interstate commerce?
  10. Is it unusual for a vaccine to be manufactured by only one company in the United States?
  11. Why was supplemental testing ordered for some lots of the anthrax vaccine by the Department of Defense? What tests are involved?
  12. Since 1970, how many times has FDA inspected the anthrax vaccine production facility in Lansing?
Answers
  1. The production facility for the anthrax vaccine, located in Lansing, Michigan, changed ownership in 1998. Who are the current owners?

    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.



  2. Did the Food and Drug Administration revoke Emergent BioSolutions' license to manufacture anthrax vaccine?
    No. Emergent BioSolutions' predecessor, the Michigan Biological Products Institute (MBPI), owned by the State of Michigan, approved renovations in 1995 for the Lansing facility. In 1997, the Food and Drug Administration (FDA) issued a notice of intent to revoke licenses issued to MBPI. MBPI responded within 30 days with a strategic plan for compliance to FDA standards. The manufacturer voluntarily closed the anthrax vaccine production line in January 1998 for renovation. Emergent BioSolutions submitted a highly detailed set of quality control documents to FDA in fall 2001. FDA approved Emergent BioSolutions' facilities and processes, as they relate to the manufacture of anthrax vaccine, on January 31, 2002.

  3. The manufacturing facility owned by Emergent BioSolutions was renovated. Was this due to any findings made by the inspections by the Food & Drug Administration?

    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.



  4. There have been questions raised about the anthrax vaccine due to the results of the FDA inspections over the past few years. Are there reasons to be concerned about the inspection results?

    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.



  5. Is there a connection between deficiencies found in the 20 February 1998 FDA Inspection Report and the fact that MBPI suspended anthrax vaccine production?
    There is no connection between the deficiencies found on the 20 February 1998 FDA inspection report and the fact that MBPI ceased production of anthrax vaccine in its original production suite. FDA did not order MBPI to suspend production. DoD in coordination with MBPI determined several years ago that the current production line would require scheduled renovation. The start of the renovation was contingent upon MBPI completing the production requirements needed to meet the terms of the production contract (DAMD 17-97-D1139). MBPI fulfilled the contract in December 1997, and the planned renovations began shortly thereafter.

  6. Given the nature of the problems identified by the FDA in their inspection of the Michigan Biological Products Institute (now BioPort) in 1996, what safeguards did DoD take to assure that the anthrax vaccine is safe and effective?
    DoD directed that supplemental testing be done on all lots in the stockpile at MBPI produced under contract DAMD 17-97-D0003. Of these lots, only lots of vaccine that passed supplemental testing were approved for shipment and use by DoD and Coast Guard personnel.

  7. Emergent BioSolutions recently received a full go-ahead from FDA. What did it take to earn this FDA approval?
    Emergent BioSolutions ceased manufacturing to renovate its vaccine production facility in February 1998. When the manufacturing process or equipment in a renovated facility or establishment differs materially from that in the former facility or establishment (CFR 21.314.70), a Biologics License Application (BLA) Supplement must be submitted for Agency approval before production can be resumed. Emergent BioSolutions' BLA Supplement consisted of many parts. Included in the BLA supplement were data validating an updated potency test, process validation test results, and information concerning the qualification and testing of three fermentation systems, raw material quality and acceptance criteria and updated procedures for operating the new facility. In addition, Emergent BioSolutions submitted test data to demonstrate that the potency, safety, sterility and composition of the vaccine were maintained when Hollister-Stier LLC, Emergent BioSolutions' contract filling facility in Spokane, WA, filled AVA into vials for distribution. Emergent BioSolutions produced three separate lots of vaccine in the renovated facility. These were analyzed to assure consistency of production. The results were submitted to the FDA for approval. After the FDA received Emergent BioSolutions' BLA supplement, a review committee was established consisting of personnel from the following Offices: Vaccines Research & Review (OVRR), Biostatistics & Epidemiology, and Compliance & Biologics Quality. This committee completed an in-depth review of the submission. An integral part of the review included an on-site inspection by the FDA of production activities at both Emergent BioSolutions and Hollister-Stier. The inspectors reviewed hundreds of documents and physically inspected areas and processes associated with the manufacture and vialing of anthrax vaccine. Following these inspections, Emergent BioSolutions was granted approval for the renovations to the AVA manufacturing suite on December 21, 2001. Hollister-Stier was approved as a contract manufacturer for the vialing of AVA on January 31, 2002.

  8. Since 1970, has anthrax vaccine been subject to additional FDA evaluation or testing?
    Some lots of the anthrax vaccine have been tested and evaluated in accordance with procedures approved by the Food & Drug Administration (FDA) for extending the shelf life of vaccines. The approved procedure used to extend the usable life of the anthrax vaccine is the same procedure applied to any other vaccine. This was funded under a DoD stability-testing contract.

  9. What is required before releasing the anthrax vaccine into interstate commerce?
    Each lot of vaccine is approved and released by the Food & Drug Administration, after specific tests for potency, purity, safety, and sterility. General Safety: General safety is determined in the following manner: two animals each of two species (mouse and guinea pig) are given doses of the vaccine and observed for 7 days for adverse effects. Each animal must survive the test period, gain weight, and show no adverse reaction. Three vials per lot will be tested for safety. General safety tests are required for lot release. Other safety studies have been performed that establish that anthrax vaccine adsorbed has a side-effect profile similar to that of other vaccines. Potency: Potency is determined in the following manner: guinea pigs are vaccinated with one of several serial dilutions of vaccine or no vaccine (control group). All guinea pigs are injected with known amounts of virulent anthrax 14 days after vaccination, and average time to death is calculated for each group. The test vaccine must be no less potent than the FDA's reference vaccine. Sterility: Sterility testing is performed on sub-lots and on final product to detect the presence of bacterial contamination. Twenty vials per lot will be tested for sterility. Purity: Requirements exist calibration and controls. Purity testing consists of four individual tests for aluminum, benzethonium chloride, sodium chloride, and formaldehyde. One vial per lot will be tested for purity.

  10. Is it unusual for a vaccine to be manufactured by only one company in the United States?
    No. About half of FDA-licensed vaccines are produced by only one manufacturer. These include: Japanese encephalitis vaccine, measles vaccine, meningococcal vaccine, mumps vaccine, pneumococcal 7-valent vaccine, pneumococcal 23-valent vaccine, injectable poliovirus vaccine, rubella vaccine, live typhoid vaccine, injectable typhoid vaccine, varicella vaccine, and yellow fever vaccine. Vaccines available from multiple manufacturers include: diphtheria toxoid, tetanus toxoid, pertussis vaccine, Haemophilus influenzae type b (Hib) vaccine, hepatitis A vaccine, hepatitis B vaccine, influenza vaccine, and rabies vaccine.

  11. Why was supplemental testing ordered for some lots of the anthrax vaccine by the Department of Defense? What tests are involved?
    The Secretary of Defense ordered supplemental testing of all lots of anthrax vaccine in the Lansing stockpile when he authorized the Anthrax Vaccine Immunization Program in December 1997. DoD requested the supplemental testing because of FDA concerns, raised during routine inspections, about the facility's quality control procedures. Supplemental testing repeats the original FDA required tests for sterility, purity, potency, and general safety. Supplemental tests were performed by the manufacturer and overseen by an independent contractor (Mitretek, McLean, Virginia). Supplemental tests are not performed on lots 040 or higher, because these lots underwent the same tests for sterility, purity, potency, and general safety more recently and the data were independently reviewed by the FDA to determine whether the lots meet approval criteria for FDA release. Lot-release tests performed by the manufacturer include: general safety, purity, potency and sterility (see question 8 for a description of each). Supplemental testing reports may be accessed at the AVIP web site.

  12. Since 1970, how many times has FDA inspected the anthrax vaccine production facility in Lansing?
    The FDA or the National Institute of Health (NIH) has inspected MBPI's (Emergent BioSolutions') Lansing facilities more than 50 times since 1969. Each inspection focused on one or more of three manufacturing activities: bacterial vaccines and toxoids, viral vaccines, or plasma derivatives. Examined during each of these inspections were elements common to the manufacturing of all products at the Lansing site, including the manufacture of anthrax vaccine. The anthrax vaccine manufacturing facilities specifically have been inspected 12 times in the years following licensure. Further, the FDA did not force Emergent BioSolutions to close its facility and rebuild. The decision to renovate the anthrax vaccine manufacturing facilities was made in an effort to meet the demand for vaccine from the Department of Defense.