More than 12,000 compounding pharmacies operate in the United States, and each year compounded product sales reach $300 million--25% of that is spent in the animal pharmaceutical industry alone. The Food & Drug Administration (FDA) has developed regulations to provide assurances for safety and efficacy of drugs and devices, to ensure food supply safety, and to regulate food chain supplies and animal foods; so how do these apply to compounding? At the 2010 American Association of Equine Practitioners (AAEP) Convention, held Dec. 4-8 in Baltimore, Md., Scott Stanley, PhD, professor of Equine Analytical Chemistry at the University of California, Davis, discussed FDA's ongoing attempts to ensure safety of drugs produced by compounding pharmacies (that provide individualized medications ordered by prescribers which are unavailable through normal means).
He described a study conducted by the FDA in which scientists analyzed 29 samples from 12 compounders. Stanley noted that 10 of the samples failed to meet the FDA standard for quality testing (which for potency is ±10% of the labeled concentration), yielding a 34% failure rate as compared to the typical 2% failure rate seen among the entire pharmaceutical industry in general. More than half of the failed samples contained less than 70% of the labeled potency.
Equine practitioners must evaluate the integrity of compounding pharmacies as well as the quality and consistency of drugs produced. Stanley remarked than many practitioners express concerns about efficacy of products that different compounding pharmacies compound, noting that just because a pharmacy prepares a product doesn't mean that it's efficacious--what an owner might perceive as a legitimate, reliable source of medication might not always be. In addition, veterinarians must consider the quality (potency, purity, and stability) and consistency of drugs as well as their liabilities for using that particular product.
Stanley explained that the FDA does not permit compounding, but rather uses "enforcement discretion," meaning that if a product cannot be obtained to control a life-threatening disease process or to control suffering, then use of a compounded product is permitted.
The Animal Medicinal Drug Use Clarification Act (AMDUCA) allows manufacturing, preparation, propagation, processing, and compounding of drugs as long as a product is not already commercially available. In addition, there must be a valid veterinarian-client-patient relationship to dispense these drugs. Three categories of drugs are available for use:
- FDA-approved "pioneer" drugs: These are studied through clinical trials that show efficacy, safety, and quality; it often costs $30 million to get a drug through the FDA-approval process;
- Generic drugs: These are subjected to an abbreviated process for verifying efficacy--companies must demonstrate that generics are the biologic and/or chemical equivalent of a drug and must meet label claims for that product; and
- Compounded drugs.
Compounding a drug is a form of adulteration, according to Stanley, since it is any manipulation of a drug formulation to produce a dosing form different from label requirements. He said that pharmacies should not provide drugs that are commercially available or those slightly altered by flavoring or by small changes in drug strength.
There is little external oversight; compounding pharmacies are mostly self-regulated. A compounded product cannot be called a generic equivalent and cannot be substituted for an available FDA-approved product. A compounder may reformulate an approved animal or human drug to change its delivery, as for example turning powder into paste, or if a formerly FDA-approved drug is no longer available. In addition, only a 72-hour supply should be kept on-hand at the pharmacy for dispensing. In every compounding case there must be a valid veterinarian-client-patient relationship. Label instructions include specific details on how it is to be used.
Before choosing a compounding pharmacy, Stanley recommends researching information about the pharmacy, asking if it is accredited by the Pharmacy Compounding Accreditation Board (PAB), if the pharmacist has obtained appropriate training, and if the pharmacy has liability insurance. He also recommends finding out if the product you're seeking is prepared using pharmaceutical or chemical (bulk) grade materials and where these were obtained.
He noted red flags that are causes for concern, such as an overly long expiration date--by law the longest expiration date on a compounded product can only be six months. Other red flags include statements of sterility, marketing materials presenting the product as cheaper than an available FDA-approved product, or AVMA or pharmaceutical complaints that have been filed. Clients should be concerned about websites that advertise compounded drugs, particularly when medications are available without necessary prescriptions.
Stanley described omeprazole as an example of compounding issues that arise. Two FDA-approved products (Gastrogard and Ulcergard) with demonstrated efficacy and stability are available. Any compounded formulation with omeprazole is currently considered pirated since Merial still owns the use patent. The pH of omeprazole is very sensitive--pH less than 7.8 results in rapid deterioration. Compounded pirated omeprazole products showed low pH values as well as dosing inconsistencies--only one of six products met FDA potency requirements upon arrival at the test lab. Similar findings occurred with non-steroidal anti-inflammatory medications: Levels were only 68% of label-claimed potency in injectable flunixin meglumine (Banamine) and 72% potency in powdered phenylbutazone (Bute).
FDA regulations on medical devices are stringent--a medical device is defined as an external device that does not result in a chemical reaction within or on the body. There are several products FDA-approved as medical devices but used as drugs for intra-articular therapies; therefore, Stanley remarked that any injectable medical "device" is considered a drug. Should a practitioner choose to use a device as a pharmaceutical, he or she should be aware that these products have not been evaluated to determine their suitability for that usage by any regulatory agency.
Stanley also stressed that a client cannot consent to substandard care (per legal standards for medical malpractice). Clients might not understand that just because a product is formulated and prepared for resale doesn't mean it is therapeutic to achieve desired results. Stanley also emphasized the importance of client education, including counseling the client regarding potential adverse reactions and possible efficacy failure.
He summed up the possibilities of what can go wrong in compounding:
- Inadequate oversight of quality assurance and control, resulting in formulation error or drug used in an improper application;
- Inadequate storage-- If the potency is low (deteriorated) then the drug might not work (therapeutic failure). If the drug degrades into a toxic intermediate, the patient can become sick or die from it;
- Lack of product testing;
- Lack of recall procedures (if a product were to test as unsafe, sufficient structure might not exist to be able to recall the products, as there would be with an FDA-approved product);
- Inadequate processing facilities regarding cleanliness (resulting in a potentially contaminated product).Improper operation and maintenance of equipment; and
- Oversight by FDA and state pharmacy boards can be difficult/limited due to economic cutbacks.
AAEP has now required PCAB accreditation of compounding pharmacies with exhibits at their annual convention trade show to meet a minimum standard.
Disclaimer: Seek the advice of a qualified veterinarian before proceeding with any diagnosis, treatment, or therapy.