Compounding the Animal Drug Debate: FDA Releases Draft Guidance Addressing Compounding of Animal Drugs From Bulk Drug Substances, Raises Specific Questions for which it Seeks Comments, and Requests Animal Bulk Substance NominationsMay 19, 2015
By Karla L. Palmer –
Notwithstanding recognizing that sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) apply to compounding of human drug products, earlier this week the Food and Drug Administration (FDA) issued draft guidance on animal drug compounding, including compounding by section 503B outsourcing facilities. FDA also withdrew its vastly different prior Compliance Policy Guide (608.400) for animal drugs promulgated over 12 years ago (and later revised). It also issued a request for nominations for bulk substances that may be used in animal drug compounding by an outsourcing facility (blogged separately), which will serve as Appendix A to the guidance. Lastly, FDA also separately requested comments from the public on a number of separate topics concerning animal drug compounding. FDA is seeking comments on certain specific issues so it can determine whether additional guidance is needed on, for example, drug repackaging or compounding from approved drug products for animal use. We will set these forth comment topics in a separate blog post as well. Comments are due 90 days from publication in the Federal Register, or on August 17, 2015.
The “non-binding” draft guidance describes conditions under which FDA does not intend to initiate enforcement action against state-licensed pharmacies, licensed veterinarians, and outsourcing facilities (“animal drug compounders”). However, these animal drug compounders must meet all the conditions set forth in the draft guidance; in addition outsourcing facilities must compound from a bulk substance that appears in Appendix A of the guidance. The draft guidance explicitly does not address compounding from approved animal or human drugs pursuant to the extra label use provisions of the law and does not address repackaging. Note the Appendix is not final (and thus lists no bulk substances).
Like the former withdrawn guidance, FDA states that, to be legally marketed, new animal drugs must be approved under FDCA § 512, or on the list of Legally Marketed Unapproved New Animal Drugs for Minor Species at FDCA § 572. Otherwise, FDA considers compounded animal drugs to be unapproved, unsafe, and adulterated. FDA recognizes limited exemptions from certain statutory requirements for approved animal drugs for extra label use under the conditions set forth in FDCA § 512 and 21 C.F.R. pt. 530. FDA is concerned about the use of drugs compounded from bulk for use in animals when approved alternatives exist that can be used in a labeled or extra-labeled manner.
FDA does not plan to take enforcement action under §§ 512(a) (new animal drug approval requirements); 501(a)(5) (unsafe new animal drug under § 512); 502(f)(1) (adequate directions for use); and 501(a)(2)(B) (current good manufacturing practices (cGMP) requirements) so long as animal drug compounders comply with the following conditions, briefly summarized below. However, FDA warns that, until the draft guidance is finalized, stakeholders should be aware that FDA intends to look at the totality of the circumstances when determining whether to take enforcement action for unlawful animal drug compounding activities.
1. The drug must be compounded by a state licensed pharmacy.
2. The drug must be dispensed for an individually identified animal patient. Specific limits on compounding in advance (based on amounts compounded over a 14-day period within previous six months).
3. The drug is not intended for use in food producing animals (as specifically defined); prescription must contain the statement, “this patient is not a food-producing animal.”
4. If the drug contains a bulk substance that is a component of any marketed animal/human drug:
a. There is a change between the compound and the FDA-approved drug that produces a “clinical difference” for the individually identified animal patient as determined by the veterinarian, and
b. The prescription or accompanying documentation contains a statement that the change would produce a clinical difference for the individually identified animal patient.
5. If there is an approved human or animal drug with the same active ingredients, the pharmacy must determine and document that the compounded drug cannot be made from the approved drug.
6. The pharmacy must receive from the veterinarian, in addition to any information required by state law:
a. Identification of the species that will receive the drug, and
b. The statement: “There are no FDA-approved animal or human drugs that can be used as labeled or in an extralabel manner under section 512(a)(4) or (5) and 21 CFR part 530 to appropriately treat the disease, symptom, or condition for which this drug is being prescribed.”
7. The bulk substance must be manufactured by an FDA-registered establishment under FDCA § 510, and accompanied by a certificate of analysis.
8. The drug must be compounded in accordance with USP/NF chapters <795> and <797> (and note that the sterile drug must be compounded in an area with air quality that meets or exceeds ISO 5 standards).
9. The drug must not be sold/transferred by an entity other than the compounder. Sale or transfer does not include administration by a veterinarian.
10. The pharmacy must report on a Form FDA-1932a any product defect or serious adverse event associated with animal drugs it compounded from bulk substances within 15 days of becoming aware of it.
11. The label of any compounded drug must indicate the species of the intended animal patient, and name of animal and owner.
1. The drug must be compounded and dispensed for an individually identified patient under his or her care.
2. The drug must not be intended for use in food producing animals
3. If the bulk substance is a component of an approved human or animal drug, there must be a change made for the individually identified patient that produces a clinical difference as determined by the veterinarian.
4. There are no approved animal or human drugs that can be used as labeled or in an extralabel manner under §§ 512(a)(4) and (5) and 21 C.F.R. part 530 to appropriately treat the disease/symptom/condition for which the drug is being prescribed.
5. Must be compounded in accordance with USP/NF chapters <795> and <797> (note that the sterile drug must be compounded in an area that meets or exceeds ISO 5 air quality standards).
6. The bulk substance must be manufactured by an FDA-registered establishment under FDCA § 510, and accompanied by a certificate of analysis.
7. The drug may not be sold/transferred by the veterinarian compounding the drug. This does not include administration by the veterinarian or dispensing of a drug compounded by the veterinarian to the owner of an animal under his or her care.
8. The pharmacy must report on a Form FDA-1932a any product defect or serious adverse event associated with animal drugs it compounded from bulk substances within 15 days of becoming aware of it.
9. The label must indicate the species, name of the animal and owner.
1. The drug must be compounded only from bulk substances appearing on Appendix A (note: list to be determined after nomination process).
2. The drug must be compounded by or under the direct supervision of a licensed pharmacist.
3. The drug must not be intended for use in food-producing animals; accompanying documentation must state: “This drug will not be dispensed for or administered to food-producing animals.”
4. The drug must be compounded in accordance with cGMP.
5. The bulk substance used in compounding must be manufactured by a FDA-registered establishment under FDCA § 510, and accompanied by a certificate of analysis.
6. The drug cannot be sold/transferred by an entity other than the facility that compounded the drug. Sale or transfer does not include administration by a veterinarian to a patient under his or her care.
7. The facility must report on a Form FDA 1932a any product defect or serious adverse event associated with animal drugs it compounded from bulk substances within 15 days of becoming aware of it.
8. All animal drugs compounded must be included on the report to FDA required under Section 503B. (See FDCA § 503B(b)(2).)
9. The veterinarian’s prescription must state that the drug is intended to treat the species and conditions for which the substance is listed in Appendix A.
10. The (what will have to be a very large….) label must include the following: (a) active ingredients; (b) dosage form, strength, and flavoring, if any; (c) directions for use; (d) quantity/volume; (e) the statement “Not for resale.”; (f) the statement “For use only in [fill in species and any associated condition or limitation listed in Appendix A].”; (g) the statement “Compounded by [name of outsourcing facility].”; (h) lot/batch number of drug; (i) special storage and handling instructions; (j) date of compounding; (k) beyond use date (BUD); (l) veterinarian prescribing/ordering the drug; (m) address and phone number of the outsourcing facility that compounded the drug; (n) inactive ingredients; (o) the statement “Adverse events associated with this compounded drug should be reported to FDA on a Form FDA 1932a.”; (p) if the drug is compounded pursuant to a patient specific prescription, the species and name of the animal patient, name, and name of the owner or caretaker.
Comments should be submitted to Docket No. FDA-2003-D-0202: Draft Guidance for Industry #230: Compounding Animal Drugs from Bulk Drug Substances.