GOOD EQUINE CLINICAL PRACTICE AND COMPOUNDED DRUGS

Essential to rational therapeutic drug use is knowledge of the quality, strength (concentration), purity and availability of the molecule in the formulation that we intend to administer. Further, the veterinarian's responsibility is to practice medicine scientifically and ethically. If we believe that these statements are valid, then we can appreciate that various levels of scientific or empirical evidence regarding the nature of a particular drug formulation provide us with various levels of assurance that patients will respond favorably to administration of a drug. The highest assurance for safe and effective use of a drug comes when the available drug formulation (dosage form, excipients, concentration, etc.) was associated with a desirable response, without untoward adverse effects, as evidenced in controlled clinical trials that evaluated safety and efficacy. When well-controlled clinical studies are lacking we must use more tenuous supportive information which includes, pharmacokinetic data, data collected from other species, case series and/or anecdotal reports. As the specificity and unbiased nature of the supporting data weaken, our confidence in the drug's effect should diminish. We must keep the value of the available evidence for safety and efficacy in mind when applying any therapeutic. Equine veterinarians are fairly familiar, and to some degree comfortable, with the use of drugs in the absence of scientific evidence. The literature is replete with case series, case reports, pharmacokinetic and in vitro data (microbiology) information, but controlled prospective clinical studies are rare.

With all of this uncertainty, the least we must know is that we are actually administering the drug we intend to administer. This is inherent for drugs approved by many government regulatory agencies (e.g., Health Canada, United States Food and Drug Administration). Regulatory agency approved formulations have high quality of manufacturing controls and support a high level of confidence regarding product content. The dilemma of equine veterinary medicine is that practitioners find themselves attending to conditions for which there are little clinical data to support therapeutic choices. Equine practitioners often must treat animals where no approved formulation exists, or where approved formulations are impractical to administer. In these situations, equine veterinarians often use compounded medications.

Drugs are administered with the hope of achieving a desirable effect. Veterinarians find themselves in situations where the only choice for treatment is a compounded medication. However, use of compounded medications is bounded ethically and scientifically by several stipulations that include, but are not limited to, the development of a veterinarian-client-patient relationship, prescription drug dispensing restrictions, and the formulation's use in the treatment of disease or to improve welfare, but not to enhance performance. In addition, there should be no government regulatory agency (e.g., Health Canada, United States Food and Drug Administration) approved product in a suitable dosage form to treat the condition.

Basic to achieving a positive effect when administering drugs, is knowing that the drug is administered in the desired strength and that the drug is available to the patient. If practitioners choose to compound, or to prescribe compounded medications, they accept the responsibility for formulation effectiveness, safety and composition. Approved drugs are consistently formulated to specification. Assurance of a formulation's composition or its availability to the patient is less certain when veterinarians prescribe compounded medications. Therefore, the veterinarian must ask some specific questions prior to choosing a firm to compound a prescribed formulation.

Does the firm compound medications for laymen?

If the answer is yes to this question, then I would suspect the actions of these compounding pharmacies and the quality of their products. Invariably, this action is not approved by pharmaceutic guidelines which specifically state that compounding of drugs should only occur by request of medical professionals and by prescription only 

Is a licensed pharmacist on staff?

I believe that having a licensed pharmacist on staff, that supervises the compounding process, is essential for quality drug compounding and, depending on the jurisdiction, may be legally required. Pharmacists have the training, and legal and ethical responsibility to follow good compounding practices as prescribed by the practice of pharmacy and as outlined by the attending jurisdictions. In the United States, these jurisdictions are predominantly the State Pharmacy Boards. Pharmacists have the training to understand the issues of quality, strength, purity, bioavailability, and stability essential to rational use of drugs. Some firms do not have pharmacists on staff or there is at best a loose association between the compounding firm and a pharmacist. Veterinarians should ask for the pharmacist's name and state license number for verification.

If bulk product is used to produce the compounded formulation, are these produced under Good Manufacturing Practices (GMP) at the source of origin?

In some situations, the use of bulk products provides for greater safety than the use of approved dosage forms in compounding. A clear example is the use of an oral tablet versus a bulk product to produce an injectable solution, or where excipients or other active ingredients in the approved formulation are potentially detrimental to the species where the compounded drug is to be used.

Clearly, the raw materials must be of high quality, for the final product to be of high quality. Good manufacturing practices ensure that the product delivered to the compounding firm has the quality attributes identified by its label and certificate of analysis. Good manufacturing practices provide for the controls necessary to assure that the resultant product has and retains the intended identity, quality, strength, and purity. A certificate of analysis should be forwarded with each shipment of product. Quality compounding firms will not hesitate to provide certificates of analysis for the bulk drug they use. Some compounding pharmacies do not verify the quality of their raw materials, and simply find the least expensive source regardless of the manufacturing controls. In fact, some bulk drug producers do not use GMP standards for all of their products. Therefore, each shipment of bulk drug should have its own certificate of analysis that is filed at the compounding pharmacy.

It is important to note that using bulk raw materials to compound drugs intended for use in food animals or for use in horses intended for human consumption is not appropriate, except in rare instances. This relates directly to the lack of assessment of the safety of these products in terms of food residues. Where horses are companion animals and not used for food, the use of bulk products for compounding is of no human food safety concern.

What type of quality testing is performed?

Ideally, each batch of the final packaged, compounded product should be quality tested. Unfortunately, this is impractical in many situations. Nevertheless, if a compounded formulation is produced on a regular basis, some form of test batch analysis should be expected. Even when GMP bulk drugs of known strength and quality are used, loss of active ingredient, or formulation errors may occur during compounding. Analysis of the compounded drug should be performed after the compounding process is complete.

Are stability data available?

The nature of equine practice demands a stable compounded product. Equine veterinarians tend to work outdoors which is not a temperature controlled environment. Chemists cannot predict, with great confidence, the stability of formulated products without data from controlled stability studies. Therefore, it is judicious to identify if and under what conditions stability testing has been performed. Quality compounding firms may collect such data. I recommend keeping adequate samples for analysis, especially if the product is prescribed with some frequency. The expiration date should be set at the time a prescription should be entirely used.

Other considerations

Equine veterinarians must not take the prescription of compounded drugs lightly. Approved drugs give us the highest assurance of quality, strength, purity and stability, as well as the best opportunity for accurate dosing. Dramatic changes in drug disposition (i.e., bioavailability) may occur with minor changes in compounding technique, even while using the same recipe. In addition, approved formulations undergo rigorous tests under various environments to define the limits of storage conditions. This assures us that the approved drugs are reasonably stable under conditions of use. Compounded drugs are rarely tested for stability.

Veterinarians rarely have the ability to establish drug stability, physical and chemical compatibility, and pharmacodynamic action of the drugs they use. Ethically, we must take responsibility for the use of compounded drugs. To do so, we must collect information on the practices of individual compounding firms. In addition, we must depend on licensed pharmacists to provide us with well-compounded drug formulations. It behooves us, our clients, and our patients to be familiar with the quality of product produced by the firms we choose to compound our needed formulations.

Creadits: Joseph J. Bertone, D.V.M., M.S., Diplomate ACVIM  - US Food and Drug Administration

Dr. Bertone is a Veterinary Medical Officer with the Center for Veterinary Medicine's Equine and Antimicrobial Drugs Branch. He was recently voted the 1996 Equine Program Speaker of the Year by attendees of the North American Veterinary Conference. Dr. Bertone received this honor in 1995,

REFERENCES

1. Upson D. AVMA Guidelines on Compounding. J Am Vet Med Assoc 1994;205:
199-200.
2. Riviere J.E. Influence of Compounding on Bioavailability. J Am Vet Med Assoc 1994;205:226-231.