The U.S. Food and Drug Administration’s draft Guidance for Industry (GFI) #256, Compounding Animal Drugs from Bulk Drug Substances, if finalized, will describe the agency’s current thinking about animal drug compounding from bulk drug substances (BDS). It identifies circumstances under which the agency does not intend to take regulatory action against the compounding of drugs from bulk drug substances when no other medically appropriate treatment options exist.
Draft GFI #256 specifically addresses:
- Compounding patient-specific prescriptions for nonfood-producing animals;
- Compounding office stock for nonfood-producing animals; and
- Compounding antidotes for food-producing animals.
Draft GFI #256 strikes a balance between FDA’s current understanding about the safety, effectiveness, and quality of animal drugs compounded from BDS and the need for those drugs when no FDA-approved (including conditionally approved) or indexed drug can be used to treat the animal. (An indexed drug is a drug identified on FDA’s Index of Legally Marketed Unapproved New Animal Drugs for Minor Species).
1. Why did FDA issue Draft GFI #256?
Veterinarians treat a wide variety of species with a range of diseases. Animal drugs are approved or indexed by FDA for use in specific species to treat particular conditions. In 1994, Congress expanded options to treat animal patients by enacting the Animal Medicinal Drug Use Clarification Act (AMDUCA) to allow veterinarians with valid veterinary-client-patient relationships to prescribe approved human and animal drugs for extralabel uses to treat animals under their care. Sometimes, however, no approved or indexed drug can be used as labeled or in an extralabel manner to treat a particular patient. In those situations, veterinarians have turned to unapproved drugs compounded from BDS. FDA issued this draft guidance to state our enforcement priorities related to drugs compounded from BDS and to clarify for veterinarians, pharmacists, and others concerned with treating sick animals the circumstances in which we do not intend to take action against drugs compounded from BDS.
2. What is 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.
3. What is an “active ingredient”?
“Active ingredient” is defined in FDA regulations as any drug component “intended to provide 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 man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.” See 21 CFR 210.3(b)(7) for the definition.
4. What is an “active moiety”?
“Active moiety” is defined in FDA regulations as “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” See 21 CFR 314.3 for the definition. For example, for the active ingredients erythromycin stearate, erythromycin ethylsuccinate, and erythromycin lactobionate, the active moiety is erythromycin.
5. What is “office stock”?
“Office stock” refers to drugs compounded by a veterinarian or pharmacist and sold to a veterinarian without a patient-specific prescription. Veterinarians maintain office stock to administer or dispense when an owner of a patient needing the drug seeks treatment from the veterinarian.
6. Is it lawful to compound animal drugs from bulk drug substances under federal law?
No. The Federal Food, Drug, and Cosmetic Act (FD&C Act) does not distinguish between compounding animal drugs from bulk drug substances and any other manufacturing or processing of animal drugs. Compounding an animal drug from bulk drug substances results in a new animal drug that must comply with, among other things, the FD&C Act’s approval and indexing requirements. Draft GFI #256 addresses compounding animal drugs from bulk drug substances.
Draft GFI #256 does not address compounding from FDA-approved animal or human drugs, which may be lawful. FDA considers compounding an animal drug from an approved animal or human drug (rather than from a bulk drug substance) a form of extralabel use, which is lawful under certain conditions (for detailed conditions, see 21 U.S.C. Section 360b(a)(4) and (5) and FDA’s regulations at 21 CFR 530 (“Extralabel Drug Use In Animals”)).
7. What are the risks associated with compounded drugs?
Compounded drugs can serve an important medical need for patients, but they do not have the same safety, quality, and effectiveness assurances as FDA-approved drugs. Because compounded drugs are not FDA-approved, FDA does not verify their safety, effectiveness, or quality before they are marketed. In addition, FDA does not review the manufacturing methods used to make them or the accuracy of their labeling. 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). Such quality problems can lead to serious patient injury and death. For example, on July 23, 2019, FDA published an alert to horse owners and veterinarians about a compounded drug product that contained approximately 18 to 21 times the amount of the active ingredient stated on the label and led to the death of three horses. A similar incident occurred in 2014 involving a different compounding pharmacy. Further, compounding drugs under insanitary conditions could lead to widespread patient harm, especially when the compounder engages in compounding office stock. FDA also has concerns about the stability of compounded drugs, especially when they are retained in inventory as office stock and not used immediately.
8. What are FDA’s enforcement priorities regarding animal drugs compounded from BDS?
FDA’s priorities generally include:
- 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 a food-producing animal, 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 FDA for human food safety.
- Compounded drugs that are copies of approved or indexed products, because they 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 has been established through the FDA review process.
- 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.
9. Does Draft GFI #256 describe situations where veterinarians will be able to compound or prescribe drugs compounded from bulk drug substances for their patients?
Yes, for nonfood-producing animals. When selecting a drug to treat a patient in their care, veterinarians should prescribe an FDA-approved or index-listed drug, if possible. If a veterinarian determines that the patient cannot be adequately treated with an approved or indexed drug, or with a drug compounded from an approved or indexed drug, the veterinarian can prescribe a compounded drug under the circumstances laid out in Draft GFI #256. 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). The pharmacist can compound the drug from BDS and dispense it, upon receiving the prescription, to the veterinarian or to the patient’s owner or caretaker. If the veterinarian compounds the drug from BDS, the veterinarian should describe in their records the reason the drug cannot be compounded from an approved or indexed product and dispense it only to the patient’s owner or caretaker or to a veterinarian in the practice at the same location.
10. Does Draft GFI #256 describe situations where state-licensed pharmacies will be able to compound drugs from bulk drug substances?
Yes, for nonfood-producing animals. When a pharmacist receives a patient-specific prescription from a veterinarian, the pharmacist can compound the drug from BDS under the circumstances laid out in Draft GFI #256. If there are FDA-approved or indexed drugs that contain the same active moiety as any active ingredient in the prescription, the pharmacist should determine whether the approved or indexed drug can be used as the source of the active ingredient. If the pharmacist determines that an approved or indexed drug cannot be used as the source, and one or more BDS must be used instead, the pharmacist should describe in their records the reason the prescription cannot be filled by compounding from approved or indexed product. The drug should be dispensed to the prescribing veterinarian or to the patient’s owner or caretaker and should not be dispensed or transferred to a third party, such as a retailer, distributor, or veterinarian who did not write the prescription.
11. Under Draft GFI #256, can veterinarians and pharmacists compound drugs that are copies of FDA-approved or indexed animal and human drugs?
Generally, no. Draft GFI #256 considers a copy to be a drug compounded from bulk drug substance that, compared to an 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. 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 Draft GFI #256, a copy can only be made from a BDS if:
- the patient is a nonfood animal; and,
- 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 in the prescription, 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 approved or indexed products.
12. Does Draft GFI #256 describe situations where veterinarians will be able to have compounded drugs on hand (office stock) for use in their clinics and to dispense?
Yes, with limitations. FDA is developing a list of BDS called the “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals,” which will be posted on FDA’s website. Under the circumstances laid out in Draft GFI #256, only BDS on this list can be compounded into drugs for office stock. FDA will include a BDS on this list only if it is intended to compound drugs needed for immediate 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. For each BDS included on the list, FDA will identify the species and indication for which the compounded drug is intended. For more information about how to nominate a BDS to the list, see the CVM Update.
13. Can drugs be compounded for food-producing animals from bulk drug substances under the circumstances in Draft GFI #256?
Generally, no. FDA is developing a list of BDS called the “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals,” which will be posted on FDA’s website. Under the circumstances laid out in Draft GFI #256, only BDS for use as antidotes and identified on this list can be compounded into drugs for food-producing animals. The public can nominate BDS for use in antidotes to include on the list. FDA intends to include only those antidotes 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).
14. Where can the public learn more about FDA-approved and indexed animal drugs?
To learn more about FDA’s approval and indexing processes and how they help protect human and animal health, please visit FDA’s webpages: FDA Regulation of Animal Drugs, New Animal Drug Applications, and Drug Indexing.
To find information about drugs that are approved, visit Animal Drugs @ FDA. For drugs that are indexed, visit The Index of Legally Marketed Unapproved New Animal Drugs for Minor Species.
15. Would finalizing Draft GFI #256 result in FDA’s regulating the practice of veterinary medicine?
No. Under the Federal Food, Drug, and Cosmetic Act, FDA is responsible for regulating the manufacturing, labeling, approval, marketing, and extralabel use of animal drugs. The draft guidance does not regulate the practice of veterinary medicine. Rather, the draft guidance, if finalized, clarifies FDA’s policy on drugs compounded from BDS.
16. Does Draft GFI #256 address compounding quality standards?
Yes. To promote the quality of compounded drugs, pharmacists and veterinarians compounding animal drugs under a patient-specific prescription or for office stock should, at a minimum, meet the standards in the United States Pharmacopeia and the National Formulary (USP–NF). The pharmacopeia is developed and published by the U.S. Pharmacopeia Convention, a private, not-for-profit, nongovernmental standard-setting organization. USP has no role in enforcement, which is the responsibility of government authorities in the United States and elsewhere. Pharmacists and veterinarians compounding drugs from BDS should meet the standards in any USP–NF monograph relevant to the ingredients and product they are compounding and the relevant standards that include General Chapters 795 and 797 describing practices for compounding nonsterile preparations and sterile preparations, respectively. Some states may have requirements that exceed the USP; pharmacists and veterinarians are responsible for meeting their state’s requirements.
17. Does Draft GFI #256 address reporting adverse events or product defects associated with drugs compounded from BDS?
Yes. 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. Report these events by following the instructions on how to submit Form FDA 1932a, which are found on How to Report Animal Drug and Device Side Effects and Product Problems.
18. Does Draft GFI #256 address labeling of drugs compounded from BDS?
Yes. Draft GFI #256 addresses labeling for compounded drugs, including the drug name and strength, patient identifying information, information about the prescriber and compounder, and other information. For more detail about the labeling information, see sections in the draft guidance for patient-specific prescriptions; office stock; and antidotes.
19. How can the public comment on Draft GFI #256?
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
20. Is there a deadline for submitting comments about the guidance?
No. Comments to Docket No. FDA-2018-D-4533, “Compounding Animal Drugs From Bulk Drug Substances,” will be accepted at any time but should be submitted no later than June 17, 2020 to ensure that the FDA takes the information into consideration before making further decisions on this issue.
21. How can the public nominate bulk drug substances for inclusion on the “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals”?
Nominations can be submitted electronically or on paper. All submissions must include Docket No. FDA-2018-N-4626 for “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals.” 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 BDS, but each bulk drug substance should be submitted to the docket as its own, separate nomination.
22. What information should be submitted with the nomination?
For a complete list of information required for a bulk drug substance nomination, see the appendix in Draft GFI #256 or Part II of the Federal Register notice requesting nominations, under the header What information Should I Submit with the Nomination?
23. Is there a deadline to nominate bulk drug substances for the “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals”?
No. Nominations may be submitted at any time to Docket No. FDA-2018-N-4626, “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals or Antidotes for Food-Producing Animals.” This docket will remain open indefinitely.
24. Does the Drug Quality and Security Act (DQSA) apply to animal drugs?
No. DQSA only applies to the compounding of human drugs and not to the compounding of animal drugs. More information on the DQSA may be found at Compounding Laws and Policies.