Meningitis outbreak shines light on compounding pharmaciesBMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e7432 (Published 05 November 2012) Cite this as: BMJ 2012;345:e7432
- Allen F Shaughnessy1
- Correspondence to:
The practice of pharmacy is not flashy. Pharmacists behind the bulwarks in chain pharmacies or isolated in hospital basements quietly and efficiently hew to their motto: providing the right medicine to the right patient at the right time. No television dramas showcase a quirky pharmacist producing and delivering life saving medications.
Similarly, life is prosaic in the Boston suburb of Framingham, Massachusetts, best known in medical circles as the site of an epidemiologic study now spanning 65 years. Framingham is also home to the now shuttered New England Compounding Center (NECC), suspected of mass producing a tainted methylprednisolone injectable used to treat hundreds of patients for back and joint problems in physicians’ offices across the country. Both the town and the practice of compounding pharmacy have been thrust into the spotlight. As of this writing, there have been 28 deaths and 377 people made ill by a fungal infection that plagues plants more than people.1
The tragedy has focused attention on pharmacy practice and has brought up questions about the safety of pharmaceuticals, the distinction between compounded and manufactured medicines, and the regulations in place that protect the public.
What is a compounding pharmacy?
Pharmaceutical compounding is the preparation of a specific medicine, based on a physician’s prescription, for a specific patient. To make the prescription, the pharmacist starts with raw chemicals and develops a finished product that is dispensed to a patient. The process of compounding may be as simple as adding a dose of a medicine to an intravenous solution or as complex as decocting a tincture from the dried leaves of a plant.
Pharmaceutical compounding was the main function of pharmacists until the modern era; through the 1950s pharmacists compounded up to 80% of the prescriptions they dispensed.
They didn’t grab a bottle of antibiotic tablets from the shelf. Instead, they prepared penicillin by weighing out the penicillin powder and admixing it with a buffering chemical to minimize its degradation by stomach acid before dispensing to a patient. Other products required several complex steps in the compounding process, which is why pharmacists are called “chemists” in other countries. Each prescription was tailor made.
The products were wide ranging. In the typical pharmacy, pharmacists would prepare and dispense powders, capsules, cachets, pearls, tablets, pills, and suppositories, as well as ointments, pastes, cerates (an ointment made with wax), plasters, lotions, liniments, tinctures, poultices, and wet dressings. Pharmacists might be asked to prepare “MacNair’s Lotion,” “Hope’s Mixture,” or “Gray’s Cough Mixture.” To make these products, pharmacists would consult the American Pharmaceutical Association’s The Pharmaceutical Recipe Book or other pharmaceutical recipe books.
During this time only a few pharmaceutical companies made finished products. Many of these products were sold without prescription. “Lydia Pinkham’s Vegetable Compound,” marketed as a women’s tonic and containing 18% alcohol, was one of the best known of these so called “patent medicines.”
Manufactured products engendered various degrees of mistrust, after disasters such as the deaths of over 100 people in 1937 when a manufacturer substituted diethylene glycol, a poisonous chemical used as antifreeze, in an antibiotic product.2
By the early 1960s, though, pharmaceutical companies began producing many finished products and, through aggressive marketing and research showing their effectiveness, manufactured pharmaceuticals overtook the use of compounded medicines. For much of the past fifty years the mortar and pestle, the symbol of pharmacy practice, sat idle and dusty on the pharmacist’s shelf. In the age of synthetic, manufactured prescriptions, compounding was not part of most pharmacy practice.
No longer. Compounding of individual medicines for individual patients re-emerged in the 1980s. Today, an estimated 1-3% of outpatient prescriptions are for compounded products; when products compounded in hospitals are included, the percentage goes up to about 10%, according to Loyd Allen, editor in chief of the International Journal of Pharmaceutical Compounding. Although pharmacists in the typical local pharmacy compound the occasional prescription, most of the practice is concentrated in the 7500 dedicated compounding pharmacies in the United States.3 Resembling laboratories, they bear little resemblance to the pharmacies of old.
Why are pharmacists still compounding?
The resurgence, according to Allen, is in part due to the discontinuation of about 8000 prescription and non-prescription products in the past 20 years. “With the merging of pharmaceutical manufacturers, slow sellers aren’t made anymore,” says Allen. “A medication that used to be available in many formulations—tablet, capsule, injection, suppository—and in many doses might now be reduced to a couple of different forms.”
In addition to discontinued drugs, compounding becomes important for the increasing number of hard to obtain medicines; 267 drugs were in short supply at some time last year, leaving pharmacists scrambling for alternatives.4
A shortage can have a major effect on patient care and costs beyond the medication. Propofol, a short acting general anesthetic, was in short supply for a couple of years due to manufacturers stopping production, according to Judy Nasca, a hospital pharmacist and pharmacy skills laboratory director at the Albany College of Pharmacy and Health Sciences, Colchester, Vermont campus.
Propofol’s fast recovery period allows for quick reversal of anesthesia. “When I told anesthesiologists that we didn’t have propofol they asked me how they are supposed to provide anesthesia for same day surgery patients,” she says. Some hospitals had to cancel ambulatory surgery cases because of the shortage. Compounding pharmacies made propofol until large scale production resumed.
Compounding pharmacists not only make unavailable products but also make custom products for unique needs. They can add flavoring to liquid prescriptions to make them more palatable to children, or produce unavailable strengths or formulations of creams or ointments. They compound special capsules when a patient is allergic to preservatives, dyes, or binders used in commercial products. Pharmacists can produce a specific dose for patients with unique needs, such as infants, or combine several medications into a single product for ease of use.
Compounding versus manufacturing
Compounding pharmacies are regulated by state boards of pharmacy and are expected to follow “good compounding practices,” a set of regulations developed by the US Pharmacopeial Convention (USP) (www.usp.org), a private group that sets standards for medicines in the US and other countries. Producers of sterile injectables also follow additional regulations developed by the USP.5
Although not a regulatory agency, the Pharmacy Compounding Accreditation Board has developed national standards to accredit pharmacies that perform a significant amount of compounding.6 The process is voluntary and the New England Compounding Center is not accredited.7
The Food and Drug Administration has two roles in the oversight of compounding pharmacies. The FDA certifies the potency and purity of the raw materials purchased by compounding pharmacies. All raw materials used by compounding pharmacies should be obtained from an FDA registered pharmaceutical ingredients supplier. However, with 80% of these materials coming from outside the United States, the FDA struggles to assure that the supply chain remains intact.
There has been a push to have the FDA play a larger role in regulating compounding pharmacies, but legislative changes have been blocked. The Supreme Court struck down a federal law, enacted in 1997, which would have allowed the FDA to regulate pharmacy compounding practices. Follow-up legislation, the Safe Drug Compounding Act of 2007, would have extended the FDA’s regulatory reach into pharmacies but was never passed.8
Where errors can occur
Although the FDA does not regulate pharmacy practice, the agency can step in if it suspects a company is functioning more as a mass producer than compounder. It is through this seam between compounding and manufacturing that regulatory enforcement can slip. Both the FDA and the Massachusetts Board of Registration in Pharmacy, both of which had numerous concerns over the past 10 years, are investigating where the chain of authority was broken that allowed possible regulatory gaps in the oversight of the New England Compounding Center.
Are existing regulations enough to assure safety?
Some blame a patchwork of state and federal regulations, but compounding pharmacists counter that existing regulations, if adhered to, would have prevented this tragedy. According to Paul Kiritsy, an associate professor at the Massachusetts College of Pharmacy and Health Sciences in Boston, the current good compounding practices protect the public: “Pharmacists have been making parenteral medications for decades. The vast majority of patients have not been adversely affected but, rather, received safe products.”
However, aseptic compounding techniques are “all or none,” according to Kiritsy. “You can’t adhere to some steps and not the others and that’s where the breakdowns usually occur,” he says.
Kiritsy says the recent deaths are not the only cases of contaminated sterile products causing infections. In the past year alone there have been reports of fungal eye infections and permanent vision loss traced to products compounded by a pharmacy in Florida. Two deaths in Alabama are alleged to have occurred due to contaminated intravenous nutritional supplements provided by a compounding pharmacy.
In the case of the New England Compounding Center, the FDA has stated that the raw ingredients were not the source of the contamination. As a result, there seems to be a breakdown in either the process of compounding or the testing for sterility, or both.9
There are renewed attempts to develop new legislation. Congressman Edward Markey, whose legislative district includes Framingham, Massachusetts, has stated that the New England Compounding Center fell into a “blackhole” [sic] between federal and state regulators and became a “compounding manufacturer” and not a compounding pharmacy.10 As a member of the committee that has jurisdiction over the FDA, he has announced that he will introduce legislation to strengthen the oversight of compounding pharmacies.
Cite this as: BMJ 2012;345:e7432
Competing interests: the author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.