For history of this situation - see Sheri Nakken’s website

http://www.nccn.net/~wwithin/anthrax.htm

Inside The Pentagon

April 26, 2001

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Bioport Prepares To Address FDA’s Anthrax Vaccine Plant Concerns

BioPort, the Pentagon’s sole supplier of anthrax vaccine, expects to submit a package of information by late summer or early fall to the Food and Drug Administration addressing concerns raised by regulators about the company’s renovated Lansing, MI, manufacturing plant, according to Bob Kramer, the company’s president and chief operating officer.

The submission, called an amended biologics license application (BLA) supplement, sets in motion a process that could lead to FDA approval of the Lansing facility later this year. The Defense Department has said it will immunize service members against anthrax only with FDA-approved vaccine.

“We will submit an amended BLA supplement to the FDA that will include everything that we committed to correct and respond to” from FDA inspections conducted in November 1999 and October 2000, Kramer told Inside the Pentagon in an April 16 interview.

Kramer declined to offer an opinion as to when FDA would conclude its review of the BioPort submission. “They will go through their normal review process,” he said. “It could be a matter of months; it could take six months. It’s completely up to them to go through their own internal review process, and they will have to do another pre-approval inspection” of the BioPort plant.

Industry officials contacted last week also turned down requests to predict how quickly BioPort could get BLA approval. The FDA at press time (April 25) declined to comment on how long the approval process would take once data is obtained from BioPort.

BioPort purchased the Lansing, MI, plant from the state of Michigan in 1998; the state had previously produced FDA-licensed vaccine there for military use. FDA inspections—in 1993, 1994, 1995 and 1996 -- revealed “significant deviations” from agency standards at the facility, and another, in 1998, uncovered stability, sterility and validation problems with the vaccine production process (ITP, March 26, 1998, p1).

Because of those problems, and to expand production capacity after the Defense Department announced plans for a mandatory anthrax vaccination program in December 1997, the Lansing plant was renovated. The project kicked off another round of inspections by FDA officials to make sure vaccine produced there meets standards for safety, sterility and potency.  Approval of the company’s BLA submission depends on addressing concerns raised in those inspections.

A pre-approval inspection took place in 1999 between Nov. 15 and 23. In a “483” report that summarized results of that inspection, FDA officials said the manufacturing process for making anthrax vaccine “is not validated” (ITP, Dec. 16, 1999, p1).

Last October, the plant was inspected by the FDA’s Team Biologics, a group of investigators who specialize in reviewing good manufacturing practices for vaccine manufacturers. The team’s subsequent 483 report, dated Oct. 26, 2000, identified problems with the company’s filling suite and questioned the sterility of products filled there, among other things (ITP, Nov. 16, 2000, p3). The filling suite was not part of the renovation to the anthrax vaccine production facility.

In the meantime, DOD was faced with a shortage of vaccine, which led Pentagon officials to dramatically scale back the vaccination program in July. Vaccine administration was suspended for all troops except those deploying for an extended time to high-risk regions (ITP, July 20, 2000, p1). Then-Deputy Defense Secretary Rudy de Leon expressed hope at the time that the program would be back on track by January 2001.

Last November, a BioPort source told ITP that the company expects to garner FDA approval for anthrax vaccine as early as this month. “We’re still on track to get FDA approval in the second quarter of calendar year 2001,” the source said. “Once approved, production could begin within a matter of weeks.”

Typically, it takes 18 to 24 months to approve a BLA, company officials say.  BioPort submitted its original BLA on Aug. 31, 1999.

But company officials reassessed how long it will take to get BLA approval in the wake of the Team Biologics inspection.

“Back a year ago, certainly before the Team Biologics inspection in October, we were anticipating that we would be able to submit everything to the FDA identified in the November 1999 inspection . .  . in the first part of this year and potentially have the approval sometime in the second quarter of this year,” Kramer said.

After last year’s inspection, the company focused on addressing concerns with the filling suite, which meant a delay in when the company could fully address all the concerns raised in plant inspections, he added.

The thorniest issue raised in the November 1999 inspection was the need to validate the process for making anthrax vaccine, company officials say. In the past few years, FDA has refocused its efforts on ensuring good manufacturing practices among vaccine producers through process validation. The goal has been to place vaccine makers under the same kind of scrutiny—for good manufacturing practices—traditionally reserved for drug makers.

“The FDA realized that not just BioPort, but all other vaccine manufacturers, have never gone through extensive process validation,” Kramer said. “They have done that with drug manufacturers but not vaccine manufacturers. So what they asked us to do as a result of the November [1999 pre-approval inspection] was to conduct process validation, which to their way of thinking, and we agree, ensures consistency of manufacturing batch after batch, dose after dose.”

Going through process validation is time-consuming, Kramer says, because “of our fermentation process. Normally, from beginning to end it will take approximately four-and-a-half months to manufacture a lot of product. And because of the lengthy manufacturing process, when we were instructed to conduct process validation on a step-by-step basis, it takes time.”

Process validation requires more than 30 protocols and technical studies that must be completed in a specific order. “We have essentially completed all the 30 protocols and technical studies; we have successfully executed all of those requirements to conduct process validation,” according to Kramer. “We’re now in the process of packaging all the data to support that . . . in order to submit to the FDA later this summer.”

BioPort plans to address concerns raised last year about its filling suite by outsourcing the work, Kramer said. The company’s filling suite is an “older facility and does not have state-of-the-art equipment,” he added.

“In the last two-and-a-half years, we have identified the need to have a redundant filling capability in addition to our own facility to have a second method of filling our product for risk mitigation,” Kramer said. “And we had established a strategy a couple of years ago to have a contract filler [as] the redundant provider of filling capacity for BioPort.

“With the Team Biologics inspection in October 2000, and the questionable sterility assurance in our filling facility, we decided to basically decommission our filling facility and aggressively pursue a contract filler as the primary filling solution for our product,” he continued.

“It’s not that we will not do any more work” on the BioPort filling suite, Kramer added. “We will not fill product in that facility until such time as we have completely addressed all FDA compliance issues.”

BioPort has selected and signed a contract with another company to serve as BioPort’s contract filler, but Kramer would not divulge the name of that company at this time. A company spokeswoman told ITP this week that BioPort wants to bring its new contractor up to speed on public affairs issues associated with such a high-profile contract. BioPort could announce the contract award next week.

Kramer did say that the contract filler is not located in Lansing. In addition, the contractor is “an independent, third-party manufacturer, and they have their own dedicated facility that we will be sending our product to in bulk form. . . . So they will not be using our facility; we will be sending product to their facility,” he said.

“We are in the process of qualifying or validating their capability to fill our product,” Kramer said. “It’s an extensive process, as all FDA compliance requirements are, and we are aggressively working with this third party to qualify them [as] our filler.”

The steps taken to get BioPort’s BLA approved are separate from the FDA’s process for qualifying the contract filler, the spokeswoman said.

While working on addressing the agency’s concerns about the production plant, BioPort is making anthrax vaccine under guidelines of studies “we went through for process validation,” she said last week.

“The purpose of that is . . . to be able to qualify and validate our contract filler and [to make sure] the product will be used for [military] purposes as soon as we get FDA approval,” according to Kramer.  “When approval comes, we won’t have to wait four-and-a-half months to then have product.”

But critics of the Pentagon’s anthrax vaccine program are less confident than Kramer about the prospects of FDA approving BioPort’s BLA for the Lansing plant. Congressional sources who oppose the program say concerns linger about BioPort potency tests using guinea pigs, and getting FDA approval for the contract filler just adds another obstacle to winning full FDA approval for anthrax vaccine production.

BioPort “continues to find more problems than they solve,” one of the congressional sources said last week. “They’re chasing the time line for approval over the horizon. I don’t think they’ll ever even catch it.”

In an April 17 interview, Lawrence Halloran, staff director and counsel for the House Government Reform national security, veterans affairs and international relations subcommittee, said the main problem is that BioPort is trying to put an antiquated, 1960s to 1970s-era manufacturing process through a modern regulatory approval process. “It won’t work,” he said. “It’s like trying to put an Edsel through a modern emissions inspection.”

The subcommittee’s chairman, Rep. Christopher Shays (R-CT), is one of the most vocal opponents of the DOD anthrax vaccine program. Last year, he led a group of lawmakers who called for suspending the mandatory program (ITP, June 1, 2000, p1).

The BioPort spokeswoman expressed confidence this week that issues surrounding potency tests with guinea pigs are being resolved. “We acknowledge we’ve had issues, but we’re on target to submit in May the data FDA needs to look over the methodology for using [guinea pigs] for potency tests,” she said.

The Pentagon’s use of anthrax vaccine has been attacked on a number of fronts. Some critics of the vaccination program argue that the vaccine—produced before the Lansing plant was renovated—is unsafe and has caused widespread adverse reactions among service members. Others say the vaccine is not supported by enough peer-reviewed scientific literature to justify its use in the services (ITP, April 13, 2000, p1). Some lawmakers say the anthrax program has hurt DOD recruiting and retention efforts and expressed concerns about the legal basis for mandatory vaccinations (ITP, April 20, 2000, p1).

On the other hand, DOD maintains that the anthrax vaccine, licensed by the FDA for decades, is both safe and effective.

Pentagon officials also say it is one of the most thoroughly studied in history.

Last May, Charles Cragin, then-principal deputy assistant defense secretary for reserve affairs, said that of all those who have taken the vaccine, only 31 have required hospitalization. And of those 31, only six have been determined by an independent panel of experts convened by the U.S. Department of Health and Human Services to have illnesses caused by the anthrax vaccination. The six service members were granted waivers from receiving future anthrax vaccinations, he said.

·        Keith J. Costa

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ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.