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January 15, 2020

FDA describes legal limits of drug compounding

Agency says few uses allowed for raw active ingredients
Published on January 02, 2020

Federal authorities plan to affirm that veterinarians and pharmacists can compound animal drugs from raw active ingredients, which the Food and Drug Administration refers to as bulk drug substances, but only under narrow circumstances.

They also plan to focus enforcement efforts against those who sell copies of approved drugs.

In November, FDA officials published draft guidance that describes which animal drug compounding methods are legal, illegal and subject to enforcement, or illegal but allowed by policy because they benefit patients. Read the guide Compounding Animal Drugs from Bulk Drug Substances.

Citing the Food, Drug, and Cosmetic Act, agency officials said an animal drug compounded from raw active ingredients is a new product that needs FDA review, whether that’s reflected in full approval, conditional approval, or the indexing that allows administration to non–food-producing species with small populations. But they acknowledge some animals benefit from exceptions.

Compounding pharmacist
The Animal Medicinal Drug Use Clarification Act, passed in 1994, lets veterinarians administer approved drugs outside their labeled indications, and that allowance applies to compounded drugs made from approved products. But it doesn’t allow administration of drugs compounded from raw pharmaceutical ingredients, even if the compounded products contain the same active ingredients as approved drugs.

A cat allergic to a drug ingredient may need a specially compounded formulation. Cattle that have eaten poisonous plants may need a compounded antidote. Office stock of compounded apomorphine hydrochloride could induce a dog to vomit in time to save its life.

Veterinarians and pharmacists still should dispense an approved drug when possible and, when none is, should consider extralabel use of an approved or indexed animal-use or human-use drug, the draft guidance states. If none meet the patient’s needs, a compounder should try to use an approved drug, a conditionally approved drug, or an indexed drug as the source of active ingredients before resorting to raw active ingredients.

Narrow exceptions

Dr. Amber McCoig, deputy director of the FDA Center for Veterinary Medicine’s Division of Compliance, said in a video presentation in November that the Animal Medicinal Drug Use Clarification Act, passed in 1994, lets veterinarians administer or authorize approved drugs outside their labeled indications, and that allowance applies to compounded drugs made from approved products. But it doesn’t allow administration of drugs compounded from raw active ingredients, even if the compounded products contain the same active ingredients as approved drugs.

FDA officials have received reports of illnesses and deaths associated with compounded drugs made from bulk ingredients that were too potent, contained incorrect ingredients, or contained contaminants, Dr. McCoig said. She cited three examples since 2009 of compounded equine-use drugs that contained too much selenium or pyrimethamine and killed at least 28 ponies and horses.

Dr. McCoig also noted that improper compounding can discourage investment in new animal drugs and undermine approved drugs.

Janice Steinschneider, regulatory counsel for the FDA CVM, said during the same presentation that veterinarians who prescribe or make a compounded animal drug need to work within a veterinarian-client-patient relationship. They also should report adverse events to the FDA.

Steinschneider said FDA policy will, under the draft guidance, let veterinarians and pharmacists use raw active ingredients to make drugs for specific, identified, non–food-producing animals when the final products need to differ from existing drugs on the basis of contents or administration route. If the compound and an approved or indexed drug have the same active ingredients, same routes of administration, and similar strength, the veterinarian should say in the prescription why the animal needed a product compounded from raw active ingredients.

The draft guidance allows making office stock of certain compounded substances that may be needed more quickly than compounding allows; those drugs are included in a list from the FDA. Plus, the bulk substances on the list can be used to make antidotes for food-producing animals, provided veterinarians tell clients how long the animals need to be held or their products discarded to keep the drugs out of the human food supply.

Get the list of stock compounds. FDA officials are accepting nominations to the list.

Concerns from compounders

Soon after the draft’s publication, AVMA volunteers started reviewing it with plans to send comments to the FDA, according to a Nov. 19, 2019, post on the AVMA @ Work blog. The post states that the AVMA is committed to preserving veterinarians’ access to compounded drugs and the FDA drug approval process.

Leaders of the Alliance for Pharmacy Compounding, formerly the International Academy of Compounding Pharmacists, said they disagree with the FDA’s interpretation that the law restricts compounding animal drugs from raw active ingredients and with the agency’s plan to apply policy through guidance rather than regulations. David Pore, governmental affairs counsel for the APC, said in late November the organization was studying details of the policy ahead of submitting comments.

Under the draft guidance, compounders would rely on enforcement discretion, he said.

Anthony Grzib, who is chair of the APC’s legislative committee and a compounding pharmacist for Wedgewood Pharmacy in Swedesboro, New Jersey, noted that the FDA’s list of approved compounds for office stock started with eight active pharmaceutical ingredients and a call to nominate more. Wedgewood uses such raw active pharmaceutical ingredients in about 2,000 animal products that account for half the company’s veterinary-use compounding, he said.

“It’s difficult to imagine how we’re going to be able to serve patients with only being able to use eight APIs,” he said.

Grzib said the guidance language also would limit compounding that modifies only the flavor or dosage form of a drug. A liquid and a chewable treat, for example, could deliver a drug in different forms but the same route of administration.

An FDA spokeswoman clarified that, while such a product would be considered a copy, a pharmacist can compound such a product when a veterinarian determines the change would be a clinical benefit for the veterinarian’s patient. The veterinarian needs to explain that decision in the prescription, and the pharmacist needs to document why the drug could not be compounded from an approved product.

Grzib said having office stocks of compounded medicines available also benefits veterinarians who travel to animals.

“The veterinarians don’t always know which animals are going to need what medication when they visit a barn or a zoo,” he said. “And so that’s why office use is much more prevalent in animal health than in human health.”

The FDA also maintains lists of bulk drug substances that can be used in compounding human medicines to address shortages or unmet clinical needs. Pore said adding drugs to those lists involves a restrictive nomination and approval process, and he expects similar scrutiny of compounded animal drugs.

FDA officials published another draft guide on compounding in May 2015 and withdrew it in November 2017 in response to comments. In that document, FDA officials described compounding animal drugs from raw ingredients as manufacturing but said they would allow limited uses for patient care.

At the time, AVMA leaders responded that they thought the proposed guidance could limit treatment options and harm animals. In an 18-page letter from then–AVMA CEO Dr. W. Ron DeHaven, the AVMA criticized provisions that would have restricted administration of drugs compounded from raw drug substances to individually identified animals, which would exclude populations in zoos and aquariums; limited veterinarians’ abilities to stock emergency-use doses of compounded drugs; and required a clinical benefit from compounding from raw ingredients over approved products, which would have prevented compounding of drugs that were approved but unavailable.