Compounding: FAQs for veterinarians
Compounding basics and key definitions
Prescribing and quality control
General rules and regulations
Compounding from bulk drug substances (GFI #256)
Compounding basics and key definitions
Q: What is compounding?
A: Compounding is any manipulation of a drug beyond that stipulated on the drug label. In veterinary medicine, compounding can be essential to meet patients' therapeutic needs, especially considering the wide range of species and breeds that veterinarians treat.
Compounding might include combining, mixing, diluting, concentrating, or flavoring a drug or drugs. This manipulation changes the dosage form. Examples of compounding include the following:
- Mixing two injectable drugs in the same syringe to avoid giving a patient two separate injections
- Creating an oral suspension from crushed tablets to make the drug easier to administer
- Adding flavoring to a commercially available drug to increase palatability
- Mixing two solutions for instilling into the ear when no otic preparation of the required drug(s) or strength is available
- Creating a transdermal gel for a drug typically given through other routes to increase compliance
Drugs should only be compounded based on a licensed veterinarian's prescription, and to meet the medical needs of a specific patient or small group of patients. In veterinary medicine, compounding must be performed by or under the direct supervision of a veterinarian or a pharmacist in a state-licensed pharmacy or federal facility.
Q: What are the two main categories animal drug compounding, and how do they differ?
A: Animal drug compounding can be described in two main categories, based on the source of active ingredient1:
- Compounding from an FDA-approved animal or human drug, which is legal extralabel use under the Animal Medicinal Drug Use Clarification Act (AMDUCA) and the Federal Food, Drug, and Cosmetic Act
- Compounding from bulk drug substances (BDS, also known as active pharmaceutical ingredients), which creates an unapproved new animal drug and violates the Federal Food, Drug, and Cosmetic Act
The benefit to compounding medications from FDA-approved, conditionally approved, or indexed products versus bulk drug substances is that FDA-approved products have been reviewed for evidence that they are safe, effective, properly manufactured, and accurately labeled. Each lot or batch of FDA-approved, conditionally approved, or indexed products is manufactured in accordance with current Good Manufacturing Practices, which require acceptance criteria2 testing of products before they're released for distribution (Code of Federal Regulations [CFR] Title 21 §211.165). In contrast, the certificate of analysis that accompanies a bulk drug substance is created by the manufacturer and does not indicate that the FDA has reviewed similar data and approved the bulk drug substance for safety, efficacy, proper manufacturing, or accurate labelling, particularly for each lot or batch.
Q: What is a "new animal drug," and what makes it new?
A: The Federal Food, Drug, and Cosmetic Act defines a new animal drug as a drug intended for use in non-human animals—including any drug intended for use in animal feed but not including the animal feed itself—that is not generally recognized by experts as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling. In other words, if a drug is generally recognized as safe and effective, then it's not a new animal drug.
A narrow exception to this definition is grandfathered drugs. These are drugs that were approved before June 25, 1938, under the 1906 Food and Drug Act, and that have not changed in labeling or composition since then. Such drugs are not considered new animal drugs.
Q: What does it mean for an animal drug to be FDA-approved, conditionally approved, or indexed?
A: An understanding of these terms is important to understanding how the regulations on animal drug compounding affect veterinarians and our patients. New animal drugs can't legally be marketed in the United States unless they have been reviewed by the FDA and approved, conditionally approved, or index-listed by the agency.
FDA-approved: This means that the animal drug is safe and effective when used according to the label. "Safe" in this context refers to both the animal to which the drug is administered, and, in the case of food-producing animals, the food products that might be derived from the animal. Approval also ensures that the drug's strength, quality, and purity are maintained from batch to batch, and that the drug's labeling is truthful, complete, and not misleading. Other factors considered in the approval process include the drug's impact on the environment, and the safety of the people who will administer the drug or may otherwise come into contact with it.
Conditionally approved: This allows sponsors to market for up to five years an animal drug that is known to be safe and reasonably effective, while performing studies to demonstrate effectiveness. Only drugs for minor species (any non-human species that is not defined as a major species), or for minor uses in a major species (horses, dogs, cats, cattle, swine, chickens, and turkeys) are eligible for conditional approval. A drug to treat a disease in sheep or goats, for example, is eligible for conditional approval because both are minor species. For major species, "minor use" is defined as use of a drug for a condition that occurs infrequently and in only a small number of animals each year, or in a limited geographic area. The pathway for conditional approval also includes certain drugs that are intended to treat some serious or life-threatening diseases, or to treat diseases that are particularly difficult to study in a major species that may not otherwise be eligible for conditional approval.
Indexed: This means the animal drug is listed on the FDA's Index of Legally Marketed Unapproved Drugs for Minor Species (the Index). The Index pertains to nonfood-producing minor species or for nonedible, very early life stages of edible species. It represents a list of new animal drugs intended for use in minor species that have had their safety and effectiveness affirmed through an alternative FDA review process. In many cases, minor species drug products are intended for uses that cannot reasonably go through the standard drug approval process. They are often intended for use in species too rare or too varied to be used in traditional safety and effectiveness studies. Indexing is especially helpful for veterinarians who treat animals or classes of animals representing markets too small to support the cost of the drug approval process, even with the incentives of the Minor Use and Minor Species (MUMS) Animal Health Act of 2004.
An important difference between FDA-approved drugs and the other two animal drug categories is that extralabel use is not permitted for conditionally approved or indexed animal drugs. The labeling for every conditionally approved drug states, "It is a violation of Federal Law to use this product other than as directed in the labeling." However, in Guidance For Industry (GFI) #256, the FDA's Center for Veterinary Medicine (CVM) states that it generally does not intend to take action against extralabel use of these drugs to compound animal drugs (meaning veterinarians may do so), which the agency believes is a less risky alternative to using drugs compounded from bulk drug substances.
Q: What is a bulk drug substance (BDS)?
A: The FDA defines a bulk drug substance (also known as an active pharmaceutical ingredient) as "any substance intended for incorporation into a finished drug product that furnishes its pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body." These substances usually take the form of a powder. They do not include intermediates used in the synthesis of the substance (21 CFR §207.1).
Q: What is an inactive pharmaceutical ingredient?
A: The FDA defines an inactive ingredient (also known as an excipient) as any component of a drug product other than the active ingredient. Such ingredients can be added during the manufacturing or compounding process to help stabilize the product, aid in its absorption or metabolism, or provide other properties unrelated to pharmacological action. Examples include binding agents, preservatives, flavoring agents, sweeteners, and absorption enhancers. Although inactive ingredients in FDA-approved, conditionally approved, or indexed products generally are safe, they could cause allergic reactions or intolerances in certain individuals.
Q: When is compounding necessary?
A: Compounding for nonfood-producing animals may be necessary when approved drugs need to be modified to sufficiently treat the patient (e.g., through flavoring, diluting, or changing the form of medications from tablet to suspension).
For example, if you need to prescribe methimazole (Felimazole®) for a hyperthyroid cat, but the owner tells you the cat will not allow the owner to "pill" it, you might need to have the product compounded into a liquid form so the cat can be adequately treated.
Compounding for nonfood animals might also be necessary when no approved drug exists, or if the approved drug isn't commercially available to treat a pet's diagnosed condition. In such circumstances, it may be necessary to use bulk drug substances to provide patients with essential medications.
There are three general sets of circumstances in which AVMA believes compounding from bulk drug substances may be necessary:
- The approved drug is not commercially available due to shortages or other reasons.
- The needed compounded preparation cannot be made from the approved drug.
- There is no approved product from which to compound the needed preparation.
For food animals, AVMA recognizes specific circumstances where compounding from bulk drug substances might be medically necessary. Specifically, poison antidotes, compounds for euthanasia or depopulation, or for sedation and anesthesia may be needed that are not approved or commercially available.
Otherwise, drugs should be compounded only from FDA-approved, conditionally approved, or indexed drugs to fulfill the regulations written to implement the Animal Medicinal Drug Use Clarification Act (AMDUCA).
The status of drug shortages can be checked on the FDA website.
Q: How do compounded medications differ from the ones I or my clients can get from a store or regular pharmacy?
A: Compounded medications may be modified versions of brand-name or generic medications you would otherwise buy at the store or pharmacy.
To gain FDA approval, all of these criteria must be met:
- Both brand-name and generic drugs must be shown to be safe and effective.
- Their label must be approved by the FDA.
- Their manufacturing facilities and processes must meet certain FDA specifications.
- The manufacturer must continually ensure the shelf stability of the product.
After approval, the FDA also provides inspectional oversight and monitoring of adverse events, product defects, and changes in manufacturing and labeling. Extralabel use of human generic drugs in animals is allowed under specific conditions within federal law, under AMDUCA3 and regulations in 21 CFR Part 530.
Compounded medications, on the other hand, are not evaluated or approved by the FDA. Consequently, there is no FDA oversight to ensure important drug characteristics like safety, bioavailability, effectiveness, quality, and stability. There also are no regulatory requirements to report adverse events or product defects.
Animal drugs compounded from bulk drug substances are of particular concern even if they have the same active ingredient as an approved generic or brand-name drug. This is because the compounded preparation may no longer perform in the same manner as the approved drug due to changes in stability, bioavailability, metabolism, and/or elimination of the drug that come with changing the dosage form.
Q: Is a compounded drug the same thing as a generic drug?
A: No. A generic drug is an FDA-approved product that has been demonstrated to be bioequivalent to a brand-name drug. It is considered an equivalent substitute for the brand-name drug, having the same dosage form, safety, strength, administration route, intended use, and other characteristics. On the other hand, a compounded drug is not FDA-approved, and has not been demonstrated to be bioequivalent. This is true even if it's made from an FDA-approved brand-name or generic drug.
Generic animal drugs have an abbreviated new animal drug application (ANADA) number assigned by the FDA's Center for Veterinary Medicine. You can typically find this number on the container. Compounded animal drugs lack an ANADA number.
Q: What is a copy drug?
A: If a bulk drug substance used to compound an animal drug is also the active ingredient in an FDA-approved product, and has the same route of administration, then the compounded drug is considered a copy drug. The notion of copy drugs is particularly important when considering compounding of patient-specific prescriptions for nonfood-producing animals, as it is expected that the medical rationale for prescribing such a product be documented in the medical record.
Prescribing and quality control
Q: Are pharmacists trained to compound for animals?
A: Traditionally, many pharmacy schools have not included veterinary pharmacotherapy in their curricula to a significant extent, although there have been recent efforts to incorporate more veterinary-specific training. In most cases, veterinary-specific pharmacy training, including compounding, is obtained through independent continuing education on the part of the pharmacist.
Because drugs and compounded preparations may behave differently in animals than in humans, veterinarians are encouraged to ask compounding pharmacists if they have specialized training or credentials in veterinary compounding. It's also advisable for veterinarians to specifically seek the compounding services of pharmacists who have specialized knowledge of veterinary compounding.
Q: How can I find a reputable compounding pharmacy?
A: Check your state board of pharmacy for information on which pharmacies are licensed to do business within your state. In addition, there are independent, third parties (such as the Pharmacy Compounding Accreditation Board) that accredit pharmacies meeting certain criteria. It's advisable for veterinarians to consider whether the pharmacy is compliant with the United States Pharmacopeial (USP) Convention standards, such as General Chapters (795) and (797) for non-sterile and sterile compounding, respectively.
Q: What information needs to be included on the label for a compounded preparation?
A: In addition to including the client's name on the label, AVMA recommends the following information be clearly conveyed to animal owners when prescribing all compounded preparations:
- Name, address, and telephone number of veterinarian
- Identification of animal(s) treated, species, and number of animals treated, when possible
- Date of treatment, prescribing, or dispensing of drug
- Name, active ingredient, and quantity of the drug (or drug preparation) to be prescribed or dispensed
- Drug strength (if more than one strength available)
- Dosage and duration
- Route of administration
- Number of refills
- Cautionary statements, as needed
- Beyond-use date (BUD)
- Slaughter withdrawal and/or milk withholding times, if applicable
This information may be on the label applied by the manufacturer or on a label attached to the product by the veterinarian or compounding pharmacist.
For more information, see AVMA's guidance on the use of prescription drugs in veterinary medicine, and be sure to check your state's pharmacy and veterinary practice rules, as well.
Q: Do compounded drugs have expiration dates?
A: While FDA-approved, conditionally approved, or indexed drugs have expiration dates, compounded preparations have beyond-use dates (BUDs). Beyond-use dates and expiration dates are not the same. Expiration dates for the chemical and physical stability of manufactured products are determined from results of rigorous analytical and performance testing. They are specific for a particular formulation in its container and at stated exposure conditions.
According to USP, a beyond-use date is the date or time beyond which a compounded sterile or nonsterile preparation may not be stored or transported, calculated from the date or time of compounding. In other words, beyond-use dates indicate the time/date after which the compounded product must not be used. Beyond that time/date, the product is at risk for physical or chemical degradation, microbial contamination and proliferation, and impact on the integrity of the container-closure system. Veterinarians are encouraged to ask the pharmacist about how the beyond-use date for a particular product was established.
Q: How many refills can be ordered on a compounded prescription?
A: The AVMA is unaware of any differences between refilling compounded preparation prescriptions versus other prescriptions. However, to be certain you are following the rules for your state, check your state's veterinary medical and pharmacy rules. Because the period from creation of a compounded preparation to its beyond-use date can be brief, more frequent refills may be indicated.
Q: Can a client use a compounded medication for another animal they own?
A: Check your state's pharmacy rules to be sure. In general, if you are treating animals as a group, herd, or flock and you have established a veterinarian-client-patient relationship, it would be acceptable to provide one prescription or dispensed product with directions for treating the group. However, you must have determined that the compounded drug is necessary for those animals, you are following FDA's extralabel drug use rules, and the patients are to be treated as a group (e.g. a litter of puppies being treated for coccidiosis). If the animals are to be treated as individuals, separate prescriptions are advised to ensure client compliance and effective treatment. Be sure you keep accurate records, and label the drug accordingly.
Q: How can I know that the compounded medication prescribed and dispensed for my patient is safe and effective?
A: Unlike with FDA-approved, conditionally approved, or indexed drugs, you don't have adequate assurances that a compounded drug will effectively and safely treat your patient. However, there are ways you can help to ensure therapeutic success in this scenario:
- Determine if a compounded drug is really necessary.
- Prescribe from a reputable and trustworthy compounding pharmacy.
- Ask the pharmacist to provide evidence to support the stability and assigned BUD.
- Ask the compounding pharmacist for evidence that the compounded drug is safe and effective.
- Contact the state board of pharmacy to determine the status of a pharmacy's license and to gain valuable information, such as the pharmacy permit number. Recognize that most state boards of pharmacy require that an out-of-state pharmacy register with their state prior to filling prescriptions to be mailed into the state.
- Consider whether the pharmacy is certified by an independent body.
Unanticipated drug precipitation, visible flocculant material, color change, or separation of liquid phases in a compounded preparation may indicate improper storage, improper transport, or an unexpected chemical/physical drug interaction. If you observe any of these characteristics, or have questions about the efficacy or safety of the preparation, consult with the compounding pharmacist.
Q: How do I register a possible adverse event or complaint about a compounded medication or a compounding pharmacy?
A: Veterinarians are encouraged to report suspected adverse events or product failures involving compounded preparations to the compounding pharmacist, the state board of pharmacy, and the FDA Center for Veterinary Medicine. Instructions for reporting adverse events to the FDA can be found on the FDA website.
Instruct pet owners to contact both the prescribing veterinarian and pharmacist immediately if a compounded preparation has caused an adverse event.
If an unlawful pharmacy practice is suspected, file a complaint with the respective state board of pharmacy, the state board where the pharmacy is located (if different), and the FDA.
Q: What's my liability if there's a problem with a compounded medication?
A: If a patient experiences adverse effects of a compounded preparation, and the animal's owner brings a claim against you, contact your liability/malpractice insurance provider. In such situations, the liability insurance provider will determine to what degree you are liable for any wrongdoing and whether/ how much they will cover in the case of such a claim.
Q: Have compounded drugs been associated with any adverse effects or animal deaths?
A: Yes. In 2009, 21 polo ponies died after receiving a compounded selenium product. In 2014, four horses died or were euthanized, and six more experienced adverse effects, after receiving a compounded product with about 20 times more pyrimethamine than the labeling indicated. And in 2019, three additional horses died after receiving compounded pyrimethamine that was approximately 18 to 21 times greater in strength than indicated on its labeling.
General rules and regulations
Q: How is compounding regulated?
A: Compounding is regulated by both the FDA and state governments. The FDA regulates compounding for animal patients as part of its extralabel drug use (ELDU) rules. The agency says it generally defers day-to-day regulation of compounding by veterinarians and pharmacists to state authorities. The state boards of pharmacy oversee pharmacy practices within states, while state veterinary medical boards oversee the practice of veterinary medicine, including prescribing.
Q: Does FDA regulate human and animal drug compounding?
A: The FDA conducts inspections, recalls, and other enforcement actions with respect to both animal and human drug compounders. All recalls monitored by the FDA are included in an enforcement report once the agency has classified them, and they may be listed prior to classification when the agency determines the firm's removal or correction of a marketed product or products meets the definition of a recall. These reports provide details on recalls, including the specific product(s) affected and the reason for the recall.
Q: When is compounding legal? What criteria must be met?
A: Compounding is considered legal when federal and state rules are followed. Veterinarians can inquire about state requirements from the relevant state boards of pharmacy and veterinary medicine. Federal rules on extralabel drug use specifically permit compounding from FDA-approved, conditionally approved, or indexed drugs when a veterinarian believes there is a need to alter the approved drug to adequately medicate a nonfood animal with a diagnosed medical condition. This means that there is an established veterinarian-client-patient relationship; the individual patient or small group of patients has a medical condition for which a prescribed medication is needed; and the veterinarian determines that a compounded drug is needed for the animal. To be in line with FDA's ELDU rules, compounding should be performed using the FDA-approved, conditionally approved, or indexed drug.
For example, let's say you need to prescribe a particular FDA-approved antimicrobial for a dog with an ear infection, but the antimicrobial only comes in an injectable form. Following the FDA's rules, you could use the FDA-approved product (e.g., amikacin) in a mixture for instilling into the ear.
On the other hand, the FDA contends that compounding from bulk drug substances for animals has been illegal for many years and continues to be illegal. Nevertheless, the agency recognizes the medical need for compounding from bulk substances within certain areas of veterinary practice and under very specific circumstances. In April 2022, the FDA finalized its Guidance for Industry (GFI) #256 Compounding Animal Drugs from Bulk Drug Substances. This document describes the conditions or situations under which the FDA does not intend to take enforcement action against people or entities compounding animal drugs from bulk drug substances (BDS). In other words, veterinarians may compound animal drugs from BDS in the described circumstances. For more information, see the FAQ section on Compounding animal drugs from bulk drug substances: Understanding GFI #256.
Q: Are there different rules/regulations for compounded preparations from FDA-approved drugs for use in food-producing animals?
A: Yes, and those rules are much more stringent. For example, compounding from a human drug for use in food-producing animals is not permitted if an approved animal drug can be used for compounding. In food animals, the use of compounded drugs is reserved only for situations when no approved new animal drug is labeled for such use and when safe use of that animal for human food purposes can be predicted following discontinuation of the drug. All federal requirements for use of drugs in food-producing animals still apply. Among these requirements:
- The veterinarian must specify a withdrawal interval that is substantially longer than that stipulated by applicable guidance for the compounded preparation, as supported by appropriate scientific information.
- The compounded preparation must be prescribed within the veterinarian-client-patient relationship.
For further information, refer to 21 CFR §530.13: Extralabel use from compounding of approved new animal and approved human drugs.
With regard to compounding from bulk drug substances for food-producing animals, GFI #256 provides very limited enforcement discretion. The only bulk drug substances that can be used are those included on the FDA's list of bulk drug substances for compounding drugs for use in food-producing animals or free-ranging wildlife species.
Q: Can controlled substances be compounded? And if so, how does the process differ from compounding non-controlled substances?
A: Yes, but you will need to follow the FDA's rules, the state's rules, and the U.S. Drug Enforcement Administration's rules. When you prescribe a compounded controlled substance, be sure that the compounding pharmacy is dispensing the product directly to your client/patient. If you do this, you're maintaining what federal authorities refer to as a "closed distribution system."
However, if you allow the compounding pharmacy to deliver the controlled substance product to your clinic for your client to pick up, you'll need to enter that delivery into your controlled substance records. This is because you've received controlled substance inventory that must, by law, be tracked through recordkeeping. Delivery of the controlled substance to your clinic may be necessary if the drug needs to be compounded for use within the clinic (for example, if the drug is needed for a hospitalized patient). Still, receipt of the drug from the pharmacy is considered registrant-to-registrant transfer of controlled substances, for which DEA has very specific rules. In this case, your records need to track the movement of the drug within the clinic at a high level of detail, like any other shipment of controlled substances you receive.
Q: Can vaccines be compounded?
A: The answer here isn't simply yes or no. The USDA's Center for Veterinary Biologics is the federal regulatory authority governing animal vaccines/biologics. When it comes to the USDA's rules, there is no term analogous to "compounding" (unlike the FDA's rules).
When reconstituting a vaccine to administer to a patient, be sure to exactly follow the manufacturer's directions. Mixing multiple vaccines in a single syringe for administration is illegal, could be a liability issue, and could render the vaccines ineffective or even harmful, especially if they are adjuvanted vaccines.
If you need an autogenous vaccine for a patient, be sure to follow AVMA's guidelines for use of autogenous biologics and USDA's rules.
Compounding animal drugs from bulk drug substances: Understanding GFI #256
Q: What are the FDA's top concerns regarding animal drugs compounded from bulk drug substances (BDS)?
A: The FDA's priorities when it comes to compounding animal drugs from BDS reflect top safety concerns given the current understanding of risks associated with this practice:
- Compounded drugs that present human or animal health concerns—for instance, because of contamination or formulation errors
- Drugs compounded for food-producing animals—because of the risk of drug residues in the meat, milk, or eggs consumed by people. When FDA approves a drug for food-producing animals, the agency evaluates human food safety data to establish residue tolerance levels, withdrawal times, and other conditions of use to prevent violative drug residues in the edible products from those animals. Drugs compounded for food-producing animals have not been evaluated by the FDA for human food safety.
- Compounded drugs that are copies of FDA-approved, conditionally approved, or indexed products—because such drugs undermine incentives for firms to invest in getting drugs approved or indexed, which can reduce the availability of animal drugs for which safety and effectiveness have been established
- Drugs compounded as "office stock" without a patient-specific prescription—because office stock exposes larger numbers of animals to drugs of unproven quality and undermines incentives to seek approval by distributing large quantities of unapproved animal drugs
These concerns are reflected in GFI #256.
Q: What is GFI #256?
A: GFI #256 is a set of FDA recommendations that aims to preserve the ability of licensed veterinarians and pharmacists to compound drugs from bulk drug substances (BDS) for veterinary patients under specific circumstances, while protecting animal and human health. It is intended to clarify existing requirements under the law when it comes to compounding from BDS.
This guidance was drafted with the input of dozens of stakeholders, including the AVMA and state and allied veterinary associations. It describes the FDA's approach to situations when veterinarians use unapproved compounded drugs to provide appropriate care for the medical needs of the diverse species we treat. The final draft of GFI #256 was published in April 2022. It does not change the legal status of drugs compounded from BDS, which remain illegal per the Federal Food, Drug, and Cosmetic Act. However, it does allow for enforcement discretion (or flexibility) in certain circumstances, meaning veterinarians may compound drugs from BDS in those circumstances.
Q: What does GFI #256 mean for veterinarians?
A: Veterinarians treat a wide variety of species for many different diseases, but animal drugs are approved by the FDA for use in specific species for particular conditions. Therefore, veterinarians also may prescribe approved human and animal drugs in an extralabel manner. Sometimes, however, no such drug can be used as labeled, or in an extralabel manner, for a particular patient. In those situations, veterinarians may need compounded drugs.
The Federal Food, Drug, and Cosmetic Act requirements regarding drug approval, drug manufacturing, product quality, and labeling may apply to animal drugs compounded from bulk drug substances, just as they apply to drugs manufactured by pharmaceutical companies. Unapproved drugs—including medications compounded from BDS—may not be marketed legally. However, the FDA recognizes that veterinarians need such products. As such, GFI #256 is meant to clarify the circumstances under which FDA does not intend to pursue enforcement action—in other words, the circumstances under which veterinarians may compound drugs from BDS.
Specifically, the policy stated in GFI #256 is:
- The FDA has developed this guidance to explain when it does not intend to take enforcement action for violations of the Federal Food, Drug, and Cosmetic Act's requirements for approval, adequate directions for use, and current Good Manufacturing Practices.
- When pharmacies and veterinarians compound animal drugs from BDS as described, FDA intends to generally defer to state licensing boards for day-to-day implementation oversight.
- Nevertheless, the FDA intends to prioritize enforcement of these provisions when any of the following apply:
- The animal drugs are compounded outside the circumstances described in GFI #256.
- The compounded drugs present particular human or animal safety concerns.
- The compounded drugs do not meet other manufacturing, product quality, labeling, or packaging requirements of the Federal Food, Drug, and Cosmetic Act (e.g., if the product is made under unsanitary conditions or the labeling is false or misleading).
- The FDA generally will rely on compounding pharmacies' home state licensing boards to provide day-to-day oversight of routine compounding practices (i.e., routine inspections for drug quality) but may provide concurrent oversight of compounding practices when considered appropriate by the agency.
- Should the FDA have cause for concern, it also may refer a case to the appropriate state licensing board(s).
The three particular instances in which veterinarians and pharmacists may compound drugs from BDS are as follows:
- Patient-specific prescriptions for nonfood-producing animals
- Office stock for immediate or urgent use in nonfood-producing species
- Antidotes for food-producing animals and sedatives or anesthetics for free-ranging wildlife
Q: What effect does GFI #256 have on my ability to access medications compounded from bulk drug substances for my patients?
A: Although there are multiple considerations for how GFI #256 may affect your practice, for nonfood-producing animals, your access to medications compounded from BDS will depend primarily on how often your prescriptions for these products are patient-specific (i.e., writing a prescription or calling a prescription into a pharmacy for an individual patient) rather than the medication being kept on your shelf as "office stock."
For patient-specific prescriptions for nonfood-producing animals, the impact of GFI #256 on access to compounded medications is minimal.
- Patient-specific prescriptions can, in general, be compounded from any suitable bulk drug substances. There are no limitations as to which BDS veterinarians can use for this purpose, provided the compounded drug is not a copy.
- If the compounded drug is a copy, the medical rationale for this use must be conveyed to the compounder, describing how the difference between the compounded drug and the FDA-approved, conditionally approved, or indexed drug will produce a clinical difference in the identified patient as determined by the treating veterinarian. Further, the compounder must maintain a record of the medical rationale. The FDA generally does not intend to question the professional judgment of the prescribing veterinarian. However, the agency does indicate that it intends to consider whether a prescription or notation relied upon by a compounder both documents that the determination was made and contains a medical rationale describing the clinical difference. When prescribing a compounded medication that is a copy of an approved product, AVMA encourages veterinarians to document in the medical record the rationale for doing so, as well as the clinical difference provided by the compounded preparation. A clinical difference encompasses a wide range of issues encountered in veterinary medicine—for example: formulation changes to exclude ingredients in the approved product that are harmful to a particular patient or their species; strength or concentration changes to accommodate wide variations in patient size; and changes in flavoring or dosage form needed to achieve patient compliance or protect individuals administering the drug. It does not include pricing differences (e.g., compounding to offer a less expensive product), prescriber or owner preferences, or the need for half strengths.
For office stock for nonfood-producing animals, the bulk drug substances that may be used are restricted to those on an FDA-reviewed list of medications that must always be accessible in anticipation of an immediate need to prevent or relieve patient suffering or death.
For food-producing animals and free-ranging wildlife, for patient-specific prescriptions and office stock, the FDA maintains a different list of BDS that may be used.
Q: What drugs may be compounded from bulk drug substances (BDS)?
A: For patient-specific prescriptions for nonfood-producing animals, there are no restrictions on which drugs may be compounded from BDS. However, the situation is different for office stock and for food-producing and free-ranging wildlife species, with the FDA Center for Veterinary Medicine overseeing and maintaining lists of BDS that may be used:
- List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals
- List of Bulk Drug Substances for Compounding Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife Species
The nonfood animal list is divided into two categories: 1) dogs, cats, and horses; and 2) nonfood-producing minor species. This list applies to compounding for office stock, whereas the food animal list applies to both office stock and patient-specific prescriptions. In both lists, you can find the BDS that a state-licensed veterinarian or pharmacy may use to compound preparations in certain dosage forms and strengths for particular species and disease indications. The FDA generally will not take enforcement action in these cases.
The list for nonfood-producing animals includes both major species (horses, dogs, cats, cattle, swine, chickens, and turkeys) and nonfood-producing minor species (e.g., various exotic and zoo species and certain captive wildlife). For food-producing animals or free-ranging wildlife, certain conditions apply. Both lists are subject to change, as the FDA plans to accept suggestions for additional BDS at any time, review these nominations, and update the lists accordingly.
Q: What drugs may not be compounded from BDS?
A: The FDA CVM also maintains a list of Bulk Drug Substances Reviewed and Not Listed. These are bulk drug substances that were nominated but not accepted for particular species and indications, so they may not be used to compound office stock in those situations. A common reason for nominations to be declined is that a human or veterinary FDA-approved, conditionally approved, or indexed drug already exists that could be used for compounding.
Q: What if I need to split an FDA-approved tablet multiple times to obtain an appropriate dose for a given patient, thereby jeopardizing the ability to provide an accurate dose. Is this an acceptable medical rationale for compounding from BDS?
A: Yes, this would be an acceptable rationale, provided no FDA-approved animal or human drug is available that would allow tablets to be split without jeopardizing the tablet's integrity and the ability to provide an accurate dose.
Q: What can I do if I think a certain drug should be added to the FDA's list of drugs that may be compounded from BDS?
A: The FDA accepts nominations of additional bulk drug substances or additional indications for these substances, and continues to review nominations and update lists. See the appendix to GFI #256 (beginning on page 19) for details on how to submit a BDS nomination.
The nominator should submit the following:
- Chemical and common name of the drug
- Dosage form, strength, and intended route of administration of the compounded drug
- Species and indication for which the compounded drug is intended
- Whether an FDA-approved, conditionally approved, or indexed drug exists for the intended species and indication
- Explanation of why compounding is necessary, such as why it is not feasible to use such a product, as well as (if known) why the FDA-approved, conditionally approved, or indexed drug cannot be used to compound the needed drug, and (if known) any human user or animal safety risks and why the risks are justified
Additional considerations for office stock and compounded drugs for use in food-producing species are included in the Appendix to GFI #256.
Before submitting your nomination, you may wish to check the lists of BDS currently under review and BDS reviewed and not listed, to ensure the nomination has not already been received. Once a nomination has been determined to meet the criteria for inclusion on the list of drugs that may be compounded from BDS, that list will be updated accordingly.
Q: Are there limitations as to which products can be nominated to the list of BDS for use as office stock?
A: Any product can be nominated, including products with an active ingredient in an FDA-approved, conditionally approved, or indexed drug.
Q: How does GFI #256 affect the cost of medications compounded from bulk drug substances?
A: AVMA doesn't anticipate a significant price difference for those new animal drugs currently allowed to be compounded from BDS, such as those on the FDA's lists. Similarly, AVMA doesn't anticipate a significant price difference for new animal drugs already compounded from FDA-approved, conditionally approved, or indexed drugs, consistent with AMDUCA3 and 21 CFR Part 530. Compounding pharmacies that currently market products compounded from BDS on a broad scale that are not FDA approved—and are therefore marketed illegally—have indicated that they anticipate an added expense related to GFI #256 compliance for those medications previously compounded from BDS that instead need to be compounded from FDA-approved drugs. The added expense would be specific to each individual prescription.
Q: What was AVMA's role in the development of GFI #256?
A: AVMA filed comments on February 3, 2020, May 18, 2020, and October 8, 2020, in response to initial drafts of GFI #256, after seeking feedback from members, volunteer leaders, state and allied veterinary associations, and other impacted stakeholders. All input was considered by expert volunteers serving on the AVMA Council on Biologic and Therapeutic Agents (COBTA) and its Clinical Practitioners Advisory Committee (CPAC). COBTA/CPAC worked with AVMA staff to compile and review the feedback and to draft AVMA's comments. AVMA also maintained a dialogue with the CVM as the agency worked to finalize GFI #256.
Q: Do veterinarians have a way to provide feedback to the FDA on GFI #256 or other compounding matters?
A: Yes. AVMA continues to work actively with the FDA CVM regarding the approach to compounding described in GFI #256 and will continue to advocate for changes if implementation of this guidance does not meet veterinarians' needs. AVMA continues to encourage feedback from members, allied organizations, and other stakeholders regarding the veterinary needs concerning compounded products.
1 Active ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans or other animals. Back to section
2 Acceptance criteria means the product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units). Back to section
3 Animal Medicinal Drug Use Clarification Act. Back to section