The U.S. Food and Drug Administration (FDA) has released a Notice of Draft Guidance and Withdrawal of Compliance Policy Guidance (Guidance Notice), along with a Draft Guidance for Industry (Draft Guidance) addressing compounding of animal drugs from bulk drug substances. A separate Notice announced that FDA is soliciting nominations for the Bulk Drug Substance List (Bulk List Notice) for use in the compounding of animal drug products. In the wake of FDA’s publication of a number of guidance documents relating to the implementation of Section 503A and 503B of the Drug Quality and Security Act (DQSA), which is only applicable to the compounding of human drugs, there remained outstanding questions as to the status of compounded animal drugs. Through this Draft Guidance, FDA is trying to provide some clarity on the remaining animal compounding issues. Comments and nominations are due by August 17, 2015.

Guidance Notice

The Guidance Notice indicates that the Draft Guidance provides information on the application of the Federal Food, Drug, and Cosmetic Act (FFDCA) to compounded animal drug products. Specifically, the Guidance Notice clarifies that sections 503A and 503B of the FFDCA do not apply to animal drugs and that, while there are exemptions for compounding from FDA approved products, FDA makes no distinction between the compounding of animal drug products from bulk substances and the manufacturing or processing of other animal drug products. Thus, the same requirements that apply to manufactured animal drugs also apply to compounded animal drugs, with the limited statutory exception provided in FFDCA sections 512(a)(4) and (a)(5) which allows for extra-label use of a compounded animal drug made from already-approved animal or human drugs. The extra-label use is exempt from FDA approval requirements and adequate directions for use if the product complies with 21 C.F.R. Part 530, which addresses extra-label use in animals of approved animal and human drugs. The Guidance Notice specifies that the Draft Guidance does not address extra-label use or repackaging of approved animal drugs. However, FDA is soliciting responses to specific questions posed in the Guidance Notice, including, but not limited to:

  • Is additional guidance needed to address the repackaging of drugs for animal use?
  • Is additional guidance needed to address the compounding of animal drugs from approved animal or human drugs under sections 512(a)(4) or (a)(5) of the FFDCA and 21 CFR Part 530?
  • Is additional guidance needed to address the compounding of animal drugs from bulk drug substances for food-producing animals?
  • Do United States Pharmacopeia and National Formulary (USP–NF) chapters <795> and <797> provide suitable standards for animal drugs compounded by veterinarians, and if not, what standards of safety, purity, and quality should apply to animal drugs compounded by veterinarians?
  • Should licensed veterinarians be able to sell or transfer an animal drug compounded from bulk drug substances by a state-licensed pharmacy or an outsourcing facility to owners or caretakers of animals under the veterinarian’s care?
  • Should the final guidance include a condition on the amount or percentage of compounded animal drugs that a state-licensed pharmacy or outsourcing facility can ship in interstate commerce? If so, what would a reasonable amount be?

The Guidance Notice also announces the withdrawal of FDA Compliance Policy Guide (CPG) Section 608.400 which was issued in 2003. FDA is withdrawing this CPG because it “is no longer consistent with FDA’s current thinking on the issue it addresses” because “it does not focus on the three main concerns FDA has about animal drug compounding.” (Guidance Notice at 28624, 28625). These concerns include: (1) using bulk drug substances to compound copies of approved animal or human drugs, (2) compounding from bulk drug substances for food producing animals, and (3) compounding office stock from bulk drug substances. Because the issuance of the Draft Guidance and the withdrawal of the CPG may lead to enforcement confusion among stakeholders, FDA has indicated that until the Draft Guidance is finalized, it will “look at the totality of the circumstances when determining whether to take enforcement action for unlawful animal drug compounding activities.” (Id.).

Draft Guidance

The Draft Guidance addresses compounding of animal drugs from bulk drug substances that do not fall within the limited extra-label use exception, as FDA is concerned that the “unrestricted compounding of animal drugs from bulk drug substances has the potential to compromise food safety, place animals or humans at undue risk from unsafe or ineffective treatment, and undermine the incentives to develop and submit new animal drug applications.” (Draft Guidance at 3). FDA does not plan to take enforcement action if a state-licensed pharmacy, licensed veterinarian, or outsourcing facility uses bulk drug substances to compound animal drugs in accordance with the conditions set out in the Draft Guidance.

For example, if an animal drug is compounded by an outsourcing facility, to satisfy the requirements spelled out in the Draft Guidance the compounded drug must:

  1. Be compounded only from bulk drug substances appearing on Appendix A of the Draft Guidance, for which FDA is currently soliciting nominations;
  2. Be compounded by or under the direct supervision of a licensed pharmacist;
  3. Not be intended for use in food-producing animals;
  4. Be compounded in accordance with current good manufacturing practices requirements;
  5. Be compounded with bulk drug substances manufactured by an establishment that is registered under section 510 of the FFDCA (21 U.S.C. § 360) and is accompanied by a valid certificate of analysis;
  6. Not be sold or transferred by an entity other than the outsourcing facility that compounded such drug;
  7. Comply with the adverse event reporting requirements, i.e., within 15 days of becoming aware of any product defect or serious adverse event associated with animal drugs it compounded from bulk drug substances, the outsourcing facility reports it to FDA, on Form FDA1932a;
  8. Be included, along with all other drugs compounded for animals by an outsourcing facility, on the report required by section 503B of the FFDCA to be submitted to FDA each June and December identifying the drugs made by the outsourcing facility during the previous six-month period;
  9. Be accompanied by a prescription or order that states the drug is intended to treat the species and condition(s) for which the substance is listed in Appendix A; and
  10. Be labeled in accordance with the Draft Guidance.

Bulk List Notice

The Bulk List Notice explains the nomination process for bulk drug substances to be included in the Draft Guidance Appendix A and is applicable only to animal drug compounding conducted by outsourcing facilities using bulk drug substances. FDA intends to review nominations for the initial version of the list based on the responses submitted to the Bulk List Notice, but will then review nominations on a rolling basis and periodically update Appendix A.

A bulk drug substance will be included in Appendix A only when the following criteria are met:

  1. There is no marketed approved, conditionally approved, or index-listed animal drug that can be used as labeled to treat the condition;
  2. There is no marketed approved animal or human drug that could be used under sections 512(a)(4) or (a)(5) of the FFDCA and 21 CFR Part 530 to treat the condition;
  3. The drug cannot be compounded from an approved animal or human drug;
  4. Immediate treatment with the compounded drug is necessary to avoid animal suffering or death; and
  5. FDA has not identified a significant safety concern specific to the use of the bulk drug substance to compound animal drugs (under the listed conditions and limitations).

FDA notes that inactive ingredients are not required to appear in Appendix A to be used in compounding animal drug products.

Comments on the Draft Guidance and nominations for the Bulk Drug Substance List are due by August 17, 2015, and can be submitted electronically to http://www.regulations.gov.