US Pharm. 2012;37(12):57-59.

The FDA has had a bad taste for pharmacy compounding for at least two or three decades. This column has devoted much attention to the adversarial relationship between pharmacy compounders and the federal government in its multifaceted and, for the most part, failed attempts to curb the practice at all but the most abusive of compounders that are really behaving as manufacturers.1,2

The Fungal Meningitis Outbreak

When the fungal meningitis cases were reported as coming from a single compounding pharmacy, it looked as if the response could be one more “salvo over the bow” by the FDA in its latest attempt to blame a compounder for a tragic set of circumstances. As time has gone on, however, and the magnitude of the problem has surpassed anything possibly related to a normal compounding pharmacy, it has become clear that the source of this catastrophe is a manufacturing entity pretending to be a pharmacy. The outcome will likely set back the legitimate compounders for decades to come as reformers take to the stage. It is a lesson on how true the adage is that one bad apple can spoil the whole barrel. Differentiating between legitimate compounding pharmacies in the eyes of the public, consumers, and regulators from the likes of the Framingham, Massachusetts–based New England Compounding Center (NECC) is going to be a difficult and perhaps insurmountable challenge.

As of late November 2012, at least 35 deaths and over 500 cases of illness in 23 states had been confirmed as attributable to batches of methylprednisolone acetate and other drugs compounded by NECC. It has been estimated that as many as 14,000 people were exposed to the tainted medications.3 Medical experts predict there will be more cases in the coming weeks and months.

Vials of the medication found at the facility, waiting to be shipped, contained Exserohilum species, common environmental fungal molds found in soil and on plants, especially grasses. In more typical cases of exposure to these fungi, clinical manifestations include mycotic keratitis, endocarditis, subcutaneous phaeohyphomycosis, osteomyelitis, and sinusitis in both normal and immunosuppressed patients.4 Here, however, the contaminated drug products were injected directly into the spinal column and other tissues, causing the far more serious injuries and deaths.

Upon inspection of the NECC facilities, the FDA and state regulators found filthy, putrid conditions and a lack of normal sterilization procedures that should have been in place while compounding these products. Some of the vials examined during the investigation contained greenish-yellow discolored liquids, while others had filamentous materials floating in them. About 25% of the steroid vials examined during October were contaminated by “greenish black foreign matter,” and all of the 50 vials sent for microscopic analysis contained fungus. The pharmacist in charge of NECC told federal inspectors that the firm “used nonsterile active pharmaceutical ingredients and raw materials, with the exception of sterilized water for injection, to make the injectable steroid linked to the fungal meningitis.” FDA representatives were unable to obtain the critical documentation that NECC’s steam autoclaves were capable of achieving product sterility.

By mid-October 2012, NECC had recalled all products made immediately prior to the meningitis outbreak and is not currently operating. The Massachusetts Board of Registration in Pharmacy permanently revoked NECC’s pharmacy license and the pharmacist licenses of the three operating officers of the organiza-tion.5 The basis for this action was that medications held in the facility were not labeled with patient-specific identifiers as required by the state’s licensing regulations. This fact alone led the board members to conclude that NECC was “acting as a manufacturer” and not as a traditional compounding pharmacy within the meaning and intent of the regulations.

As might be expected with a tragedy of this proportion, Gov. Deval Patrick announced that Massachusetts will now regulate compounding pharmacies more strictly. According to the governor, the state will require “all pharmacies to submit annual reports on the quantities of medications they are producing and shipping” so that “we can identify those acting like manufacturers” rather than traditional compounders.Massachusetts will also conduct annual inspections of the 25 compounding pharmacies in the state and require them to report to state public health officials all interactions with federal authorities. “In this administration, we’re going to take a different tack,” Gov. Patrick said. “No one should live in fear that their medicine is unsafe.”6

Was This Crisis Avoidable?

Unfortunately, before its license was revoked and long before this disastrous situation became so widespread, NECC had received numerous complaints. The organization was also the subject of investigations by the Massachusetts pharmacy board that culminated in a 2006 consent agreement in which NECC agreed to rectify problems in its record-keeping and other procedures to escape more onerous sanctions. NECC had also received warning letters from the FDA.

The excuses for not shutting down this production facility—that it was just a compounding pharmacy—are suspect at best. Federal and Massachusetts officials said that they lacked clear authority to take action earlier against the now-shuttered specialty pharmacy that set off safety alarms 6 years ago. “The officials described a murky, archaic regulatory apparatus that hampered their ability to keep pace with the rapid changes in compounding pharmacies. That industry, which traditionally has consisted of mom-and-pop operations making customized medicines for individual patients, has expanded to include high-volume pharmacies that rival the production of drug manufacturers.”7 Compounding pharmacies, which custom-mix medications, fall into a gray area of federal regulation. The FDA has to a great extent left their supervision to state boards of pharmacy. Some lawmakers are now calling for the FDA to be given more authority to regulate the industry.8

Well before this outbreak, in January 2012, the facility’s own monitoring procedures had detected bacteria and molds in the “clean” rooms where the supposedly sterile vials were produced. Federal and state inspectors reported they could not find evidence that the pharmacy had moved to fix the problems it found on its own.

This flies in the face of NECC’s marketing materials claiming that the firm’s “high quality” products were made from “quality ingredients” by “extensively trained” pharmacists in a facility adhering to industry standards. In light of this outbreak, such a statement seems unfathomable. However, NECC did submit samples of its products to independent analytical laboratories for certification of sterility. One lab stated that the samples from a batch of compounded steroids found responsible for the meningitis outbreak were sterile in May 2012.9 That certification was used to market NECC’s services to a new customer, which started ordering injectable drugs from the facility. The problem was that the batch sample tested was too small according to industry standards. Two vials out of a batch of 6,528 total packages from three batch lots were submitted for analysis. The minimum sample size called for in the USP protocol, for example, would be approximately 20 vials. Some labs routinely ask for double that number to be certain of catching any contaminants.

Another problem is that NECC often shipped batches of drugs before sterility sampling results were returned to the company from an analytical lab. NECC marketing materials claimed the organization routinely quarantined batches until after sterility testing results came back negative.

The Conigliaro family enterprise that NECC was part of is extensive, ranging from recycling services to an actual pharmaceutical manufacturer, Ameridose. The compounding center had become a major supplier of tailor-made drugs to hospitals, clinics, and physician’s offices across the country. There must be money in these endeavors, as the owner’s portfolio includes a $4.2 million, four-bedroom penthouse over-looking the Charles River in Boston; a $3.5 million home in Southborough, Massachusetts; and a $2.35 million vacation home on Cape Cod.10

Massachusetts records show that NECC was formed as part of the family business in 1998 as a private company. Two pharmacists, the daughter of the family patriarch and her husband, both graduates of the University of Rhode Island’s College of Pharmacy, were supposedly running the day-to-day operations of the “pharmacy.” But according to former employees, an anesthesi-ologist who specialized in pain management was really in charge of manufacturing and marketing. The two pharmacists built a 13-room house in Wrentham, Massachusetts, assessed at $1.8 million in 2005. In 2009, they paid $785,000 for, and then renovated, a waterfront home in North Kingston, Rhode Island.11

Analysis

It seems that it often takes a catastrophe before lawmakers move in to remedy a problem everyone knew existed before the damage occurred. There is no way that NECC could justify its existence as a pharmacy. Even the most avid of advocates for compounding would not claim that NECC belongs in the fold of compounding pharmacies. While we should be quick to defend our own, we should be just as quick to condemn the scofflaws who make the rest of us honest, hard-working professionals look bad.

For further analysis of this topic, please visit my PharmQD blog at www.pharmqd.com/blogs/jessevivian.

REFERENCES

1. Vivian JC. FDA tries to compound the compounding rules. US Pharm. 2011;36(11):68-71. www.uspharmacist.com/content/d/pharmacy_law/c/31071/. Accessed October 26, 2012.
2. Vivian JC. The FDA mandate: never give up, never. US Pharm. 2006;31(11);84-88. www.uspharmacist.com/content/d/pharmacy_law/c/11518/. Accessed October 26, 2012.
3. Burton T, Rockoff J. Pharmacy faulted further by FDA. Wall Street Journal. October 26, 2012. http://professional.wsj.com/article/SB20001424052970204598504578080850473926278.html. Accessed October 26, 2012.
4. Exserohilum sp. Mycology Online. The University of Adelaide. www.mycology.adelaide.edu.au/Fungal_Descriptions/Hyphomycetes_%28dematiaceous%29/Exserohilum/. Accessed October 26, 2012.
5. Begley S. Mass. to revoke license of firm tied to meningitis. Rueters. October 23, 2012. http://vitals.nbcnews.com/_news/2012/10/23/14651193-mass-to-revoke-license-of-firm-tied-to-meningitis?lite. Accessed October 26, 2012.
6. See Note 5.
7. Sun L, Kliff S, Brown D. Officials say they lacked authority over pharmacy involved in meningitis outbreak. Washington Post. October 11, 2012. www.washingtonpost.com/national/health-science/officials-say-they-lacked-authority-over-pharmacy-involved-in-meningitis-outbreak/2012/10/11/331d1c4a-13e8-11e2-bf18-a8a596df4bee_story.html. Accessed October 26, 2012.
8. See Note 3.
9. Martin TW. Tainted drug passed lab test. Wall Street Journal. October 24, 2012. http://professional.wsj.com/article/SB10001424052970204076204578076891268537914.html. Accessed October 26, 2012.
10. Goodnough A, Tavernise S, Pollack A. Spotlight put on founders of drug firm in outbreak. NY Times. October 24, 2012. http://professional.wsj.com/article/TPNYTFEED020121025e8ap00068.html. Accessed October 26, 2012.
11. See Note 10.

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