Anthrax vaccine audit gives Pentagon, Congress concern.

A routine audit of Michigan Biologics Products Institute of Lansing, MI, stirred controversy about the safety of an anthrax vaccine that reverberated all the way up to the Pentagon and Capitol Hill.

The beginning of the controversy for Secretary of Defense William Cohen was when the "Team Biologics" inspection turned up 53 deviations resulting in a 19-page 483. Remarkably, the facility, then owned by the state of Michigan, managed to dodge a warning letter, according to agency records.

The Feb. 4-20, 1998, inspection led investigators to conclude in the records that "the manufacturing process for anthrax vaccine is not validated," citing 13 specific instances of validation failures, including:

* Qualify a formulation tank for long-term storage of bulk anthrax.

* Qualify a formulation tank for mixing time to demonstrate homogeneity (the 483 noted that the product "settles quickly in the tank").

* Perform media fill challenges.

* Validate an unnamed substance as a sporicide.

* Validate analytical methods with regard to accuracy, precision, linearity and specificity.

* Validate time that subplots are held (subplots were noted to have been held for up to three years.

* Validate cleaning of product contact equipment.

* Validate transportation of water for injection (WFI) "to assure that the WFI retains its critical quality attributes."

Potency testing also was deemed lacking because procedures called for "testing one finished product vial, an aliquot from the formulated bulk tank or a pilot bulk sample." The 483 stated that Michigan Biologics had no "data demonstrating that these samples are representative of the lot." The letter also noted that "expiration dates are assigned based on the latest valid potency test, [but] there is no correlation between this date and formulation of bulk or filling of the finished product."

The fourth and fifth citations on the 483 probably had as much to do with the anxiety raised over the vaccine's efficacy and sterility. The fourth observation stated that "there is no justification for redating lots of anthrax vaccine that have expired." This section also stated that "there is no documentation of testing for container/closure integrity or container/ closure compatibility for periods up to seven years."

In the fifth section, the 483 noted that "the firm's stability program did not start until 1997. There is no justification for placing lots manufactured as early as 1991 into the stability program." FDA also pointed out that "the firm does not have a system in place to investigate and report stability failures." This citation then detailed seven instances of stability failures, including three lots manufactured in 1991.

The 483 noted also that the firm failed to investigate seven instances of lots failing potency tests that were never investigated.

Michigan sold the institute last year to BioPort, whose ownership team includes retired Adm. William Crowe, the one-time chairman of the Joint Chiefs of Staff, and supporter of President Clinton in his first run for the presidency in 1992.

According to an article in the July 10 issue of "Lancet," the British medical journal, BioPort was experiencing a cash-flow crunch and had asked the U.S. government "to advance it $10 million, allow it to sell as much as 20% of its production to outside customers, and pay substantially more per dose for the vaccine - perhaps as much as three times the price set in the original agreement."

Critics have weighed in generously on both sides, but the powers that be in Congress tend to have taken a pro-regulatory stand.

Rep. Christopher Shays (R-CT), who spent much of the last four years seeking tougher FDA regulation of biologics as chairman of a House oversight committee, noted that the Pentagon's credibility was shaky on such matters. He noted that "radiation testing, Agent Orange, the reckless use of experimental drugs and the mysterious Gulf War illnesses have made military men and women understandably distrustful of the Pentagon on medical matters."

House steps in

In December, members of the House Government Reform and Armed Services committees asked FDA to put the vaccine back on IND status. The move was designed to force the agency to readdress data used to approve the product.

Committee Chairman Dan Burton (R-IN) and Shays, now chairman of the National Security Subcommittee, were among the signatories, and the text of the letter was attributed to Rep. Walter Jones (R-NC), who is on the Armed Services Committee.

BioPort has filed a new BLA for the facility, which it recently overhauled. House members evidently pressed the agency for information on the BLA, but the agency refused due to the fact it contains confidential business information.

Responding to the congressmen, FDA Associate Commissioner for Legislation Melinda Plaisier assured that the agency "will not approve an application until a manufacturer demonstrates that a product can be consistently manufactured under...GMPs to meet product specifications." Plaisier also commented that proposed rules governing animal studies when human studies cannot be ethically conducted were published on Oct. 5 and that the final rule would not be codified until docket respondents had made their opinions known.

On the other side, critics have defended FDA and the Defense Department. In the Dec. 8 edition of "The Journal of the American Medical Assn.," a letter signed by Drs. Arthur Friedlander, Phillip Pittman and Gerald Parker stated: "While the possibility of a rare, previously unknown adverse effect occurring during large-scale use of [the vaccine] exists, there is no evidence that such problems have occurred in nearly 30 years of use," or in FDA's Vaccine Adverse Experience Reporting System. The authors are affiliated with the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick, MD.

In the Dec. 15 "Wall Street Journal," conservative writer Michael Fumento - who frequently challenges the benefits of government regulation and perceived risks -- stated that of 352,000 persons vaccinated since 1970, only 362 adverse events have been reported, "and most of those came after the negative publicity began." Fumento went on to insist that "the government has already been far too craven in placating Gulf War syndrome activists. If it caves in to the anthrax vaccine hysteria, it could cripple America's ability to defend itself."

Michigan Biologic Products Institute/Bioport, 2/4-20/98, Doc. 108530M, $19.50 plus retrieval.

RELATED ARTICLE: The Checklist - Michigan Biologics Products Institute, 'Team Biologics'

* Process validation