The manufacturing process for Anthrax Vaccine is not validated.[i]

The anthrax vaccine’s manufacturer has had an interesting ownership history, beginning in 1968 as the Michigan Department of Public Health (MDPH), a public entity that manufactured the earliest vaccine through 1997, when it spun off its ‘biologics’ division into a for-profit entity, the Michigan Biologic Products Institute (MBPI), BioPort, Inc. quickly bought MBPI in 1998. While management and ownership structure changed, one thing has remained remarkably consistent: how badly the vaccine has been manufactured from when it first began being inspected. BioPort/MBPI/MDPH has continued to violate the regulations governing the manufacture of the vaccine and current Good Manufacturing Practices (cGMP) for as long as it has records of inspections. The regulations regarding the manufacture of biologic products is fairly tedious, but the underlying philosophy can best be summarized by the first pull-quote above: the manufacturing process for the anthrax vaccine is not validated.

Because Anthrax Vaccine Adsorbed (AVA) is a biologic product designed for human consumption, it is controlled by very stringent requirements. A GAO report pointed this out and explained the necessity for it:

The inspection process for ensuring vaccine safety is more stringent and complex than for chemical drug because vaccines have three distinguishing features. First, either they have no clearly chemically defined composition, or chemical analysis is extremely difficult. Second, proper evaluation of vaccines generally requires measuring their effects in animals. Finally, quality cannot be guaranteed from final tests on random samples but only from a combination of in-process tests, end-product tests, and strict controls of the entire manufacturing process.[ii]

Biologic products are regulated by the Public Health Service Act (PHS) and the Federal Food, Drug, and Cosmetic Act (FDCA). 42 U.S. Code §262 describes the regulation of biologic products according to the PHS Act. Chapter 9 of Title 21 of the U.S. Code contains the FDCA.

The FDCA provides the following definition of an adulterated drug:

A drug shall be deemed to adulterated (a)(1) (A) if it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby it may have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controls for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this chapter as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.[iii]

In sum, a drug is adulterated if it is either (a) made under “insanitary conditions” or, (b) if the manufacturer does not comport with current Good Manufacturing Practices (cGMPs). The Code of Federal Regulations, specifically 21 C.F.R. §600 and following, sets forth the current Good Manufacturing Practices for Biologic products. 21 C.F.R. §601.12 reads, in part:

(a) General. As provided by this section, an applicant shall inform Food and Drug Administration (FDA) about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling, established in the approved license. Before distributing a product made using a change, an applicant shall demonstrate through appropriate validation and/or other clinical and/or non-clinical laboratory studies, the lack of adverse effect of the change on the identity, strength, quality, purity, or potency of the product as they may relate to the safety or effectiveness of the product.

(b) Changes requiring supplemental submission and approval prior to distribution of the product made using the change (major changes). (1) A supplement shall be submitted for any change in the product, production process, quality controls, equipment, facilities, or responsible personnel that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the product as they may relate to the safety and effectiveness of the product. (2) These changes include but are not limited to: (i) Changes in the qualitative or quantitative formulation or other specifications as provided in the approved application or in the regulations; (vi) Changes which may affect product sterility assurance, such as changes in product or component sterilization method(s), or an addition, deletion or substitution of steps in a aseptic processing operation.

Until a 1988 contract with the DoD, the production of Anthrax Vaccine Adsorbed (AVA) was infrequent, a batch being produced every three to four years, with the largest being 7500 doses. MDPH had one production line for AVA that they alternately used for other vaccine products. The 1988 contract with DoD called for a drastic increase in the amount of production of the anthrax vaccine: 300,000 doses over a five-year period. The only possible way to meet the requirements of the DoD contract was to increase the production facility itself. One production line would simply not meet the demands of that new contract.

The first production line, and only one licensed by the FDA, was built around a 100-liter sintered glass-lined fermenter, where the anthrax bacteria was cultured and grown. In 1990, two new stainless-steel fermenters were added to grow the bacteria. In 1991, the original, licensed glass-lined fermenter was removed and two more new stainless-steel fermenters were added, bringing the number of production lines to four.

None of the new fermentors were approved by the FDA prior to being installed and beginning to produce the anthrax vaccine. This was not news to anyone; MDPH was aware of the need for prior FDA approval. Documents show that Dr. Robert Myers, the Responsible Head of MDPH, was well-briefed in the FDA requirements for amending the Establishment License Agreement (ELA). Dr. Myers notified the Center for Biologics Evaluation and Research (CBER) in June 1990 that BioPort would replace the approved fermenter and chill tank on or about 15 August 1990 with a new fermenter. A 9 July 1990 Conversation Record by FDA employee Rebecca Devine to Dr. Myers indicates that he was informed that this would be considered a major change and should be submitted in the form of an ELA amendment. An FDA official also communicated to Dr. Myers that the new equipment was considered a “major change” to the facility’s Establishment License Agreement (ELA) in December 1990.[iv]

MDPH applied for the necessary amendment to the ELA in December 1990 for the first two new fermenters installed in that same year.[v] This ELA amendment request indicates, however, that the renovation had already taken place. Additionally, the two production lines added in 1990 consisted of stainless-steel fermenters, stainless-steel chill tanks, and low-protein-binding nylon membrane filters, while the production line in the original ELA consisted of glass-lined fermenters, a glass-lined chill tank, and sintered-glass filters. The 1990 ELA amendment request, while indicating that stainless-steel equipment was being used, failed to identify this as a change in equipment type for the additional production lines. As a result, the FDA was unaware of the substantial likelihood of the amendment request to have an adverse effect on the “identity, strength, quality, purity, or potency of the product as they may relate to the safety and effectiveness of the product.” Finally, the FDA did not approve these fermenters in 1993.[vi] No amendment was ever sought for the subsequent two stainless steel fermenters, nor was there ever an amendment made to the Product License Amendment for this change in how the cultured bacteria was being grown.

More troubling is that a July 1990 Trip Report to the Michigan facility by a member of the U.S. Army Medical Research and Development Command (USAMRD) indicates that at least one 100-liter fermenter had been added to the AVA production line and that a recently delivered 100-liter fermenter could be diverted from production of another vaccine to the AVA production line. A September 1990 Trip Report to the Michigan facility discusses the necessity and the ability to put the recently acquired additional fermenter into AVA production. Also discussed is the total number of fermenters that the facility could hold, i.e. three additional fermenters for a total of four fermenters producing AVA. This Trip Report also indicates that FDA must approve the change in fermenter types from glass-lined to stainless steel and that FDA approval will require developing the definitive data that the product from the stainless steel fermenters is the same as the glass-lined fermenters.

It also bears noting that each of the production lines did not produce individual lots of the vaccine. After 1990, while the old (licensed) line was running, alongside the  two new stainless-steel lines, each production line’s output was stored as a sublot and then combined for shipment to form what was labeled as the “final anthrax vaccine” lot (FAV-001, FAV-002, etc.). The stainless steel sublots supposedly produced a more potent vaccine. As a result, MDPH delivered a least one dose of AVA to DoD that was produced after the major manufacturing change had occurred and before the ELA amendment was approved.

As if all of the above-listed, unapproved changes were not enough, MDPH changed the type of filter used in the manufacturing process. This filter is the only part of the manufacturing process that purifies the vaccine. There were no amendments sought to either the ELA or the PLA. This means that all of the anthrax vaccine produced from these lines was and is, by definition, adulterated. Every dose delivered since the 1990 manufacturing change has occurred without an ELA amendment for the change in filter type. Lest this appear to be scientific or legal quibbling, when the FDA conducted inspections through 1995, this specific filter would fail inspection.

The FDA inspectors conducted numerous inspections of the anthrax production facility over some 7 or 8 years. During this time, the inspectors would cite repeated and serious problems with the manufacturing process. Below is a bulleted list of some of the major findings.

1988.[vii]

“There is no written procedure for assessing stability characteristics of final biological products.”

“No direct physical accountability for packaged undated anthrax vaccine which was stored alongside of packaged and dated vaccine with the same lot number. Nine hundred and six vials of unfinished vaccine were distributed freely in 3 cardboard boxes with unknown number of vials in each carton. Removal of vials as needed was not indicated.”

1990.[viii]

“Anthrax prod. fac. was observed to be in a state of general disrepair in that there was: (A) Paint peeling from the walls (B) Exposed light fixtures (C) Cracked ceiling (D) Exposed raceways (E) Dirt & filth & dust on overhead pipes (F) Cluttered work space.”

“Anthrax prod. records are inconsistent in that procedures used to formulate Lot #21 are different from those used to formulate Lots #25, 26 & 27 in that media is autoclaved for sterilization for Lot #21 and filtered for sterilization for Lots #25, 26 & 27.”

1992.[ix]

“Changes in the manufacturing methods for…were not submitted as amendments to the product license application prior to releasing the material for distribution…”

“No SOP [standard operating procedure] exists to describe procedures for handling potentially infectious material…”

1993.[x]

“There are insufficient personnel to assure compliance with current GMP regulations, e.g., failure to report changes in manufacturing, failure to maintain calibration records adequately, failure to adequately validate equipment used in the formulation or testing of product.”

1994.[xi]

“There are insufficient personnel to assure compliance with current GMP regulations, e.g., failure to maintain calibration records adequately, failure to maintain environmental controls adequately in that production area temperatures were above 80°F, and failure to submit changes to CBER.”

“There is no annual review of production batch records [anthrax].”

“Raw material [anthrax vaccine materials] stored in an unapproved warehouse, building (redacted) i.e., no ELA [establishment license application] supplement has been submitted for this area.”

1995.[xii]

“the company did not inform FDA of the procedural and equipment change during the production of…”

“facilities and equipment were not adequate.”

“SOP’s did not exist for many procedures.”

“SOP’s were incomplete or incorrect.”

“SOP’s were not adhered to.”

Frequent contamination during vaccine manufacturing was documented but not investigated.

Finally, on June 22, 1995, the CBER Inspection Task Force recommended the issuance of a Warning Letter to MDPH. Another Warning Letter was issued to MDPH on 31 August 1995. Subsequent inspections found that the warning had no effect on the quality of the product being produced.

1996.[xiii]

“The firm had not completed cleaning validation studies for routine cleaning procedures on multi-use equipment.”

“Validation studies to demonstrate microbial retention and compatibility have not been conducted for sterilizing filters…”

There was condensate dripping onto open (redacted) tanks…

“There was no procedure for clean-up of live rabies virus spills…”

The anthrax production facility was not inspected because “it comes under military inspection.”[xiv]

In 1997, after some ten years of continuous violations of CGMPs, CBER issued a “Notice of Intent to Revoke” the license of MBPI.[xv] The Army responded by sending in a team to assist the manufacturer develop a “strategic compliance plan.” In January 1998, anticipating another inspection by the FDA, MBPI decided to “voluntarily” shut down its production.[xvi] An FDA inspection in February returned a report which concluded:

“The manufacturing process for Anthrax Vaccine is not validated.”

The report also noted that “[t]here are no written procedures, including specifications, for the examination, rejection, and disposition of Anthrax and Rabies.”  And, finally, what should have been reported seven years earlier: “Prior to August 1997, the (redacted) filters used for harvest of Anthrax vaccine were neither validated nor integrity tested. This filter is the only sterile filtration step in the Anthrax manufacturing process.” An inspector “questioned W. White, D. Slabbekoorn, and T. Wilsey regarding the filters used prior to this validation. Each reported that the filters used prior to the introduction of the [redacted] filters had not been integrity validated nor were they routinely integrity tested.” The filters were approved in August 1997, however, a February 1998 inspection revealed that the validation process used to gain the approval was not valid. Incredibly, the validation for the filters was not done using the anthrax vaccine. “Validation of microbial retention by the (redacted) filters used for harvest of Anthrax vaccine was performed only with (redacted) media, which is used in tetanus production. Studies were not performed using Anthrax product or media.” This means that there had been no test done to determine if the filters would even work to filter out the necessary impurities in the anthrax vaccine, but instead had been done on the tetanus vaccine.

Another finding was that “[t]he firm does not trend multiple contaminations with microorganisms in sublots.” As a result of this February inspection, MBPI “voluntarily” quarantined 11 lots of AVA. The failure of FDA to recall the quarantined vaccine and order it destroyed resulted in some of it being shipped to the Canadian military and being used on their servicemembers.[xvii] The list of violations, unfortunately, does not end here.  Another inspection took place in October 1998, finding:[xviii]

“Stability testing has not always been performed in accordance with stability protocols, for example…”

“CBER has not been notified in accordance with Error and Accident reporting of the following…

On 6/30/98, the firm installed a new reaction tank mixer on Tank (redacted). There is no data documenting that the new mixer is equivalent to the old mixer, including mixing profiles. In addition, CBER has not been notified of this change.”

Yet again, in 1999, the FDA found that “[t]he manufacturing process for Anthrax Vaccine Adsorbed is not validated.”[xix]

Thirty observations were noted. The inspection report ends with this comment.  “The observations noted in this FDA-483 are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self-audits to identify and correct any and all violations of the GMP regulation.” What is unique about these findings is not that they are out of the past trend-line of the manufacturer, but these were found at the new facility! The old facility had been razed in 1998 and a new one built in an extraordinary windfall from the U.S. taxpayers approved by the DoD, which will be discussed in some detail later. Despite all of this, in 2000:[xx]

“The design and construction…do not assure sterility of products filled…”

“The following product lots failed initial sterility testing for release or for stability testing…Investigations into these initial sterility failures are incomplete…”

“Investigations are incomplete, inaccurate, or not conducted.”

“There is no assurance equipment is operating as designed.”

In addition to these violations in manufacture, there were also significant problems in what happened to the vaccine after it was made. A product can be adulterated even after it is manufactured correctly (which didn’t happen in this case) if it is “prepared, packed, or held under insanitary conditions”. The regulations regarding processing also apply to packing and holding. Thus, “[t]he failure to comply with any regulation set forth in this part and in parts 211 through 226 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action.”[xxi]

Biologic products also have expiration dates as described in Part 600 of 21 C.F.R. Modifications to the expiration dates “shall be made only upon written approval, in the form of a supplement [amendment] of the product license, issued by the Director of the Center for Biologics Evaluation and Research.” Expiration dates are also regulated under the current good manufacturing practices. The reason for this is that biologic products by their very nature may break down chemically over time. In order to “assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in §211.166.”  21 C.F.R. § 211.166 states in part:

There shall be a written stability testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expirations dates.

In 1997, MBPI relabeled 1.5 million doses of AVA. That is, MBPI took vials of AVA that were already labeled with an expiration date and soaked the labels off. They then relabeled the vials with new expiration dates. These 1.5 million doses of AVA are adulterated for that reason alone. Also, at the time of the relabeling, MBPI had no approved stability testing program, as observed in the February 1998 FDA inspection. They also had no approved procedures for removing and relabeling filled vials of vaccine. In other words, there was no certified process to guarantee that the originally labeled vials were the same ones when relabeled. In other words, MBPI could not assure that the vials would be re-identified correctly, i.e. FAV008, or FAV009, etc. Hopefully, whoever soaked the labels off, got the right number back on the right bottle.

MBPI also “re-dated” bulk vaccine that had expired without justification or approved procedures. These doses, too are legally & scientifically “adulterated.” Both of these practices, relabeling and re-dating, require a supplement to the product license IAW 21 C.F.R. § 610.53(d). No supplement was sought or approved at the time of these events. Current good manufacturing practice regulations require compliance with these parts of the C.F.R. Non-compliance renders the drug adulterated.

There is no other way to express the violations of FDA regulations by the manufacturer of the anthrax vaccine as anything other than laughably abhorrent. Two things make it worse: First, the FDA’s failure to police a manufacturer who is wantonly violating regulations designed to protect the health of U.S. citizens, and second, the DoD’s actions in light of these continued violations, of which it had full knowledge. The public actions of both of these agencies are almost too incredible to believe in light of what both knew was going on at the production facility, but they happened. Now that we’ve considered the manufactures actions, I turn first to the DoD’s actions and then to the FDA’s.

Endnotes

[i] FDA Form 483 Inspectional Observations Feb. 4-20, 1998.

[ii] GAO Report T-NSIAD-00-48 (Oct. 12, 1999).

[iii] 21 U.S.C. § 351 (2000)(emphasis added)

[iv] Conversation record memo from Rebecca Devine to Dr. Myers, 9 July 1990.

[v] MDPH letter to CBER seeking to amend establishment license for new equipment, 6 December 1990.

[vi] CBER letter to MDPH granting approval of new equipment, 27 July 1993.

[vii] FDA Form 483 Inspectional Observations, 26-27 April 1988.

[viii] MDPH letter to CBER responding to FDA inspectional observations made on 12-13 September 1990, 10 October 1990.

[ix] FDA Form 483 Inspectional Observations, 29-31 July 1992.

[x] FDA Form 483 Inspectional Observations, 4-7 May 1993.

[xi] FDA Form 483 Inspectional Observations, 31 May – 3 June 1994.

[xii] FDA Form 483 Inspectional Observations, 23 April 1995 – 5 May 1995,

[xiii] FDA Form 483 Inspectional Observations, 18-27 November 1996.

[xiv] Summary of Findings Report, 14 January 1997.

[xv] CBER NOIR letter to MBPI, 11 March 1997.

[xvi] FDA Form 483 Inspectional Observations, 4-20 February 1998.

[xvii] Ann Rees, “Their Dangerous Dose”, The Province [Vancouver, Canada], 25 Jun 2000

[xviii] FDA Form 483 Inspectional Observations, 19-23 October 1998

[xix] FDA Form 483 Inspectional Observations, 25-23 November 1999.

[xx] FDA Form 483 Inspectional Observations, 10-26 October 2000.

[xxi] 21 C.F.R. 210(b)

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