Compounding Animal Drugs from Bulk Drug Substances

This version of the guidance replaces the version made available April 2022. This revision provides the approved information collection OMB Control No. 0910-0904

The release of this FDA GUIDANCE has stimulated a lot of discussion. The FDA will receive comments on it as described below. To strengthen our voice, please join APC and participate in the educational programming offered on this topic and read and participate in the discussions on the IJPC Compounders' Network List.

Over the next several weeks, this Newsletter will present a section per week in an easy-to-read- format that should only take a few minutes to become acquainted with the document. The highlighted section in the TOC below will be covered in the respective Newsletters.

This guidance represents the Food and Drug Administration's (FDA or Agency) current thinking on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

Table of Contents

1. INTRODUCTION (Discussed in this Newsletter)
2. BACKGROUND
   1. Legal Marketing Pathways for Animal Drugs
   2. Animal Drugs Compounded from Bulk Drug Substances
3. POLICY
   1. Compounding for Nonfood-Producing Animals: Patient-Specific Prescriptions
   2. Compounding for Nonfood-Producing Animals: Without Patient-Specific Prescriptions (“Office Stock�)
   3. Compounding for Food-Producing Animals: Drugs for Use as Antidotes for Food-Producing Animals or Sedatives and Anesthetics for Free-Ranging Wildlife Species
4. PAPERWORK REDUCTION ACT OF 1995
   APPENDIX – Request for Nominations to:
   1. The List of Bulk Drug Substances for Compounding Office Stock Drugs for Use in Nonfood-Producing Animals; or
   2. The List of Bulk Drug Substances for Compounding Drugs for Use in Food-Producing Animals or Free-Ranging Wildlife Species

   I. INTRODUCTION

   This guidance describes the Food and Drug Administration's (FDA) enforcement policy regarding the compounding of animal drugs from bulk drug substances (also known as Active Pharmaceutical Ingredients (APIs)). FDA regulations define "bulk drug substance" and "active pharmaceutical ingredient" as "any substance that is intended for incorporation into a finished drug product and 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. The terms do not include intermediates used in the synthesis of the substance. 21 CFR 207.1. "Active ingredient" is defined as "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 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." Any component other than an active ingredient is an "inactive ingredient." 21 CFR 210.3(b)(8). Inactive ingredients used in compounded drug products commonly include flavorings, dyes, diluents, or other excipients by or under the direct supervision of: Veterinarians, or Pharmacists in either State-licensed pharmacies or Federal facilities (i.e., facilities operated by the Federal government).

   Throughout this guidance, the terms "pharmacists," "pharmacies," and "veterinarians" refer to those persons or entities that are State-licensed and operate in full compliance with State laws and regulations governing their practice.

   This guidance does not apply to:

   • animal drugs compounded for use in investigations of new animal drugs or to
   • animal drugs compounded from FDA-approved animal or human drugs, which are considered legal extralabel uses of such drugs.

   The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract. This document is intended only to provide clarity to the public regarding existing requirements under the law. FDA's guidance documents should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

   As described later in section II. Background, animal drugs compounded from bulk drug substances by pharmacists and veterinarians do not meet certain important requirements of the Federal Food, Drug, and Cosmetic Act (FD&C Act). To be legally marketed under the animal drug approval requirements of the FD&C Act, an approval, conditional approval, or listing on the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species is required, and compounded drugs do not go through any of these pre-market review processes. Further, all animal drugs are required to, among other things, be made in accordance with current good manufacturing practice (CGMP) requirements and have adequate directions for use, requirements not met by compounded drugs.

   Thus, drugs compounded from bulk drug substances violate the FD&C Act because:

   • they are not approved or indexed,
   • are not made according to CGMP, and
   • cannot satisfy the FD&C Act's adequate directions for use provision (which requires, among other things, that a prescription drug have FDA-approved labeling). However, FDA has generally refrained from taking enforcement action against animal drugs compounded from bulk drug substances under certain circumstances when no other medically appropriate treatment options exist. This guidance continues this practice to balance FDA's concerns about the risks of animal drugs compounded from bulk drug substances, which have not gone through Agency premarket review, with the need for such drugs when no FDA-approved or indexed drug is medically appropriate to treat the animal. This guidance is intended to provide additional information and clarify FDA's current thinking about animal drug compounding from bulk drug substances.

   At this time and based on our current understanding of the risks of animal drugs compounded from bulk drug substances, FDA generally does not intend to take enforcement action for violations of the FD&C Act's requirements for approval, adequate directions for use, and CGMP for compounding of products under the circumstances below. The policies described in this document are intended to protect human and animal health by limiting the use of animal drugs compounded from bulk drug substances to when a veterinarian is acting within a valid veterinarian-client-patient relationship (VCPR).

   A valid VCPR is a relationship in which, among other things, the veterinarian:

   • (1) has assumed responsibility for making medical judgments concerning the health of the animal patient and the need for medical treatment;
   • (2) is familiar enough with the animal patient to make a general diagnosis of the medical condition; and determines there is no medically appropriate human or animal drug that is FDA-approved,
   • (3) is readily available for follow-up should an adverse reaction occur or the prescribed therapy is not effective. For a complete definition of VCPR, see 21 CFR 530.3(i).

   Unless explicitly limited to "animal drugs," the term "FDA-approved drugs" includes FDA-approved human drugs, FDA-approved animal drugs, conditionally approved animal drugs, and licensed human biologics. These policies are also intended to focus FDA's enforcement activities on animal drugs compounded from bulk drug substances that present the most significant concerns, including compounded drugs that:

   • present particular human or animal safety concerns;
   • are intended for use in food-producing animals;
   • are copies of marketed FDA-approved or indexed drugs; or
   • are compounded without a patient-specific prescription (i.e., office stock).

   FDA will make enforcement decisions on a case-by-case basis, recognizing that it needs to make the best use of limited Agency resources.

   A complete copy of the Guidance with footnotes and comments may be downloaded at:
   guidance-documents, or www.regulations.gov.
   Compounding Animal Drugs from Bulk Drug Substances Guidance for Industry

   Submit comments on this guidance at any time. Submit electronic comments to www.regulations.gov. Submit written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number FDA-2018-D-4533.

   For further information regarding this document, contact AskCVM@fda.hhs.gov.

   Additional copies of this guidance document may be requested from the Policy and Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

   U.S. Department of Health and Human Services Food and Drug Administration Center for Veterinary Medicine August 2022 OMB Control No. 0910-0904 Current expiration date available at www.reginfo.gov See additional PRA statement in Section IV of this guidance.

   Continued in next week’s newsletter.

   
   
   Loyd V. Allen, Jr., PhD, RPh
   Editor-in-Chief
   International Journal of Pharmaceutical Compounding
   Remington: The Science and Practice of Pharmacy Twenty-second edition