Compounding from bulk drug substances

Patient-specific compounding

Patient-specific compounding is compounding for nonfood-producing species that is done for a specific patient. For example, when a prescription is written by a veterinarian within the context of a veterinarian-client-patient relationship (VCPR) for an individual patient or group of patients and then is filled by a compounding pharmacist, or when a veterinarian compounds within their practice for that same purpose.

According to GFI #256, for a specific patient or group of patients, veterinarians can write a prescription for a product to be compounded from bulk drug substances, or may compound from bulk drug substances in their practice, if the following conditions are met: 

• A VCPR meeting the federal definition found at 21 CFR Sec. 530.3(i) is established.
• Compounding is done under the direct supervision of a veterinarian or pharmacist.
• The labeling (which includes the label on the product as well as additional documents to share when dispensing) lists the drug name; strength; species; patient ID as provided by the veterinarian (whether an individual patient or a group of patients); contact information for the compounding pharmacy or compounding veterinarian, and contact information for prescribing veterinarian; beyond use date (BUD); a statement indicating that any adverse events be reported to both the compounder and the FDA CVM using FDA’s Form 1932a; a statement indicating that the product is a compounded drug and not an FDA-approved,  or indexed drug; and the statement  “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian”.
• Compounding complies with state laws and regulations governing drugs, pharmacy, and veterinary medicine.
• Drugs dispensed or distributed by pharmacists are transferred directly to the veterinarian or the animal owner/caretaker, but not to a third party.
• Drugs dispensed by veterinarians are transferred directly to other veterinarians at the same facility or to the animal owner/caretaker, but not to a third party.
• Compounding must adhere to any applicable United States Pharmacopeia (USP)-NF (National Formulary) monograph, as well as comply with other FDCA requirements for drug components.^[i] In addition, the product cannot be a copy (a product having the same active pharmaceutical ingredient [API] and route of administration as an FDA-approved or indexed product) unless the product produces a clinical difference for the specific patient(s).
  
  A clinical difference encompasses a wide range of issues encountered in veterinary medicine, such as 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. However, it does not include pricing differences (e.g., compounding to offer a less expensive product).
  
  In cases in which a copy is prescribed, the person compounding the product is obligated to maintain a record of the medical rationale for why an approved product was not chosen for the patient, including in cases where the veterinarian is compounding the product. GFI #256 indicates that when the veterinarian is merely the prescriber and not the compounder, the veterinarian is not required to put this medical rationale on the prescription, although the compounder may call the veterinarian to obtain it.
  
  FDA examples of an appropriate rationale include that an ingredient is toxic to the species being treated, the patient has an allergy to an ingredient in the approved product, too many tablets would be required, or the tablet is not scored to accomplish the fractionated dose. FDA has indicated that reasons such as the compounded product is less expensive, or that a certain compounded product/compounder is preferred, are not acceptable reasons for prescribing a copy of an approved drug.
• The compounder is also required to maintain the rationale for why an approved product was not chosen as the starting material for the compounded product.  Acceptable reasons may include that the chemical properties of the FDA-approved or indexed drug(s) prevent its practical and effective use in the compounding of a specific drug, an inactive ingredient in the FDA-approved, conditionally approved, or indexed drug(s) is toxic to the target species and cannot be readily separated or that the FDA-approved, conditionally approved, or indexed drug(s) that contains that active moiety is not available for compounding.
• Upon becoming aware of any adverse event or product defect, the pharmacist or veterinarian who compounded the drug reports the event on Form FDA 1932a, which is available online, within 15 business days.

Office stock compounding

According to GFI #256, products can be compounded from bulk drug substances for nonfood-producing species as office stock if the following conditions are met: 

• The drug is compounded from a bulk drug substance listed on the FDA CVM’s “List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals” or the “List of Nominated Bulk Drug Substances Currently Under Review.”
• Compounding is done under the direct supervision of a veterinarian or pharmacist.
• The label lists the drug name; strength; species; BUD; contact information for the compounding pharmacy or compounding veterinarian, and contact information for prescribing veterinarian; statement indicating that any adverse events be reported to both the compounder and the FDA CVM using FDA’s Form 1932a; a statement indicating that the product is a compounded drug and not an FDA-approved or indexed drug; and the statement “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian”. 
• Compounding complies with state laws and regulations governing drugs, pharmacy, and veterinary medicine.
• Compounding must adhere to any applicable United States Pharmacopeia (USP)-NF (National Formulary) monograph, as well as comply with other FDCA requirements for drug components.
• Upon becoming aware of any adverse event or product defect, the pharmacist or veterinarian who compounded the drug reports the event on Form FDA 1932a, which is available online, within 15 business days.
• The veterinarian who stocks the drug dispenses or transfers it only to the owner of caretaker of the animal patient or to another veterinarian in the same practice.

Compounded products might be needed for use as antidotes for food-producing species or as sedatives for free-ranging wildlife. According to GFI #256, these products can be compounded from bulk drug substances if the following conditions are met: 

• The drug is compounded from a bulk drug substance listed on the FDA CVM’s “List of Bulk Drug Substances for Compounding  Drugs for use in Food-Producing Animals or Free Ranging Wildlife” or the “List of Nominated Bulk Drug Substances Currently Under Review.”
• The prescribing veterinarian holds a VCPR.
• Compounding is done under the direct supervision of a veterinarian or pharmacist.
• The label lists the drug name; strength; species; BUD; contact information for the compounding pharmacy or compounding veterinarian, and contact information for prescribing veterinarian or wildlife health professional;  withdrawal time; a statement indicating that any adverse events be reported to both the compounder and the FDA CVM using FDA’s Form 1932a; a statement indicating that the product is a compounded drug and not an FDA-approved or indexed drug; and the statement “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian”. 
• Upon becoming aware of any adverse event or product defect, the pharmacist or veterinarian who compounded the drug reports the event on Form FDA 1932a, which is available online, within 15 business days.

withdrawal time

When compounding from bulk drug substances for antidotes for food-producing species or sedatives or anesthetics for free-ranging wildlife, a veterinarian must specify a scientifically based withdrawal time that ensures violative residues of the compounded antidote or sedative/anesthetic are not present in the animal at the time of slaughter or harvest, or the veterinarian must ensure the animal does not enter the food supply too soon or at all.

This can be done by confining the treated animal for the needed withdrawal time or identifying the animal that has been treated (e.g., a tag for free-ranging wildlife containing language such as, “Do not consume if harvested before [enter date after completed withdrawal period]; call [enter phone number of veterinarian or animal health professional]”).

Drugs compounded from bulk drug substances for euthanasia and depopulation

In emergency situations where the need for drug for euthanasia or depopulation of food-producing species cannot be met using an FDA-approved, conditionally approved, or indexed drug or by other non-drug depopulation methods, the guidance indicates that veterinarians should contact CVM’s Emergency Response Coordinators directly at CVMCERTINVfda [dot] hhs [dot] 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.

Drugs compounded from bulk drug substances during times of shortage

For animal drugs that are temporarily in shortage, FDA will apply its process for mitigating shortages. Actions may include working with drug manufacturers and others in the animal health industry, speeding up the animal drug review and approval process, encouraging sponsors of alternate products to increase production, or refraining from taking action against imports of foreign-approved versions of the drug product.

• 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
• List of Bulk Drug Substances Currently Under Review
• Bulk Drug Substances Reviewed and Not Listed

Nomination process

The FDA CVM is accepting nominations to the “List of Bulk Drug Substances for  Compounding Office Stock Drugs for Use in Nonfood-Producing Animals” and the “List of Bulk Drug Substances for Use in Compounding Drugs in Food-Producing Animals or Free Ranging Wildlife”. These are the criteria for nomination to these lists:

Requested information

• Name of bulk drug substance including chemical and common name
• Species
• Indication
• Dosage
• Strength
• Route of administration
• For nomination to the list for food-producing species only—Relevant scientific literature or other evidence that demonstrates the prescribing veterinarian has a basis for determining appropriate withdrawal, withholding, or discard time(s) for meat, milk, eggs, or any food that might be derived from the treated animal(s).
• Confirmation that there is no marketed FDA-approved, conditionally approved, or indexed drug(s) that could be prescribed to treat the condition in the species that the drug compounded with the nominated substance is intended to address.
• If an FDA-approved, conditionally approved, or indexed product exists with the same species and disease indication, include reasons why a compounded drug is necessary.
• If known by the nominator, if the nominated bulk drug substance is an active ingredient in a marketed FDA-approved, conditionally approved, or indexed animal or human drug(s), an explanation of why the animal drug cannot be compounded from the marketed FDA-approved, conditionally approved, or indexed animal or human drug.
• If known by the nominator, a description of any human user or animal safety concerns associated with use of the nominated bulk drug substance or finished compounded drug for the condition(s) in the species that the compounded drug is intended to address. If there are concerns, an explanation of why the concerns should not preclude inclusion of that nominated bulk drug substance on the List.
• For compounded drugs intended as office stock for nonfood-producing animals, an explanation of why the animal drug to be compounded with the nominated bulk drug substance is important to have available to the veterinarian for urgent treatment to avoid animal suffering or death, e.g., why animal suffering or death will result if treatment is delayed until a compounded animal drug can be obtained pursuant to a prescription for an individually identified animal.

Nominators are encouraged to put forth nominations even if they don’t have all the answers. 

Determination

Once a nomination is received by FDA CVM, the bulk drug substance will go on a review list, so long as no serious reason to exclude it is identified. A serious reason for exclusion could include an import alert or serious safety concern. Products on the review list can continue to be compounded from bulk drug substances for office stock until a final determination is made as to their status.

A drug will be added to the list when these conditions are met:

• There is no commercially available FDA-approved, conditionally approved, or indexed animal drug or human drug that can be used as labeled or in an extralabel manner.
• Immediate treatment with the compounded drug is necessary to avoid animal suffering or death (for nonfood-producing species only).
• The FDA CVM has not identified a significant safety concern specific to use of the bulk drug substance in veterinary patients.
• There is sufficient scientific information for the prescribing 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).

An explanation will be provided if, after review, a drug is not added to the positive list. Nominators will then have the opportunity to provide additional information.

FDA CVM has agreed to continue to work with stakeholders to support the nomination process.