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Compounding Regulations

A quick search of the news will provide a variety of historical cases in both human and veterinary medicine where poor-quality compounds resulted in significant morbidity and mortality. In these cases, it is often argued that something was not done legally, and if all relevant laws had been followed, the compounds would not have been made. Therefore, it behooves anyone preparing compounded medications to be well aware of the regulations surrounding compounding.

Clenbuterol Toxicosis in Three Horses in 2006 [1-3]: Three horses displayed toxicity symptoms between 12 and 24?h after receiving a clenbuterol compound that contained 70-fold the amount of clenbuterol indicated on the labeling. The label indicated that the product contained 72.5?mcg/ml of clenbuterol when it actually contained 5?mg/ml. The commercial product containing clenbuterol at 72?mcg/ml had previously been used in at least one of the horses without issue. Two of the three horses were euthanized due to complications. The illegal "compounded" product was obtained from an unidentified source and administered without a prescription.

Twenty-one Polo Ponies Die Due to Compounding Error in 2009 [4, 5]: Twenty-one polo ponies competing at the US Open Polo Championship in 2009 collapsed with most dying within hours due to a selenium overdose. Franck's Pharmacy in Ocala, FL had made an error when compounding a vitamin mixture containing B-12, selenium, and other minerals, which resulted in 100 times more selenium than intended. It was determined that the horses had 10-15 times more selenium in their blood and 10-20 times more in their liver than the normal amount, which led to their deaths. The prescribed compound was intended to mimic Biodyl, which is used commonly in Europe, Asia, and Latin America. However, Biodyl is not a Food and Drug Administration (FDA)-approved product.

Fungal Meningitis Outbreak in 2012-2013 [6-8]: Three lots of a contaminated preservative-free methylprednisolone acetate injection compounded by the New England Compounding Center (NECC) in Framingham, MA were responsible for 778 fungal infections resulting in 76 deaths across 20 states. The three lots included more than 17?000 vials of the medication which were improperly sterilized through a nonverified sterilization process and improperly tested to ensure sterility prior to being shipped throughout the United States.

Upon investigation of the compounding facility, it was noted that drugs were routinely shipped before sterility testing results were received, compounds were prepared utilizing expired ingredients, and cleaning logs were ignored as was the presence of mold and bacteria in the clean rooms. Additionally, the NECC was attempting to conceal that a technician whose license had been revoked by the Massachusetts Board of Pharmacy (BOP) was responsible for compounding sterile products.

Compounded Equine Protozoal Myeloencephalitis (EPM) Drug Linked to Equine Deaths in 2014 [9, 10]: Ten horses (eight in Florida and two in Kentucky) experienced adverse effects including seizures and fever with four horses dying after receiving a compounded EPM medication. A toltrazuril/pyrimethamine product was compounded as a paste and suspension by Wickliffe Veterinary Pharmacy of Lexington, KY containing more pyrimethamine than indicated on the labeling. Typically, the compounded paste contains 416-mg/ml toltrazuril and 17-mg/ml pyrimethamine. The lawsuit states that when the implicated product was tested, it actually contained 22?mg/ml of toltrazuril and 229?mg/ml of pyrimethamine.

Compounded EPM Drug Linked to Equine Deaths in 2019 [11, 12]: One lot of a compounded paste labeled to contain 416-mg/ml toltrazuril and 17-mg/ml pyrimethamine and compounded by Rapid Equine Solutions in Aston, PA was found to contain 18-21 times the labeled pyrimethamine concentration. The product was recalled and tested after adverse effects followed by death were noted in at least three horses. Specifically, the affected lot was found to contain 13.5 and 11.2?mg/ml of toltrazuril (3% of the labeled concentration) and 361 and 307?mg/ml of pyrimethamine (2122 and 1808% of the labeled concentration) in the two separate samples that were tested by the FDA.

However, veterinary compounding regulations are not always black and white. Common causes of confusion include the following:

• Regulations may not clearly address practical concerns.
• Human compounding regulations are often unclear whether they apply to veterinary compounding.
• Federal regulations that exempt animal patients on the federal level may be applied to animal patients at the state level.
• Compounding is largely regulated by the states resulting in significant state-to-state variation.
• Guidance for Industry (GFI) and Compliance Policy Guides (CPG) do not have the force of law but are often given significant weight.
• The regulatory landscape surrounding veterinary compounding is continuously changing and evolving to address problems and concerns that arise.
• What qualifies as compounding varies depending on which definition is being referenced.

Due to wide state-to-state variation, and regulations and standards that frequently change, this chapter is only designed to provide an overview and a starting point for further research into regulations applicable to your practice.

Organizations and Regulatory Agencies Involved with Compounding

Compounding regulations fall under a variety of agencies including:

• Food and Drug Administration
• United States Pharmacopeia (USP)
• Drug Enforcement Administration (DEA)
• State Boards of Pharmacy
• State Veterinary Boards

Food and Drug Administration

The FDA is an agency with an overall mission to "protect the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices; and by ensuring the safety of our nation's food supply, cosmetics, and products that emit radiation?." [13]. It is further divided into nine centers, which includes the Center for Veterinary Medicine, which has a mission of "protecting human and animal health." The FDA is responsible for drug approval in the United States. Compounded drugs are not approved products, but the FDA maintains oversight through compounding regulations. However, patient-specific compounding is largely turfed to the states to regulate. Potentially, the FDA could conduct inspections, issue warning letters, and take additional actions such as injunctions, seizures, and criminal prosecution. Practically, the FDA only inspects compounding pharmacies on a "for cause" basis. Limiting factors that prevent the FDA from conducting regular inspections of compounding pharmacies include a lack of a comprehensive list of all compounding pharmacies because there is no requirement to register with the FDA, and a lack of resources to inspect the thousands of compounding pharmacies and veterinarians [14].

The FDA does complete a handful of compounding pharmacy inspections each year based on reports of adverse effects or illegal compounding. Between 2003 and 2015, the FDA conducted 39 inspections. Two reasons for warning letters issued by the FDA include large-scale compounding from bulk chemicals and compounding without a documented medical need. As a result of these inspections, multiple legal cases over the past two decades have challenged the FDA's oversight of compounded medications demonstrating that the exact role of the FDA in regulating compounded medications for nonfood animals remains unclear [14].

United States Pharmacopeia

The USP is an independent, nonprofit organization established in 1820 by a group of physicians. The physicians had noticed that ordering the same compounded medication from different apothecaries produced very different efficacy and safety. The initial intent of the USP was to standardize the quality of compounded medications. The USP evolved over the years to incorporate representatives from many different professions and to adjust to new advances such as the transition from using primarily compounded medications to manufactured medications being the predominant medication source. USP's mission statement is "To improve global health through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods" [15].

The USP is not a government agency. Instead, it operates as a standard setting body that works with FDA representatives and other government agencies. USP-NF is two compendia: the USP and the National Formulary (NF). Standards that are included in the USP-NF are based in science and developed through a transparent process that seeks stakeholder input. Active drugs that meet the USP standards are indicated with "USP" following the drug name (e.g. methimazole, USP). Compounding excipients that meet the USP standards are indicated with "NF" following the excipient name (e.g. Simple Syrup, NF). Since the USP is not a regulatory body, it does not enforce its standards. USP-NF is recognized in the Food, Drug,...