P&T Journal...January 2013
On April 11, 2011, Lisa Cornett,
an inspector for the Colorado Board of Pharmacy, wrote a "special
report" memo to the board detailing her inspection seven days earlier of
the Sky Ridge Medical Center pharmacy in Lone Tree, Colorado. Cornett had found
15 vials of methachlorine (y) phenol (kit) solution, 5x5 ML, all of them
shipped from the New England Compounding Center (NECC). That "bulk"
shipment of compounded drugs caused Cornett to check with the Food and Drug
Administration (FDA) to see whether the NECC was registered as a
"manufacturer." Compounders who sell drugs in bulk to hospitals are
suppose to be licensed by the FDA as manufacturers. Regina Barrell, an FDA
official, e-mailed back to say "no," the NECC was not licensed. As a
result Colorado issued a cease and desist order to the NECC on April 15, 2011.
That notification triggered an
enforcement action by the Colorado Pharmacy Board which resulted in Sky Ridge
paying a $5500 fine based on its purchase of multiple doses without providing
individual prescriptions, as state law requires. One would have thought that
other Colorado hospital pharmacies would have gotten the message. But one year
later, a second Colorado investigator, Susan Martin, found 46 vials of
hyaluronidase 150u/ML, 1 ML injection at Delta County Memorial Hospital in
Delta, CO. The vials were shipped by the NECC. That find sparked a
communication from the Colorado Board to the Massachusetts Board of Pharmacy alerting
it to the fact that NECC, a non-manufacturer, was selling bulk, compounded
drugs to hospital pharmacies. The Massachusetts board ignored that alert. Had
it conducted an immediate inspection of the NECC's facilities in Framingham,
Mass., it might have discovered the non-sterile conditions which led to the
bacterial contamination of the methylprednisolone
acetate (MPA)
doses which have so far led to 32 deaths and over 400 illnesses. Massachusetts
and the FDA eventually shut down the NECC and Ameridose, a second compounder
which is licensed by the FDA but linked to the NECC via management.
Meanwhile, the Colorado Pharmacy Board
has not taken final action against the Delta hospital pharmacy, nor against a
third pharmacy, Exempla Good Samaritan Medical Center in Lafayette, CO, which
received repeated bulk shipments from the NECC prior to the Sky Ridge purchases
in 2011. Cory Everett-Lozano, spokesman for the
Colorado Pharmacy Board and the larger state department in which it is housed,
says, "The Board has not yet decided what to do
with the hospital in Delta. It's complicated for a couple reasons which
are not public at this time. The Board will decide what to do in the near
future."
There are two primary issues, each with
thorny complexities, concerning hospital pharmacy use of compounded drugs arising
from the NECC contamination disaster, none of which have really been answered,
nor elevated to headline-level issues. The obvious one has to do with hospital
purchases of compounded drugs from outside vendors. New federal and state laws
may diminish access to those drugs, and increase their costs, as outside
vendors spend capital (or go out of business) to comply with new regulations. But
hospitals themselves are significant compounders, and their adherence to United States Pharmacopeial Convention (USP)
standards, and enforcement of those standards and other state laws, is likely
to emerge into the spotlight, too.
So far, press and congressional criticism
has focused narrowly on the NECC and on enforcement failures in that regard by
Massachusetts and the Food and Drug Administration. But Members of Congress
have now sought explanations from state boards of pharmacy about their policies
and enforcement actions regarding compounding. These could well lead to boards
in states such as Colorado having to explain how they police hospital
pharmacies, and enforce (or not) compounding laws, which of course vary from
state to state.
Hospitals depend heavily on compounding.
At hearings on November 15, 2012 in the Senate Health, Education, Labor and
Pensions (HELP) Committee, David Miller, R. Ph., IACP Executive Vice-President and CEO, the
International
Academy of Compounding Pharmacists (IACP), said: "Many, if not most, of the lifesaving
intravenous drugs given in hospitals and clinics are compounded. Because
hospital patients are often on multiple medications, compounding them into one
treatment saves the hospital personnel time and the patient multiple injections
or administrations."
William W. Churchill MS,
R.Ph., Chief of Service, Department of Pharmacy, Brigham and Women's Hospital
in Boston, says his hospital provides approximately 8 million doses of drugs to
its patients annually. Of that total, about 1.5 million are compounded sterile
products, about 300,000 of those are provided by outside vendors. Those outside
compounded drugs typically fall into a several categories, including total
parenteral nutrition PCA syringes, epidural solutions, and intrathecal pain
medications. "We have a group of chronic pain patients who can only be
treated with compounded medications because we cannot get them in the concentrations
the patients need from commercial suppliers," Churchill explains.
In an interview with the Associated
Press, Daniel Ashby, the Director of the Johns Hopkins Hospital pharmacy in
Baltimore, said he buys 26 drugs out of a total of 3,000 from three compounding
companies, including Ameridose. The other two are AnazaoHealth in Tampa and
PharMEDium of Lake Forest, Ill. As is the case with many hospital pharmacies,
Hopkins buys compounded drugs when there is a shortage of the commercial
alternative manufactured by an FDA-regulated manufacturer. Ameridose, which
ceased operations on October 12, 2012 in the wake of an FDA and state
inspection, sold six drugs which are on the FDA's shortage list: sodium
bicarbonate injection, succinylcholine injection, atropine sulfate injection,
bupivaccine hydrochloride injection, lidocain hydrochloride injection and
furosemide injection.
But despite that
dependence, hospital pharmacists are often unaware of state and federal laws
regarding compounding, the U.S. Pharmacopeia "chapters" governing
on-site compounding, and the conditions at compounding vendors such as NECC. Churchill
says BWH was using the NECC mostly for intrathecal pain medications and
compounded “topical use”-only solutions. Many of these solutions were
compounded and sterilized from raw chemicals in order to meet patient
medication needs. Brigham and Women's was using Ameridose for
"sterile-to-sterile” compounded products, and had been doing so for many
years. Brigham and Women's had conducted its own, scheduled on-site audits of
both of these facilities, and had been satisfied with their services until the
recent issues came to light. However, the audits were not as extensive as the
FDA or state regulatory agencies because the hospital lacks legal authority.
Theoretically, Churchill could have
checked to see whether the NECC and Ameridose were accredited by the Pharmacy
Compounding Accreditation Board (PCAB), which has been in existence since 2004.
It was founded by a group of pharmacy organizations such as the American
Pharmacists Association, National Community Pharmacists Association, and IACPs.
Churchill says, "I was previously unaware that the PCAB existed.
Furthermore, the value of their accreditation would have been unclear given our
lack of familiarity with the agency, its past performance, or how rigorous
their accreditation process is.”
Joe Cabaleiro R.Ph., Executive Director, PCAB,
says neither the NECC nor Ameridose are accredited. The organization lists
accredited pharmacies on its website at: http://www.pcab.org/accredited-pharmacies.
The organization has a 50-page manual which describes the conditions and
procedures it requires pharmacies to maintain. (see:
In the section of "Compliance Indicators," one of the two
elements is "The pharmacy
demonstrates that it has access to all current and applicable standards of the
United States Pharmacopeial Convention (USP)." The section on
"Sterile Compounding" takes up about half of one page. It contains
the only mention of USP 797 in the manual, requiring that "sterile
portions of the compounding process such as weighing
must, at a minimum, be performed in equipment meeting the requirements above
for nonsterile compounding. The equipment must be situated in an environment
meeting USP 797 standards." There are no references in the manual to USP
71 or 795.
USP
General Chapter 797 describes conditions and practices
to prevent harm to patients that could result from microbial contamination,
excessive bacterial endotoxins, variability in intended strength, unintended
chemical and physical contaminants, and ingredients of inappropriate quality in
compounded sterile preparations.
General Chapter 795
provides guidance on applying good compounding practices in the preparation of
nonsterile compounded formulations for dispensing and/or administration to
humans or animals. The latest revision which became official May 1, 2011
includes categories of compounding (simple, moderate, and complex); definitions
for terms (e.g., beyond-use date, hazardous drug, stability); and criteria for
compounding each drug preparation (e.g., suitable compounding environment, use
of appropriate equipment).
General
Chapter 71 specifies how sterility testing of a compounded drug should
be done.
While the three USP chapters are good as
far as they go, many hospital pharmacists are still unfamiliar with them.
Moreover, neither state nor federal regulatory bodies inspect either hospital
or retail compounding pharmacies for compliance with those standards. The IACP's
Miller told the Senate Health, Education, Labor and Pensions Committee, " The
IACP believes that all states must adopt mandatory compliance with USP 795 and
797 standards." Only 17 states have done so. While some accreditation
bodies appear to use the USP standards, there is no assurance that those bodies
go back to pharmacies once they are accredited to make sure facilities still
have floors which can be eaten off of.
With
regard to in-house compounding, which averages about 1 million doses a year,
Churchill says his pharmacy adheres to USP 797, 795 and 71. He is fortunate
because hospital leadership has supported his use of an outside expert
consultant to assist his leadership team in assuring that Brigham and Women's
is complying with those USP regulations. "The USP chapters 797, 795 and 71
have many intricate details and nuances and that is why our consultant is so
valuable to us," he explains. "But there is a lack of process and
lack of resources to ensure compliance," Churchill explains.
One might expect The Joint Commission or
the federal government--because of Medicare conditions of participation, for
example--to survey hospital pharmacies for adherence to USP standards.
"The federal government doesn't walk into a lot of hospital pharmacies,"
notes Churchill.
The Joint Commission doesn't look at that
issue when it visits hospital pharmacies, according to one hospital pharmacist.
"They don't have the resources," he explains.
One former USP official, who declines to be
identified, says, The Joint Commission's last official statement on USP 797 was
in 2004. " I am not sure they will even
know what USP 795 or 17 are," he adds. Amy Panagopoulos RN, MBA, Senior
Director, Quality, Evaluation and Strategy, Division of Healthcare Quality
Evaluation, The Joint Commission, failed to provide any information on The Joint
Commission inspections of hospital pharmacies with regard to USP standards.
Complicating
the issue of USP compliance further is confusion over whether the Food and Drug
Administration has the authority to enforce the three USP standards, even if it
did have the inspection staff to do so, either at places like the NECC or in
hospitals. What is clear is that the FDA has the authority to regulate
"manufacturers" of compounded drugs, whether non-sterile-to-sterile,
or sterile-to-sterile. Ameridose was licensed as a manufacturer. Compounders
such as the NECC who consider themselves "non-manufacturers" are not
licensed by the FDA and are not allowed, theoretically, to supply compounded
drugs to a physician or hospital pharmacy without getting an individual
prescription for that dose in advance. It is the responsibility of the state
board of pharmacy to blow the whistle when violations of the individual
prescription law occur. FDA-licensed manufacturers can supply compounded drugs
in bulk. In the middle of those two scenarios is "anticipatory
compounding," where a hospital or an outside vendor can make or supply
multiple doses in "reasonable quantities" without a prescription
based on "historical need" of a hospital or other health care
facility, such as a pain clinic, according to Miller of the IACP.
But testimony at House and
Senate hearings in November produced numerous allusions to the grey areas in
federal law. Margaret Hamburg, Commissioner of the FDA, explained that the FDA
first published a compliance guide on compounding in 1992. The compounding
industry had objections to it, and went to Congress looking for changes. The
Food and Drug Administration Modernization Act of 1997 added a new section to
the Food, Drug and Cosmetic Act exempting compounded drugs from three critical
provisions of the existing law. The new sections also limited advertising of
compounded drugs, and solicitation by compounders of prescriptions. "These
provisions were the subject of subsequent court challenges, which have produced
conflicting case law and amplified the perceived gaps and ambiguity associated
with the FDA's authority over compounding pharmacies," Hamburg explained.
Lauren Smith, MD, MP,
Interim Commissioner, Massachusetts Department of Public Health (MDPH), says
there is a "black hole" between state and federal regulation of
compounding pharmacies.
Nonetheless, the FDA did
inspect the NECC in conjunction with Massachusetts in 2002 and 2006. The FDA did the 2002 inspection based on MedWatch reports of meningitis symptoms
in people taking MPA, and also because of complaints related to betamethasone. In the aftermath of the 2006
inspection, which looked at different issues, the FDA wrote a "warning
letter" threatening to shut the facility down. That never happened. The
Massachusetts Board of Pharmacy inspected the NECC facility in Framingham, MA
in 2011, looking at sterile conditions, among other things, and rated the
facility "satisfactory" based on that inspection. The FDA never
inspected NECC after 2006. At the hearings in the House Energy and Commerce
Subcommittee on Oversight and Investigations on November 14, Rep. Cliff Stearns
(R-Fla.), Chairman of the subcommittee, complained that the FDA repeatedly
documented problems at NECC, some identical to the same problem that caused the
recent outbreak. Stearns asked Hamburg, the FDA Commissioner, whether the
agency had the authority to shut down the NECC. "That is a very, very
complex question," she answered.
Hamburg asked both the House and Senate to
clarify that ambiguity by adopting legislation which would modify the Food,
Drug and Cosmetic Act to recognize two categories of compounding pharmacies:
traditional and non-traditional. Pharmacies in the latter category would have
to comply with federal current good manufacturing practices (cGMPs), for
example, from which they were exempted by the 1997 law. That would give the FDA
more authority to deal with the kind of potential contamination that brought
low the NECC and Ameridose. Besides mandating cGMP compliance for
non-traditional pharmacies, the FDA-suggested reforms would bar compounding of
certain products under any circumstance, with certain exceptions. These would
include compounding of drugs which are copies of FDA-approved drugs absent a
shortage designation and complex dosage forms such as extended release products.
One congressional reform bill has already
been introduced by Rep. Ed
Markey (D-MA). It is called the Verifying
Authority and Legality in Drug (VALID) Compounding Act (H.R. 6584). It
will:
Ensure that compounding pharmacies
that are operating as drug manufacturers are regulated by the FDA as drug
manufacturers;
Allow compounding pharmacies with a
legitimate reason to compound drugs before the receipt of a valid prescription
to request a waiver to enable them to do so;
Allow the FDA to waive the
requirement to compound drugs solely for individual patients with valid
prescriptions in the event of a drug shortage or to protect public health;
Increases transparency to the public
by mandating that compounded drugs be labeled to ensure that recipients know
that the drugs have not been tested for safety or effectiveness, publishing a
“Do Not Compound” list of unsafe or ineffective drugs, and reporting of bad
reactions to compounded drugs or any drug that poses a safety risk.
The American Society of Health System
Pharmacists (ASHP) thinks the gray areas between state and federal regulation
need to be eliminated. "Previous
attempts to define compounding in federal law contained certain elements that
should be examined in light of practice changes since 1997," says Kasey
Thompson, Vice President of Policy, Planning and Communications for the ASHP.
"Recent legislative proposals merit further discussion and exploration,
since they may reflect those practice changes and allow for the regulatory
flexibility among state boards of pharmacy and the FDA that would ensure that
hospitals continue to be allowed to obtain compounded medications in
anticipation of patient need."
Congress has tried in the past to clear up
some of this Federal-State enforcement confusion. At the Senate hearings, Sen.
Pat Roberts (R-KS) noted the IACP itself had blocked remedial efforts. He asked
the IACP's Miller and the ASHP's Thompson if they were willing to work with
Congress this time to fill in the gaps between federal and state regulation of
compounding pharmacies. Both answered affirmatively.
However, Miller's testimony seemed to suggest his group had certain red lines it didn't want Congress to cross. He indicated that states had the authority to quickly address issues such as the NECC contamination issue, and that Massachusetts should have done so. He also noted that the FDA had plenty of reason--and authority--to force the NECC to become licensed as a manufacturer, thus making it easier for the FDA to inspect its premises. At the same time, though, he noted that state boards of pharmacy are underfunded.
The spokeswoman for Sky Ridge Medical Center did not return a phone call. So it is hard to know whether that hospital knew it was breaking Colorado law by dealing with the NECC. But hospitals across the country, and their pharmacy directors, now have little excuse for claiming ignorance about state and federal compounding laws, which are likely to be tightened. If that is not done carefully, reform could complicate the already problematic drug shortage problem.
