In a recent issue of a veterinary journal, vaccines for bees (for American Foul Brood – AFB) made the headlines. Veterinarians would oversee administering the vaccine and possibly in “compounding” the vaccine for specific queen bees. Honeybees are food animals because they produce honey for human consumption and because they have a role in crop pollination and are therefore covered by the FD&C Act.

On further reading, there was an article on a recent FDA Guidance for Industry (CVM GFI #256 (here) on April 14, 2023, for Compounding Animal Drugs from Bulk Drug Substances. This guidance is for veterinarians, State-licensed pharmacies, and Federal facilities that may compound animal drugs from bulk drug substances for use in non-food-producing animals, as antidotes in food-producing animals, or as sedatives or anesthetics in free-ranging wildlife when no other medically appropriate treatment options exist.

The Federal Food, Drug, and Cosmetic Act (FD&C Act) permits compounding of animal drugs when the source of the active ingredient is a finished FDA-approved drug, and not a bulk drug substance. A “bulk drug substance” is a substance used to make a drug that becomes an active ingredient in the finished dosage form of the drug. Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), the compounding of an animal drug from bulk drug substances results in a “new animal drug” that must comply with the FD&C Act’s animal drug approval, conditional approval, or indexing requirements (Sections 512, 517, and 572 of the FD&C Act). All animal drugs are required to be made in accordance with current good manufacturing practice (cGMP) requirements (Section 501(a)(2)(B) of the FD&C Act) and have adequate directions for use (Section 502(f)(1) of the FD&C Act). Compounding animal drugs using finished FDA-approved animal or human drug products as the source of the active ingredients is an extralabel use of an approved drug, which is legal under the FD&C Act if the conditions of 21 CFR Part 530 are met.

Compounding animal drugs using bulk drug substances (BDS) not on the FDA’s “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals” or the “List of Bulk Drug Substances for Compounding Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife Species”, produces compounded animal drugs that violate the FD&C Act. The above lists are referred to as the dynamic lists.

When there is no medically appropriate drug that is FDA-approved, conditionally approved, or on the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species (indexed) to treat the animal/patient, and when an FDA-approved drug cannot be used as a source of active ingredient(s) for compounding, an animal drug compounded from a bulk drug may be a medically necessary drug.

The GFI describes the Agency’s approach where veterinarians need access to these unapproved drugs to provide appropriate care for the medical needs of the diverse species they treat (including the bees).

Three elements that veterinarians need to focus on from the GFI 256 are the dynamic lists, making a medical rationale for use of a compounded drug that is not in compliance with the FD&C Act, and adverse events reporting. The Guidance also requires that all compounded office stock medications be compounded from materials on the FDA list of approved bulk drug substances for animal use. Although medications that are not on the approved list may still be prescribed for patients can be ordered, these drugs may not be ordered for in-office use. A medical rationale (in addition to a patient specific prescription) is required for medications compounded from bulk drug substances not on the dynamic lists of bulk drug substances. In addition, veterinarians are required to report adverse events to FDA using Form 1932a.

Other considerations for veterinarians include: having a valid veterinary-client-patient relationship (VCPR); whether an FDA approved (animal or human) drug or indexed drug can be used as labeled or in an extralabel manner, including compounding with the approved or indexed product to treat the patient; that distribution is appropriate to the patient’s owner or caretaker or another veterinarian in the practice at the same location; reporting adverse events; and prescribing drugs for specific animal patients that are to be compounded from BDS by a pharmacy. Veterinarians should check to see if the patient is not a food-producing animal. If for a food-producing animal, they should follow FDA’s recommendations for food-producing animals.

Elements that compounding personnel/pharmacists need to focus on include: confirming whether the patient(s) is a nonfood-producing animal or a food-producing animal; following all state laws and regulations that apply to compounding animal drugs; meeting USP standards and FD&C Act requirements; compounding with BDS and other components that meet the standards set in any USP-NF monographs for the ingredient, if such monographs exist, and FD&C Act requirements for drug components, including all required labeling information on the labeling of the compounded drug.

Given the history of bacterial and fungal contamination of drugs compounded under insanitary conditions, FDA has stated concern about widespread harm to animals. FDA stated specific concern about the potential risk of harm when animal drugs are compounded from bulk drug substances for office stock – meaning, product meant to be kept in a veterinarian’s inventory. Because these products are made in larger quantities and may be widely distributed to veterinary hospitals, these office stock products could endanger many animals if compounded improperly or under insanitary conditions.

Under the circumstances described in GFI 256, FDA intends to exercise enforcement discretion for office stock for nonfood-producing animals, antidotes for food-producing animals, and sedatives and anesthetics for free-ranging wildlife that are compounded from bulk drug substances on the dynamic lists.

FDA’s final guidance balances the agency’s objectives of (1) ensuring veterinarians have access to drugs to treat the broad diversity of animal patients; (2) protecting animals and humans from unsafe animal drugs; and (3) preserving the integrity of the FDA animal drug approval process.

Veterinarians are highly recommended to send nominations of additional bulk drug substances at any time to FDA and recognize that FDA will continue to review the nominations and update the dynamic lists on a rolling basis. The agency will prioritize office stock for enforcement action, as well as any products made under poor compounding practices.