Pharmaceutical compounding: who's following the rules? (Proceedings)
Veterinarians are faced daily with the therapeutic challenge of treating species and conditions for which no approved drug exists. Other challenges include the differing needs of patients that have species-specific requirements, as well as individual needs for palatability and formulation. Some of these needs can be met by extra-label drug use under the regulations of the Animal Medicinal Drug Use Clarification Act of 1994. However, extra-label drug use is insufficient if a drug is no longer available as either a human or veterinary formulation, if the palatability of a formulation is poor, if a formulation needs to be a different strength from the approved product. Under these circumstances, compounded drugs are often used. Drug compounding can be described as a change in the dosage form of a drug from that of the approved product. Although provisions for compounding are included under AMDUCA, much of the regular practice of compounding stands outside of clear regulatory guidelines. In the wake of considerable regulatory confusion and disturbing accounts of therapeutic failure with compounded products, veterinarians, pharmacists, and regulators are revisiting the role of compounding pharmacies in veterinary practice.
What are the rules?
There are several laws and regulations to consider in the legality of drug compounding. First, the federal government was given regulatory authority over drugs by the Pure Food and Drug along with the Food, Drug and Cosmetic Acts of 1906 and 1938. However, regulations that specifically covered drug compounding took longer. Human compounding was addressed by the Food and Drug Administration Modernization Act in 1997, but veterinary use was ignored. Like extra-label drug use, veterinary use of compounding was included in the 1994 Animal Medicinal Drug Use Clarification Act (AMDUCA). This act laid the provisions for both extra-label drug use and for drug compounding, resulting in some confusion among veterinary practitioners about which regulations cover which specific practice.Given these combinations of provisions, guidelines for drug compounding are described by the AVMA as:
• A valid Veterinarian-Client-Patient relationship (VCPR) must exist.
• The health of an animal must be threatened or suffering or death may result from failure to treat.
• There must be no FDA-approved, commercially available animal or human drug that, when used as labeled or in an extra-label fashion in its available dosage form and concentration, will appropriately treat the patient.
• The product must be made from an FDA-approved commercially available animal or human drug.
• The product must be compounded by a licensed veterinarian or a licensed pharmacist on the order of a veterinarian within the practice of veterinary medicine.
• The compounded product must be safe and effective.
• The amount of product compounded must be commensurate with the need of the animal identified in the VCPR-based prescription.
• For animals produced for human consumption, the veterinarian must establish an extended withdrawal interval for the compounded product and ensure food safety. Compounding is not permitted if it results in violative food residue, or any residue that may present a risk to public health.
• No drug may be compounded for food animals from drugs listed on the prohibited list.
• Veterinarians must comply with all aspects of the federal extralabel drug use regulations including record-keeping and labeling requirements.
• All relevant state laws relating to compounding must be followed.
A quick review of these requirements reveals several areas where common compounding practices may deviate from federal regulations. First, the need for a valid VCPR dictates that compounding cannot occur independent of the needs of a specific patient. As a consequence, the practice of stocking compounded drugs before the need for these drugs arises would be in violation of the first and seventh requirements. This presents a problem for veterinary practices that routinely need compounded products on an emergency basis, without the luxury of time required to fill a prescription and obtain the final compounded product. The 2004 FDA Compliance Policy Guide, last issued in 2003, attempts to clarify some of the confusion arising from existing compounding regulations with regards to obtaining compounded product without a VCPR and to resale of a compounded product. The CPG states that FDA regulatory enforcement may be undertaken under the condition of, "compounding of drugs in anticipation of receiving prescriptions, except in very limited quantities in relation to the amounts of drugs compounded after receiving prescriptions issued within the confines of a valid VCPR." The CPG further opposes third party (e.g. veterinarian) sale of drugs compounded by a pharmacy. State pharmacy regulations also apply and may differ somewhat, with some allowing a practitioner to stock and sell a small supply of compounded medications sufficient for an anticipated patient need until the compounded prescription can be filled. Taken together, these statements suggest that practitioners may keep a very limited supply of routinely needed medications on hand to administer or dispense while a compounded prescription is concurrently filled. However, the practice of purchasing large amounts of compounded medications in the absence of a specific patient in need of that compounded product and especially of reselling such products is clearly discouraged by the FDA CPG and by most state pharmacy regulations.
The third requirement of drug compounding, that no FDA approved, veterinary or human drug currently exists that can meet the needs of the patient, is clearly counter to common practice. A perusal of catalogs of compounding pharmacies will show many products and formulations that are substituted for approved drugs. The practice of substituting compounded drugs for approved drugs may be necessary in a few special circumstances, such as when the concentration of the approved drug is inappropriate for an individual patient or when palatability of the approved product is an issue. However, substitution of compounded products for approved products is more commonly performed in an effort reduce costs of drug therapy. A price reducing intention is clearly counter to FDA guidance and can expose patients to unnecessary risk, as some of these substitute products are prepared from drug stocks of unknown purity and potency. This raises what has become the most contentious issue currently surrounding the practice of veterinary compounding: the use of bulk drugs to prepare the compounded product. Bulk drug is a compound in its raw, often powdered form that is ordered directly from a chemical or pharmaceutical manufacturer. Some drugs, such as cisapride and some antidotes, are not currently manufactured as approved drugs and so can only be prepared from bulk ingredients. Other compounded drugs may be prepared from bulk supplies in order to meet a specific concentration need. However, the majority of drugs compounded from bulk chemicals have the appearance of being cost-saving measures.
In order to put the use of bulk chemicals into perspective, let's compare the manufacture of approved drugs with that of bulk drugs used in compounding. Pharmaceutical companies will use bulk drugs as one step of the manufacturing process. However, pharmaceutical companies are also subject to strict oversight and regulations, such as Good Manufacturing Practice, that are designed to establish and maintain the purity, potency, stability, and sterility (if applicable) of the final manufactured product. Compounding pharmacies are bound to no such manufacturing regulations, with the result that the patient, client, and veterinarian are left to trust completely that a compounding pharmacy can reliably ascertain whether the drug source, preparation steps, and product stability all meet high standards. Several independent studies of compounded pharmaceutical products have demonstrated that compounded drugs often fail to meet such standards. While bulk drug may be certified by the United States Pharmacopeia (USP) to be of high purity, use of many USP drugs will result in final compounded product that is at least as expensive as the FDA approved product. Therefore, many bulk drugs are instead obtained from uncertain and questionable sources where certificates of analysis are not performed by independent testing. Given the not too distant melamine scare in pet foods, independent testing for purity and potency has become a matter of great concern when using drugs of unknown origin. Further, the use of bulk drugs introduces an extra preparation step that a pharmacy technician must undertake, which can increase the chance of formulation errors. In 2009, the shocking deaths of 21 polo ponies that received a compounded vitamin supplement illustrated the worst of the compounding industry woes, where a seemingly small measurement error can have disastrous consequences for all involved.