Pill graphic

Digital art by Tamara Rees
Sources: Shutterstock/AKaiser, whanwhan.ai

Unable for years to decide an approach to handling a key aspect of veterinary drug compounding, the U.S. Food and Drug Administration is taking another crack at it

In answer to a perennially perplexing question about the nature of ingredients that compounding pharmacies may use to make custom drugs for veterinary patients, the FDA has proffered a new draft guidance for industry, "Compounding Animal Drugs from Bulk Drug Substances." Also known as GFI #256, the proposal details circumstances under which the FDA would not enforce rules prohibiting drug compounding from bulk ingredients.

The FDA released the proposal in late November and is taking public comments through Oct. 15 (an extension of a deadline originally set for Feb. 18). Chances are that at least some of the comments will underscore the ongoing difficult nature of the issue. 

Compounding is a practice by which drugs are altered in dosage, form and/or flavor to accommodate the specific needs of individual patients. Compounding is an especially important tool in veterinary medicine because patients range in size from grams to tons, and variously have feathers, fur, scales, claws, fangs, hooves or beaks. All of these factors require creativity when it comes to dose strength and medication formulation.

But the landscape of veterinary drug compounding is more complex and shifting than a five-year game of Dungeons and Dragons. Players abound, and the rules are Byzantine and legislatively vague.

Two laws — the Food Drug and Cosmetic Act of 1938 and the Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) — have long made provisions for the need of veterinarians to have compounded drugs available for their patients. However, the ingredients from which those drugs are compounded is a key sticking point.

FDA maintains that compounded preparations given to veterinary patients should be made from existing FDA-approved products whenever possible; the agency generally frowns upon compounding veterinary preparations from bulk chemicals, also called bulk active pharmaceutical ingredients, or APIs.

Conversely, a number of large compounding pharmacies preferentially compound from bulk APIs. They maintain that the FDA lacks the legal authority to regulate the process. The question of authority is complicated because the practice of pharmacy is governed by states, not the federal government. However, compounding has become a big business such that some contend it more closely resembles drug manufacturing, an area over which the FDA has jurisdiction.

The thorny issue of bulk ingredients in veterinary compounding dates to the 1990s, when AMDUCA was enacted. According to the FDA, while AMDUCA allows for extralabel drug compounding, the provision "does not permit animal drug compounding from active pharmaceutical ingredients (bulk drugs)."

At the same time, the agency acknowledges that the use of bulk ingredients is sometimes justified. That acknowledgment led the FDA to develop a "compliance policy guide," or CPG, outlining under what circumstances the agency's enforcement officers would look the other way when bulk ingredients were used. The agency initially had a lenient policy. In 2003, it put out a much more restrictive guide containing no allowances for compounded preparations made for companion animals. That guide caused such an uproar that the FDA promised in 2004 that it would draft a new version.

Years passed. Finally, in 2015, the agency issued a draft Guidance for Industry #230. It, too, met with heavy resistance from veterinarians, advocacy groups and compounding pharmacists alike. Like the current draft guide, GFI #230 was an attempt to clarify the circumstances under which veterinarians and pharmacists could compound animal drugs from bulk ingredients. However, the provisions widely were considered confusing and overly restrictive. The FDA did not finalize the document. Instead, it withdrew the draft guidance two years later, in 2017.

The latest draft proposal, GFI #256, again lists conditions under which FDA would not enforce the rules against compounding from bulk; for example, when creating antidotes to toxins for food animals, or when a significant difference exists between the drug compounded from bulk and an FDA-approved drug with the same active ingredients. It also provides more specific language than GFI #230 in terms of dispensing and sale of compounded drugs. And, unlike GFI #230, it makes allowances for maintaining so-called "office stock" of compounded drugs under certain circumstances.

The new version leaves some still dissatisfied. For example, Wedgewood Pharmaceuticals, one of the largest compounding pharmacies in the country, would like a much more expansive allowance of bulk ingredients. Wedgewood president and CEO Marcy Bliss told the VIN News Service: "Although the FDA takes a position that compounding from bulk is illegal in animal health, they have taken no such position in human health. In addition, their position has been tested in court and the court found this claim to be lacking the support of actual law."

Asked to respond to Bliss's statement, the FDA replied by email that the federal Food, Drug and Cosmetic Act allows for the use of bulk ingredients for human drugs under some circumstances, but does not do the same for animal drugs.

"However," the statement reads, "because FDA recognizes that in some situations a drug compounded from bulk drug substances may be the only appropriate treatment option for a particular animal, it has released this guidance to describe when it does not intend to take enforcement action against a compounded animal drug. We believe this provides more flexibility to veterinarians and pharmacies, not less."

The statement continues: "But we also realize that there may be factors we have not taken into account that may have unintended effects that could impact animal health or practicality for the veterinarian. That’s why we welcome input from all stakeholders during the open comment period, so that we can consider all points of view before working on a final version."

Wedgewood's position is that using bulk drugs isn't a "sometimes" affair. The company's preference is to routinely use bulk APIs for compounding, maintaining that that approach ensures a safer, more consistent product.

Bliss said: "To put it simply, the variability of potency of the finished goods [meaning FDA approved drugs] are an unknown to a compounding pharmacy. These finished goods can vary in potency plus or minus 15%, so you are starting from a potency that is possibly quite off. There are narrow therapeutic margins for many veterinary medications, which are dosed by weight, and this lowers the assurance of potency and therefore quality. In addition, there are excipients in finished goods that may be harmful to the patient, such as xylitol [an artificial sweetener toxic to dogs] and others."

The FDA takes the opposite stance regarding the relative safety and consistency of bulk APIs vs. finished drugs. The agency told VIN News: "… Animal drugs compounded from bulk drug substances have not been evaluated by FDA to determine if they are safe, effective, properly manufactured, and adequately labeled. Consequently, animal health is actually best served through the use of approved products, which have been demonstrated to be safe and effective, and manufactured and labeled appropriately."

Lauren Forsythe, a clinical veterinary pharmacist, closely follows veterinary compounding regulations and recommendations. While her take on current compounding law around bulk-ingredient use aligns more closely with that of the FDA than of Wedgewood, she has some concerns about the FDA's latest proposal.

"We've always had to justify why we need to use bulk chemicals," she said, but she believes the FDA's reasoning on why some medications did not make it onto the bulk compounding list doesn't take into account available stability studies and formulation requirements. An example she gave is the formulation of transdermal medications — drugs that are applied to and absorbed through the skin. "Transdermal medications shouldn't be compounded from tablets," Forsythe said.

The American Veterinary Medical Association has not yet stated a position on the FDA's new proposed guidance, but is formulating a response based upon feedback it recently solicited from its members. Meanwhile, the AVMA has posted a summary of the draft proposal.

Update: This story has been changed from the original to reflect that the FDA extended the deadline for comments. The comment deadline is Oct. 15.