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  1. #1



    Drug Topics® Archive
    Jan. 6, 2003



    As more reports surface about improperly compounded drugs, will new restrictions be placed on the practice?

    The long-smoldering debate about pharmacy compounding has flared into a raging controversy, fanned by media coverage of patients dying from improperly compounded drugs and calls for more regulation of what critics see as one area of practice run amok.

    The media have focused the public spotlight in recent months on errors and contaminated drugs traced back to pharmacies doing large-scale compounding. Major daily newspaper articles and national network news programs have portrayed the practice in unflattering terms, referring to makeshift labs, minimal oversight, and bad medicine that add up to a prescription for disaster.

    The most recent uproar was triggered when four North Carolina patients were sickened and one died from fungal meningitis found in methylprednisolone injections compounded by Urgent Care Pharmacy in Spartansburg, S.C. The state pharmacy board shut down the compounding operation of the pharmacy, which recalled the contaminated drug. Tests by the Food & Drug Administration and the Centers for Disease Control & Prevention found that unopened vials from three separate lots were contaminated.

    The South Carolina pharmacy board inspection of Urgent Care found improper operation of an autoclave, inadequate cleanroom practices based on ASHP's guidelines, and no testing for sterility or quality, according to CDC's Morbidity and Mortality Review (MMR) of Dec. 13, 2002. The FDA issued a nationwide alert against use of all Urgent Care compounded drugs.

    After reviewing the Urgent Care incident, the MMR report stated, "Clinicians should consider the possibility of improperly compounded medications as a source of infection in patients after epidural or intra-articular injections."

    By pointing the finger at pharmacies compounding sterile injectables, the CDC underscored what some critics have been saying all along. To them, such large-scale compounding is a dangerous, unregulated practice conducted outside good manufacturing practices that puts patients at risk.

    "Compounding has become a very big industry, and we don't know the scope of it, but our patients are vulnerable," said Sarah Sellers, Pharm.D., an Illinois-based consultant on policy and regulation. "We're going to have to start considering in our differential diagnoses whether treatment failure is due to exposure to substandard [compounded] drugs. England has identified extemporaneous compounding as an added risk to the provision of pharmaceutical care, and so they basically prohibit compounding."

    Another risk factor for patients is that compounding pharmacies cannot vouch for the quality of the bulk chemicals they buy, said Sellers, who served on the Pharmacy Compounding Advisory Committee of the Center for Drug Evaluation & Research (CDER) in the FDA. She also raised the specter of counterfeit bulk chemicals making their way to patients.

    "We don't have a good idea of the quality of the chemicals," said Sellers. "When the bulk [chemical] jars get to the pharmacy, the pharmacists rely on their sixth sense to determine the potency and quality of the chemicals. Repackagers have been found taking expired drugs and repacking them with new expiration dates. Right now we might not even be able to determine where the bulk chemical was actually manufactured and when. If you're not starting with a quality material, no matter what you're doing in your compounding process, you're not going to end up with a quality product."

    The charge that pharmacy organizations have been apologists for compounding's bad actors rings true for Carmen Catizone, executive director, National Association of Boards of Pharmacy. "One argument that's difficult to refute is that if you have a pharmacy shipping 40,000 doses, even those for individual patients, at some point that mom-and-pop pharmacy has become a manufacturer," he said. "I don't care if they're doing it right and following all the state laws, when you make a certain quantity, it leaves the 'old shoe box.' That's a belief we can't get pharmacy to accept, and that creates problems."

    It wouldn't matter how much the American Pharmaceutical Association condemned compounding's bad apples, it wouldn't be enough for some critics, countered Susan Winckler, v.p.-policy and communication and general counsel. "APhA's challenge is that when we defend compounding, some people think we defend all who are compounding," she said. "That's incorrect, but you have some people certainly interpreting our words that way."

    If patients are getting substandard drugs, lay out the evidence, said L. D. King, executive director, International Academy of Compounding Pharmacists (IACP). "It's estimated that 1% of all prescriptions are compounded, which is quite a huge number," he said. "When you put it in the perspective of the number of incidents of substandard drugs leading to patient harm, it's a very safe practice."

    The champions of compounding may point to its safety record, but that's misleading because no one is keeping track of adverse events, according to Larry Sasich, Pharm.D., M.P.H., research analyst, Public Citizen Research Group. "There is no reporting requirement and, for all practical purposes, no regulatory oversight of these pharmacists," he said. "We could be knocking off a few people here and a few people there and nobody knows about it. I am ashamed of the position organized pharmacy has taken. I think the public's esteem for the profession is going to suffer tremendously because the profession hasn't spoken up. It was just a matter of time before we began to see problems, and it's beginning to float into view in the public periscope. And there is interest in doing something on Capitol Hill."

    Sure enough, six members of Congress recently sounded an alarm about hospitalizations and deaths traced to compounding pharmacies. The Representatives wrote that "compounding should not be a loophole to circumvent the established role of the FDA in ensuring the highest level of quality for the nation's drug supply" in an Oct. 21, 2002, letter to the new FDA commissioner, Mark McClellan.

    "While we believe the practice of pharmacy compounding in which a pharmacist modifies a prescription on an individual patient basis has a time-honored and important role to play in our healthcare delivery system, we share the FDA's concern that when 'the scope and nature of a pharmacy's activities raise the kinds of concerns normally associated with a drug manufacturer,' enforcement action is necessary to protect the health of the public," the letter continued. "We urge you to vigorously enforce against such practices."

    The 900-lb. gorilla

    Congressional calls for the FDA to get more involved are not music to the profession's ears. Pharmacy organizations have been squabbling for years with the FDA over regulation of compounding. When manning the ramparts against the federal agency, such organizations take the stance that compounding is a traditional right of pharmacists and only the state pharmacy boards have the authority to regulate it.

    The ongoing battle culminated in a Supreme Court decision last spring that struck down section 503A of the Food & Drug Administration Modernization Act of 1997. Compounding pharmacists had sued over being barred from advertising that they compounded specific drugs. The Supreme Court agreed and its decision knocked down the entire section, not just the commercial speech aspect.

    As a result, the FDA issued a compounding policy guidance document last June laying out its stance on drawing the line between compounding and manufacturing. Noting that the agency recognized traditional compounding, the FDA stated its belief "that an increasing number of establishments with retail pharmacy licenses are engaged in manufacturing and distributing unapproved new drugs for human use in a manner that is clearly outside the bounds of traditional pharmacy practice."

    Despite FDA protestations of leaving regulation of traditional compounding to the states, the National Community Pharmacists Association doesn't buy it. Standing up for independent pharmacists who make up the bulk of compounders, NCPA believes that "the FDA has no authority to regulate pharmacy compounding because it's just not their business," said John Rector, general counsel, senior v.p.-government affairs. "We say if the FDA finds people manufacturing who are not licensed to do so, bust them. They don't need jurisdiction over pharmacy compounding to sanction or respond to those manufacturers without proper credentials. The FDA seems to be on the warpath because it lost its intrusive authority regarding compounding."

    While pharmacy is adamant that the FDA has no legal authority over compounding, the agency begs to differ in two areas: manufacturing masquerading as compounding and patient safety, said David Horowitz, CDER director of compliance. "We cannot allow compounders to compound large volumes of drugs and engage in activities that are more similar to drug manufacturing without being regulated as drug manufacturing," he said. "A tougher issue for us to come to grips with is those that might not be large-volume compounders but that might raise significant public health issues. In those cases, we want to work with the states and support their actions, and, if necessary, take FDA action."

    Most compounding advocates contend that state pharmacy boards are the proper regulatory watchdogs. IACP's King pointed out that one-third of the states are in the process of revising their regulations. "The states are becoming more sophisticated about regulating compounding," he said. "As the states become more equipped to address compounding, we hope the FDA will feel less inclined to get involved."

    State pharmacy boards already have a blueprint for good compounding practices developed by NABP, said Catizone. However, he added, "some states have implemented them; others ignore them. There is no uniformity, just a patchwork of standards and regulation."

    While critics contend that state pharmacy boards merely react to complaints instead of actively policing compounding pharmacies, the hard facts of regulatory life dictate how boards operate. There simply is no money in strapped state budgets to pay for more inspectors. "The criticism is why can't the boards be more proactive and monitor for compounding and enforce the standards and put some of these people out of business?" said Catizone "But it's a matter of resources. I don't know how the boards can justify inspecting every pharmacy that's compounding."

    Despite pharmacy's fear of the FDA, the agency is really not that powerful, given its own lack of resources, said Public Citizen's Sasich. "Most people think the FDA is a 900-lb. bureaucratic gorilla with a big stick, but it's really pretty weak," he said.

    Credentials, please

    One move pharmacy is mulling over to give a jittery public a yardstick is the creation of a credential that compounding pharmacists could earn and perhaps accreditation of compounding sites by an outside organization. For instance, King said IACP has held discussion with the Board of Pharmaceutical Specialties and the National Institute for Standards in Pharmacist Credentialing.

    BPS is "very anxious" to work with the compounding community to create a certification program for compounding as a special advanced practice area, said executive director Richard Bertin, Ph.D. The next step is up to a group to petition BPS to recognize compounding as a new specialty, followed by national hearings and a review process.

    "Right now there is no way that the patient, payer, healthcare professionals, or others in pharmacy can really identify those compounders with the appropriate level of skills and knowledge for what they're doing," said Bertin. "Sooner rather than later, they need a credential that will be believable and give them the credibility they need in the pharmacy community and beyond, which may be even more important."

    There may be some reluctance among compounders to commit to BPS certification because the process is rigorous and costly, said Bertin. "My impression is that there's a little bit of fear of the BPS process. Some are concerned that if there is certification, somewhere along the line regulators will want to mandate that all compounders have that certification. There is interest, but I think they're trying to see whether there are other alternatives that, quite frankly, might be cheaper and easier."

    APhA has also been working closely with IACP and others to figure out whether certification is the way to go, said Winckler. While simple compounding might not justify a certificate credential, she feels, "if a pharmacist is going to get into sterile product preparation, there should be a certification program, so he or she can say, 'Here's my knowledge in this area.' "

    On another front, the U.S. Pharmacopeia has proposed a new general chapter on good compounding practices to give compounders and regulators detailed information on compounding, including the compounder's responsibilities, training requirements, procedures and documentation, and the facilities and equipment needed. There is also a table indicating various levels of the difficulty of compounding the preparation.

    Wish lists

    Most of the players interested in compounding have a wish list for the direction in which they'd like to see the practice move. Of course, most of them would go their separate ways.

    New legislation that spells out what cannot or should not be done by compounding pharmacists is the top wish for Public Citizen's Sasich. "The first thing I'd start out with is a list of drugs that cannot be safely manufactured in a back room of the pharmacy or outside a regulated facility under good manufacturing guidelines," he said. "At the top of that list would be sterile products, including injections and inhalation solutions. Then there has to be some kind of public disclosure of the fact that compounded drugs have not been tested for safety and effectiveness and are not produced under good manufacturing practices."

    APhA's Winckler would second the notion that patients should know when they're taking a compounded drug and why. She would also like to see the profession pull together a resource of all compounding regulations to evaluate what's working.

    For NABP, the top job is getting the state boards of pharmacy, the profession, and the FDA to agree on the distinction between compounding and manufacturing, said NABP's Catizone, "and then getting the bad players out of the system."

    The FDA wants to work with the states, the U.S. Pharmacopeia, and other stakeholders to develop a new legislative framework. "We intend to pursue the possibility of new legislation," said Horowitz, "because we believe that both the compounding community and consumers would be better off if there were greater clarity than we can achieve using our compounding policy guide."

    Representing 1,800 compounding pharmacists, IACP wants the FDA to help the profession understand the differences between compounding and manufacturing, said King. He also favors further development of standards for compounding practice. "The bottom line is that we have to make medication that is safe and effective for our patients," he said. "And we'll do everything in our power to make sure that exists."

    Carol Ukens

    Bad news

    In recent years, compounding has been involved in several incidents that captured media attention and triggered calls for more regulation, including the following:

    • In North Carolina, one patient died and three became ill from fungal meningitis traced to methylprednisolone compounded by Urgent Care Pharmacy of Spartansburg, S.C. In September 2002, the pharmacy recalled the contaminated product. State and federal inspections found several instances of nonadherence to sterile technique. However, when Urgent Care refused to recall all its compounded products, the Food & Drug Administration issued a national alert advising against use of any products compounded by the pharmacy.

    • On Sept. 20, the FDA put Med-Mart Pulmonary Services of Novato, Calif., on notice that it was operating as a drug manufacturer, not a retail pharmacy. Citing concerns about "large-scale production of massive quantities of inhalation solutions," the FDA threatened actions such as seizure and/or injunction if the firm did not provide a plan to correct numerous operational deficiencies.

    • Although Robert Courtney's dilution of chemotherapy drugs was not strictly compounding, the finer points of the Kansas City pharmacist's operation were lost on the media and the public following discovery of his criminal actions in August 2001. He was recently sentenced to 30 years in prison.

    • Last July, two pharmacists and six healthcare professionals were convicted in Miami of defrauding Medicare of millions of dollars with bogus billing for compounded aerosol medications through South Beach Pharmacy, LaModerna Pharmacy, and/or CDC of South Florida Inc. The compounded drugs contained little or no active ingredients.

    • On Sept. 18, 2002, the U.S. Department of Justice sent a letter to Pharmaceutical Compounding Centers of America (PCCA) informing the Houston firm that the huge volume of chemicals it had supplied to Miami pharmacies should have been a "red flag" that there was Medicare fraud going on. The firm was also informed that its actions "have assisted in the systematic defrauding of the Medicare Trust Fund."

    • PCCA was also the target of an FDA warning letter in July 2001 taking the firm to task for violations of good manufacturing practices, including failure to ensure against cross contamination between cephalosporins and penicillin repackaged on common equipment. The FDA also alleged that PCCA had been repacking and distributing bulk drugs that had been removed from the market, such as phenacetin, dipyrone, and adenosine phosphate.

    • On April 10, 2002, the FDA warned three pharmacies that the nicotine lollipops and lip balm they were selling were illegal because they were compounded without an Rx and were made from nicotine salicylate, which is not approved for compounding.

    • Last June, Portage Pharmacy, Portage, Mich., issued a class I recall of 791 vials of compounded drugs, including methylprednisolone, due to contamination and a class II recall of 175 vials of other compounded medications due to lack of assurance of sterility.

    • Two patients in Michigan who had received compounded medication for spinal injection became ill with Chryseomonas meningitis last year, according to CDC.

    • In March 2001, four Atlanta patients had severe adverse reactions to a compounded thyroid drug prescribed for Wilson's syndrome, a quack diagnosis created by a Florida doctor who lost his license. One R.Ph. was put on probation for five years and the owner-R.Ph. surrendered his license. He had been sanctioned in 1986 for felony convictions for mail fraud and misbranding and adulteration of drugs.

    • Thirteen people were hospitalized and three others died from meningitis traced to contaminated betamethasone compounded by Doc's Pharmacy in Walnut Creek, Calif., in May 2001. The pharmacist-owner's license was revoked for one year, but a young pharmacist who co-owned the pharmacy later committed suicide following a 90-day license suspension.

    Compounding flunks FDA test

    Among 29 samples taken from 12 compounding pharmacies that advertise their wares over the Internet, 10 failed to meet standard quality tests, according to small study by the Food & Drug Administration.

    • The 34% failure rate for the compounded samples was "significant," compared with the 2% failure rate among drug manufacturers, according to researchers in the FDA's Center for Drug Evaluation & Research. Nine of the 10 failures were for subpotency; the other was for contamination.

    • More than half the samples had less than 70% of the potency stated on the labeling. Three additional samples failed an initial test but there was insufficient product for retesting, so they were not counted among the failures.

    • The FDA study is on the Web at .

  2. #2
    Sorry about this very long posting but it lists a litany of complaints that the FDA has relating to compounding pharmacies. Although it is not mentioned 4-AP is right on the top of the list of substances that the FDA is very concerned out.

  3. #3
    Super Moderator Sue Pendleton's Avatar
    Join Date
    Jul 2001
    Wisconsin USA
    Most states have laws that require a doctor that prescribes drugs for a patient to actually see the patient for the specific complaint or has an ongoing relationship with a patient for a chronic condition. Doctors that prescribe via the internet and tied to compounding pharmacies worry me more than whether a pharmacy qualifies as a manufacturer or a retailer.

    I didn't realize that the sterile practices guide lines were the same though for injectibles and inhalants that are compounded as any manufacturer's good practices guide lines. That sterility is not being met for these drugs is scary.

    Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

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