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
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
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
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.
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.
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.
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.
Accessed October 26, 2012.
8. See Note 3.
9. Martin TW. Tainted drug passed lab test. Wall Street Journal.
October 24, 2012.
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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