Q&A: GFI #256 - Compounding Animal Drugs from Bulk Drug Substances

Updated January 31, 2024 to add the Medical Rationales section.

Key Terms

“Animal drug compounding” is the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual animal or a small group of animals. Animal drug compounders use either an FDA-approved drug (in its finished dosage form) or a bulk drug substance as the source of the active ingredient(s).

A “bulk drug substance,” can be thought of as the part of a compounded drug that creates the desired pharmacologic effect as an active ingredient. It’s also referred to as the active pharmaceutical ingredient (API).

An “active moiety” is the molecule or ion that drives the action of the drug. For example, for the active ingredients erythromycin stearate, erythromycin ethylsuccinate, and erythromycin lactobionate, the active moiety is erythromycin. See 21 CFR 314.3 for the full regulatory definition.

“Office stock” refers to compounded drugs kept on hand by veterinarians for patients. Office stock is generally compounded by a veterinarian, or by a pharmacist and sold to a veterinarian to have on hand, without a patient-specific prescription.

Animal Drug Compounding
Key Points about GFI #256
More Information for Veterinarians and Pharmacists
Medical Rationales
Resources on Animal Drug Compounding from Bulk Drug Substances

Animal Drug Compounding

Why are animal drugs compounded?

There are thousands of FDA-approved medications, including low-cost generic options, that veterinarians can prescribe for their patients. But, due to the wide variety of animal species, each with their own conditions, diseases, and specific needs, there may not always be an FDA-approved, conditionally approved, or indexed product that can be safely used to treat a particular animal in the finished dosage form. Some reasons for choosing a compounded drug over an FDA-approved, conditionally approved, or indexed drug include the need for flavoring (to encourage the patient to take the drug), a different route of administration (such as a capsule instead of a liquid), or a particular dosage that is not approved (such as for a very large or very small animal).

Are compounded animal drugs FDA-approved?

No. Although animal drug compounders might start the process with an FDA-approved drug (for example, grinding up the FDA-approved drug in pill form and compounding it into a liquid with flavoring), the resulting product is not FDA-approved. FDA does encourage animal drug compounders to use FDA-approved drugs as the source material from compounding when possible. But in some cases, animal drug compounders use bulk drug substances, which are not FDA-approved.

An animal drug compounded from a bulk drug substance is not equivalent to an FDA-approved drug, even if they contain the same active ingredient. When evaluating a drug for approval, FDA looks at the finished form of the product, including any other ingredients in the drug and how it is manufactured. The evidence that FDA evaluates for an approved product cannot be applied to compounded products because compounding generally results in significant changes in formulation, dosage form, and/or production processes.

Are compounded animal drugs legal?

It depends. Animal drugs compounded from bulk drug substances violate the Federal Food, Drug, and Cosmetic Act (FD&C Act) because they are not approved or indexed, are not made in accordance with current good manufacturing practice (CGMP) requirements, and cannot satisfy the FD&C Act provision for adequate directions for use. The FD&C Act gives FDA the authority to regulate animal drugs, which includes animal drugs compounded from bulk drug substances.

On the other hand, compounding animal drugs from FDA-approved, conditionally approved, or indexed drugs is generally permissible under certain conditions. Although the resulting compounded drug is not considered FDA-approved, the process starts with a substance that has been evaluated by FDA, which provides some assurance of safety and effectiveness.

What are the risks associated with compounded drugs?

Unlike with approved drugs, animal drug compounders do not submit any data to FDA about the safety or effectiveness of their products before marketing them. FDA does not receive information about how compounded animal drugs are produced, nor does the agency inspect the compounding site to verify how these products are made. And, while sponsors of FDA-approved animal drugs must regularly report to FDA any adverse events and side effects associated with their products, animal drug compounders face no such requirement. This means that safety or effectiveness issues with compounded animal drugs could go undetected.

FDA is especially concerned about the potential risk of widespread harm when office stock is compounded under “insanitary” (unsanitary) conditions. Poor compounding practices can result in serious drug quality problems, such as bacterial or fungal contamination of a drug that is intended to be sterile, or a drug that has either too much or too little of the active ingredient(s). These problems can and have led to serious injury or death of the patient.

FDA also has concerns about the stability of compounded drugs, especially when they are retained in inventory as office stock for an extended period of time.

Have there been any injuries, illnesses, or deaths related to compounded animal drugs?

Yes. Despite the lack of requirement to report adverse events associated with compounded animal drugs to FDA, the agency is aware of some tragic situations in which animals died as a result of poorly-compounded drugs. In one example, on July 23, 2019, three horses died due to the use of a compounded drug that contained approximately twenty times the active ingredient amount stated on the label. FDA published an alert to horse owners and veterinarians about this compounded drug product. A similar incident occurred in 2014 involving a different compounding pharmacy. At least one other incident resulted in the death of 21 horses in a mass-casualty event. Because neither compounding pharmacies nor veterinarians are required to report adverse events (injury, ineffectiveness, etc.) associated with these products, FDA may not be aware of all incidents related to compounded animal drugs.

FDA has taken action with regard to several firms that engage in animal drug compounding. For more information see Inspections, Recalls, and other Actions with Respect to Firms that Engage in Animal Drug Compounding.

Key Points about GFI #256

What is GFI #256?

Compounding Animal Drugs from Bulk Drug Substances, also known as Guidance for Industry (GFI) #256, describes the agency’s approach to situations where veterinarians need access to unapproved drugs compounded from bulk drug substances (BDS) to provide appropriate care for the medical needs of the diverse species they treat when no FDA-approved (including conditionally approved) or indexed drug can be used to treat the animal.

The FDA’s final guidance balances the agency’s primary objectives:

ensuring veterinarians have access to drugs to treat the broad diversity of animal patients;
protecting animals and humans from unsafe animal drugs;
preserving the integrity of the FDA animal drug approval process, which requires agency scientific review before approval and monitoring for continued safety and effectiveness once the drug is marketed.

What is included in GFI #256?

GFI #256 specifically addresses compounding from bulk drug substances for:

patient-specific prescriptions for nonfood-producing animals;
office stock for nonfood-producing animals
antidotes for food-producing animals; and
sedatives and anesthetics for free-ranging wildlife species.

What is not included in GFI #256?

GFI #256 does not address compounding using FDA-approved drugs, because this is already allowed under extralabel use as described in the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) and 21 CFR 530. Common practices, like crushing tablets of an FDA-approved medication into a paste or liquid, adding flavor to a medication, or combining two injectable medications in a syringe, are all generally acceptable under certain conditions described in AMDUCA.

What has changed since FDA published the draft guidance?

The FDA released draft GFI #256, “Compounding Animal Drugs from Bulk Drug Substances,” in 2019 and received many comments from veterinarians, pharmacy compounders, and other stakeholders. In response, the agency has made significant changes to the final guidance to provide recommendations for veterinarians seeking to access animal drugs compounded from bulk drug substances for those animals that need them. Because the safety and effectiveness of drugs compounded from bulk drug substances is unknown, FDA recommends they only be used after the prescribing veterinarian considers whether other FDA-approved treatment options can be used.

When will FDA implement this guidance?

The FDA understands there may be many questions about the final guidance and has committed to a proactive outreach and education period for veterinarians and animal drug compounding pharmacies as part of implementation. During this period, the FDA will meet with interested stakeholders, host webinars, and otherwise engage to discuss the new guidance and address questions about content and implementation. The agency has also created a library of tools to help inform stakeholders on details of the policy. These tools include informational handouts for veterinarians and pharmacists, as well as a webinar. The FDA recognizes that this final guidance will impact a wide range of stakeholders and plans to focus on education and stakeholder engagement before shifting resources toward inspectional activities in Fiscal Year 2023. Stakeholders with additional questions can contact the agency through AskCVM@fda.hhs.gov.

How will FDA implement this guidance?

FDA recognizes the need for veterinarians to have access to safe and effective animal drugs to treat their patients. The agency also realizes that there are situations where there is no FDA-approved, conditionally approved, or indexed drug that is medically appropriate. Accordingly, GFI #256 describes:

The agency’s priorities for determining when to take regulatory action against the compounding of animal drugs from bulk drug substances; and
Circumstances under which the agency does not intend to take regulatory action against the compounding of animal drugs from bulk drug substances when no other medically appropriate treatment options exist.

What are FDA’s enforcement priorities regarding animal drugs compounded from bulk drug substances?

FDA’s priorities generally include compounded drugs:

That present human or animal health concerns; for instance, because of contamination or formulation errors (e.g., potency issues)
For food-producing animals, because of the risk of drug residues in the meat, milk, or eggs consumed by people. When FDA evaluates a drug for a food-producing animal, the agency reviews human food safety data to establish residue tolerance levels, withdrawal times, and other conditions of use to prevent illegal drug residues in the edible products from those animals. Drugs compounded for food-producing animals have not been subject to this thorough evaluation by FDA.
That are copies of FDA-approved or indexed products, because they have not undergone the same rigorous evaluation as the approved drug and undermine incentives for firms to invest in getting drugs approved or indexed. This can reduce the availability of animal drugs that the FDA evaluation process has established as safe and effective.
Distributed 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 FDA evaluation and approval.

Will veterinarians or owners be able to get appropriate medicine for nonfood-producing animals (including pets)?

Yes. In addition to the numerous FDA-approved, conditionally approved, or indexed drugs that can be prescribed or used as the source ingredient for compounding animal drugs, GFI #256 describes FDA’s policy for animal drugs compounded from bulk drug substances. FDA recognizes that there are times when there may not be an FDA-approved, conditionally approved, or indexed drug that can be used (either for its approved use or under extralabel use) in a particular patient. GFI #256 describes circumstances for using a drug compounded from a bulk drug substance when a veterinarian determines that there is no approved or indexed product that can appropriately treat a patient under their care.

Can veterinarians still prescribe compounded animal drugs for their patients?

Yes. As described in the guidance, veterinarians can continue to prescribe animal drugs compounded from FDA-approved, conditionally approved, or indexed drugs as the starting point.

Second, although animal drugs compounded from bulk drug substances are unapproved drugs, GFI #256 describes when these drugs are eligible for enforcement discretion (a decision by FDA not to take enforcement action under certain circumstances). Generally, patient-specific prescriptions for nonfood-producing animals are eligible when the veterinarian determines that there is a difference between the compounded drug and the approved/indexed drug that will produce a clinical difference in the identified patient. Office stock (drugs without a patient-specific prescription) are eligible when urgently necessary to prevent animal suffering or death under the circumstances described in GFI #256.

Will veterinarians be able to have compounded drugs on hand (office stock) for use in their clinics and to dispense?

Yes, veterinarians can continue to have office stock compounded from FDA-approved products to have on hand.

Veterinarians can also have office stock compounded from the List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals under the circumstances described in GFI #256. FDA has developed the initial entries for this list and expects the list to expand as the agency reviews additional nominations.

Under the circumstances laid out in GFI #256, only bulk drug substances on this dynamic list can be used for compounding office stock animal drugs for use in nonfood-producing animals. Bulk drug substances on this list are only intended for compounding those animal drugs needed for urgent treatment to avoid animal suffering or death, in situations where there is not enough time to wait for a pharmacy to compound and dispense the drug under a patient-specific prescription.

How does GFI #256 address drugs being compounded from bulk drug substances for food-producing animals and free-ranging wildlife?

FDA has developed an initial List of Bulk Drug Substances for Compounding Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife Species. FDA also expects this list to expand as the agency reviews additional nominations. Under the circumstances outlined in GFI #256, only bulk drug substances identified on this list should be compounded into drugs for food-producing animals or free-ranging wildlife. FDA intends to include only those drugs that have sufficient scientific information for the veterinarian to determine appropriate withdrawal, withholding, or discard time(s) for meat, milk, eggs, or any food which might be derived from the treated animal(s).

How can I nominate a drug to either list?

For more information about how to nominate a bulk drug substance to either the 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, see the Nominations page and this quick reference, “Nominations in Brief.”

Nominations can be submitted electronically or on paper. All submissions must include Docket No. FDA-2018-N-4626 for “Lists of Bulk Drug Substances for Compounding: Office Stock Drugs for Use in Nonfood-Producing Animals or Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife Species.” You may submit electronic nominations through the Federal eRulemaking Portal, https://www.regulations.gov. The information to support nominations can be uploaded as attachments to the nomination. You may submit nominations on paper by mailing them to:

Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Nominators may submit nominations for more than one bulk drug substance, but each bulk drug substance should be submitted to the docket as its own, separate nomination. Nominations may be submitted at any time and this docket will remain open indefinitely. If you have any questions while preparing or submitting your nominations, please contact CVM for assistance via email by clicking following link: CVM Compounding.

What information should be submitted with each bulk drug substance nomination?

For a complete list of information required for a bulk drug substance nomination, see the appendix to GFI #256 or section II. Nominating Bulk Drug Substances in the Federal Register notice requesting nominations, under header C. What information Should I Submit with the Nomination? If you have any questions while preparing or submitting your nominations, please email CVM Compounding for assistance.

Can the public still comment on GFI #256?

Yes. You can submit comments on the guidance at any time. Comments may be submitted electronically or on paper. All submissions must include the Docket No. FDA-2018-D-4533 for “Compounding Animal Drugs from Bulk Drug Substances.” You may submit electronic comments through the Federal eRulemaking Portal, https://www.regulations.gov, which has instructions on how to submit comments through the portal. You may submit comments on paper by mailing them to:

Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

More Information for Veterinarians and Pharmacists

Should copies of FDA-approved drugs or indexed animal drugs be compounded from bulk drug substances (BDS)?

Generally, no. As explained in GFI #256, FDA considers a copy of an animal drug to be a drug compounded from a bulk drug substance that, compared to an FDA-approved or indexed drug, (1) has the same active ingredient; (2) is given by the same route of administration; and (3) is in the same, similar, or easily substitutable strength. For instance, if there is an approved animal drug that is a tablet containing 1 mg of active ingredient X, a compounded tablet containing 0.5 mg of active ingredient X would be considered a copy. But a compounded injectable dosage form of active ingredient X would not be considered a copy of a tablet dosage form because it is given by a different route of administration. Under the circumstances laid out in GFI #256, a copy should only be made from bulk drug substances if:

the patient is a nonfood-producing animal;
the prescribing veterinarian determines that there is a difference between the compounded drug and the approved/indexed drug that will produce a clinical difference in the identified patient;
the medical rationale is documented by the pharmacist, either by retaining a copy of a prescription on which the veterinarian has noted the medical rationale, or by contacting the veterinarian to obtain their medical rationale and noting it on the prescription or a document kept with it, or if a veterinarian is compounding the drug, the medical rationale is noted in the patient’s medical record; and
the compounder determines that the approved/indexed drug cannot be used as the source of the active ingredient and describes in the records the reason the prescription cannot be filled by compounding from FDA-approved or indexed products.

What are some examples of a “clinical difference” for a copy of an FDA-approved, conditionally approved, or indexed drug?

Examples of clinical difference as determined by the treating veterinarian, may include:

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.

For information on how you should document the medical rational explaining the clinical difference as it applies to an identified patient, see “Medical Rationale” below.

How does GFI #256 address reporting adverse events or product defects associated with drugs compounded from bulk drug substances?

Although sponsors of FDA-approved, conditionally approved, or indexed drugs are required to report adverse events or product defects to FDA on a regular basis, there is no regulatory requirement for animal drug compounders to do so. FDA sees this difference as a problematic gap in monitoring the safety and effectiveness of compounded animal drugs, particularly those compounded from bulk drug substances.

In an effort to close this gap, the pharmacist or veterinarian who compounded the animal drug should notify the FDA of any adverse event or product defect associated with use of the drug within 15 days of learning about the problem. Veterinarians, animal owners, and caretakers can also report to FDA problems with any drug, whether FDA-approved, conditionally approved, indexed, or unapproved, including compounded animal drugs.

Report these events by following the instructions on how to submit Form FDA 1932a, which is found at How to Report Animal Drug and Device Side Effects and Product Problems.

What should pharmacists document when compounding from bulk drug substances for a specific patient or group of animals?

If a pharmacy will compound the drug, the veterinarian should provide the pharmacist with a prescription that identifies the patient (a single animal, or a group of animals at a specific location). After compounding the drug from bulk drug substances, the pharmacist should dispense it, upon receiving the prescription, to the veterinarian or to the animal owner or caretaker. If the veterinarian compounds the drug from bulk drug substances, the veterinarian should describe in their records the reason the drug cannot be compounded from an FDA-approved or indexed drug and dispense it only to the animal(s)’ owner or caretaker or to a veterinarian in the practice at the same location.

If FDA-approved drug(s) are in shortage, is it acceptable to compound copies of the approved drug?

FDA has several ways to address animal drug shortages, including working with drug manufacturers and the animal health industry, speeding up the animal drug review process, and exercising enforcement discretion. Enforcement discretion may include not taking action against unapproved animal drugs that are compounded from bulk drug substances. However, FDA addresses each drug shortage on a case-by-case basis. GFI #256 does not provide blanket enforcement discretion to compound copies of drugs in shortage.

If FDA-approved drug(s) are unavailable, can bulk drug substances be used as the source of active ingredients for compounding?

As described in GFI #256, the unavailability of an FDA-approved product is a specific reason to compound from a bulk drug substance instead of an approved product. A brief explanation regarding lack of availability should be documented as the rationale for using a bulk drug substance.

Can euthanasia solution be compounded using bulk drug substances in the case of a disease outbreak? 

Depending on the disease outbreak and population size, mass-euthanasia methods would very likely be determined via a collaborative effort among federal and state agencies (e.g., USDA-APHIS, FDA, EPA). In situations where the need for drugs for euthanasia or depopulation of animals cannot be met using FDA-approved drug products or other non-drug depopulation methods, the totality of the situation would be considered to allow for regulatory discretion for use of nonFDA-approved drugs in emergency situations (e.g., an animal disease outbreak).

In emergency situations where the need for euthanasia or depopulation drugs for food-producing species cannot be met using an FDA-approved or indexed drug or by other non-drug depopulation methods, veterinarians should contact CVM’s Emergency Response Coordinators directly at CVMCERTINV@fda.hhs.gov. FDA will work with our public health partners to consider the use of drugs compounded from bulk drug substances on a case-by-case basis.

Medical Rationales

Q: What does FDA look for when reviewing medical rationales?

The goal of a medical rationale identifying the clinical difference for a specific patient should be to explain why any of the FDA-approved drug(s) that contain the same active moiety and route of administration as the compounded drug cannot be used to treat the patient. The medical rationale, therefore, should describe the link between a specific characteristic of the identified patient and a specific characteristic of each FDA-approved drug which makes each FDA approved product(s) unsuitable for the identified patient, but which makes the compounded preparation suitable.

Q: What are acceptable methods for a pharmacy to document the medical rationale?

A pharmacy may use paper or electronic means to document the medical rationale; however, the pharmacy should ensure they file the records in a manner that clearly provides the veterinarian’s medical rationale for every individual prescription and that is readily available when requested by FDA.

FDA is aware some pharmacies using electronic systems have implemented drop-down menus with prefilled medical rationales. While FDA does not object to using this approach as part of their documentation, we note that, as discussed in our responses to other questions, broad/imprecise drop-down categories alone would not sufficiently explain the medical rationale in most cases. For example, a single-tier drop-down menu with the category “patient allergic to FDA approved-products” provides inadequate information unless accompanied by additional information; namely, the identity of the ingredient to which the patient is allergic.

Given the patient-specific nature of a medical rationale, FDA does not believe it is generally possible to create prefilled dropdown menus that could cover every possible circumstance. We encourage anyone implementing a drop-down menu approach to ensure their systems also allow for freewriting text so the pharmacy can accurately and adequately capture the patient-specific medical rationale provided by the veterinarian.

Q: If a medical rationale describing the clinical difference is not provided by the veterinarian to the pharmacy, can the pharmacy create a medical rationale for the veterinarian’s patient instead?

No. The medical rationale should originate from the veterinarian because it is the veterinarian, not a pharmacist, who has established a veterinarian-client-patient relationship (VCPR) where the veterinarian has gained knowledge of the individual patient from which they can provide a medical rationale describing the clinical difference in that specific patient.

In exercising enforcement discretion, FDA relies on the veterinarian to provide a truthful medical rationale and on the pharmacist to accurately document the medical rationale provided by the veterinarian. Anyone who knowingly and willfully makes materially false representations to the U.S. government may be subject to criminal penalties under 18 U.S.C. 1001.

Q: How do GFI #256 recommendations regarding medical rationale apply to refills of previous prescriptions?

For identical refills, pharmacies can generally rely on medical rationales maintained in the pharmacy records with the original prescription. The pharmacy should be able to verify in their records it was already obtained when accepting an identical new prescription and should be able to readily provide it to FDA upon request (such as a request based on recent dispensing of the new prescription).

The pharmacy should consider whether the original medical rationale remains applicable and contains adequate detail. In particular, if a new FDA approved/indexed product comes to market containing the active moiety for the same route of administration (i.e., the compounded drug becomes a copy of a new product after the original prescription was written), the pharmacist should determine whether the rationale remains adequate before dispensing the refill. If the newly approved or indexed drug will adequately meet the patient’s medical needs, the legally marketed drug should be dispensed instead of the compounded copy.

Q: How is the medical rationale affected by the existence of multiple FDA-approved products with the same active ingredient moiety and same route of administration as the compounded product?

A compounded drug can simultaneously be a copy of multiple FDA-approved or indexed drugs. The veterinarian should consider all approved human and animal drugs containing that active moiety and provide rationale(s) why none of them are suitable for the specific patient. If individual rationales are needed to explain the unsuitability of each existing approved drug for which the compounded drug is a copy, multiple rationales should be provided and documented.

For example, if a compounded drug is a copy of approved drugs that are available as a capsule, a chewable tablet, and an oral solution, a medical rationale that the “patient cannot safely be pilled” would only apply to the capsule and would not apply to the chewable tablet or the oral solution. A rationale applicable to the chewable tablet and oral solution should also be provided and documented.

Q: What is expected for the patient-specific medical rationale when the patient is a group of animals in an identified location?

The patient-specific rationale should apply to all of the applicable animals in that same identified location and all the animals in the identified location should share the characteristic(s) that make the FDA approved drug(s) unsuitable. For example:

Example 1: All human and animal FDA-approved or indexed products with the relevant active moiety contain xylitol. A prescription would be written for all the “dogs in shelter kennel X” and the medical rationale would explain that the approved product contains xylitol, which is toxic to dogs. Because xylitol is toxic to all dogs, the same medical rationale applies to all dogs in the group.
Example 2: The only FDA-approved product with the relevant active moiety is apple-flavored. A prescription for a differently flavored medication is written for the group of 100 horses in a specific barn and contains the rationale that “horses will not take the FDA-approved apple-flavored medication.” Because horses typically like apple flavoring, this medical rationale is implausible on its face without documentation that each of the 100 horses will not take apple-flavored medication.

Q: What should the pharmacist do to ensure the adequacy of the medical rationale provided by a veterinarian under GFI #256?

As the compounder who chooses whether to fill the prescription, the pharmacist should obtain and document the medical rationale if the pharmacist wants to receive enforcement discretion as described in the guidance. The pharmacist should:

Ensure that the information provided by the veterinarian actually constitutes a medical rationale as defined in the guidance (i.e., that it contains adequate detail to explain how the compounded drug will produce a clinical difference in the identified patient, and if the patient is a group that the rationale applies to the entire group).
Ensure the prescription is reasonable and consistent with the rationale (e.g., the quantity prescribed is not in excess of the amount needed to treat the patient as labeled or before the beyond use date).