Ensuring the safe, reliable compounding of drugs is the aim of a new Kentucky regulation

Ensuring the safe, reliable compounding of drugs is the aim of a new Kentucky regulation

Anne M. Eberhardt

Three Years Later, Wickliffe Case Brings Rule Change

Kentucky regulator adopts national standards for compounding pharmacies.

Three years after the deaths of horses in Kentucky and Florida were linked to a Lexington compounding pharmacy, the Kentucky Board of Pharmacy strengthened its regulation of the industry in a move it hopes will protect animal—and human—lives.

It's a change many see as a needed step forward in terms of safety, and several acknowledge it may have never happened if not for the Thoroughbred deaths linked to a Kentucky compounder.

State regulators cited Lexington compounding pharmacy Wickliffe in 2014 for numerous violations following the deaths of four Thoroughbreds—two in Kentucky and two in Florida—who received an improperly mixed treatment for equine protozoal myeloencephalitis from the compounder. 

Despite opposition from some Kentucky pharmacists, the KBP voted May 11 to adopt as state regulation national standards in place for compounders, as opposed to allowing those standards to serve as merely a guideline while giving pharmacists discretion if they viewed a standard to not be practical. The board approved the change that applies to all state compounders—those who prepare human or veterinary drugs—in a 3-2 vote.

KBP president Scott Greenwell said the effort to strengthen regulations began in early 2015. The change will now move to the Kentucky Legislative Research Commission and the board hopes it is implemented this year. 

According to KBP executive director Steve Hart, the problems at Wickliffe three years ago motivated the staff to work toward changes. 

"It's been fuel for the staff side of the equation to continue this push," Hart said of the Wickliffe case. 

While the U.S. Food and Drug Administration oversees the manufacture of drugs, whether they be brand name or generic, compounding pharmacies are largely regulated at the state level. Compounding pharmacies exist to mix drugs to a patient's needs. For instance, an infant may need a special, small dose prepared from what would be an adult dose of a medication. Or a compounder could prepare a medication in injection form for a patient who is unable to swallow an oral dose.

Compounders are important on the veterinary side because, animals like horses come in many different sizes. Also, if an FDA-approved drug is no longer being manufactured, a compounder is allowed to make a substitute. This situation happens frequently on the veterinary side, making reliable compounders a horse industry need.

Some problems associated with compounders include gray areas where they may arguably be acting more as a drug manufacturer than compounder. Drug manufacture is supposed to fall under FDA oversight. In horse racing, compounders also have been linked to making performance-enhancing substances. The May 11 regulation largely concerns itself with ensuring that compounders mixing prescribed drugs are acting in a safe manner.

Ensuring the safe, reliable compounding of drugs is the aim of the new Kentucky regulation. Greenwell said allowing compounding pharmacies to determine which guidelines they will follow compromises the regulator's ability to enforce rules and creates confusion on the industry being regulated.

"I don't know how we're doing our job of protecting the public if it's up to each individual pharmacist to choose," Greenwell said. "I think that's the concern, versus having a totally wide open (system), with essentially no real ability to enforce deviations from (the standards)."

In 2014 the KBP inspected Wickliffe after horses who received a compounded drug to treat equine protozoal myeloencephalitis from the Lexington pharmacy died in Kentucky and Florida. An FDA lab analysis cited in the KBP's report on the incident found that the horses received an overdose of pyrimethamine after the compounder incorrectly mixed the levels of that drug and toltrazuril.

The FDA reports that high doses of pyrimethamine in horses can lead to seizure, fever, and death.

A KBP inspection of Wickliffe found violations that included technicians performing functions without immediate supervision of a pharmacist, improper storage of hazardous drugs, and transferring of active pharmaceutical ingredients into smaller containers not properly identified with the component name, original supplier, and important dates. The regulator also determined Wickliffe had not prepared all hazardous drugs in a biological safety cabinet or compounding aseptic containment isolator, prescription labels didn't contain adequate directions, drug utilization review was not performed by a pharmacist, and permitted prescription medications were left outside the pharmacy for pickup.

The regulator didn't file a formal complaint or schedule a hearing, as it reached an agreed order with Wickliffe that saw the compounder fined $100,000 and placed on probation for three years. That probation put specific standards in place that were subject to quarterly inspections.

In Florida, owners of the Thoroughbreds that became sick or died filed a federal lawsuit that was settled in 2015.

Under the rule passed May 11, the required Kentucky standard for handling of non-sterile preparations and sterile preparations will match the standards of the U.S. Pharmacopeial Convention, as outlined in its respective standards 795 and 797, which address non-sterile and sterile preparations, respectively.

At the May 11 hearing, Kentucky Pharmacists Association president Trish Freeman said her organization supports those standards but believes that the requirement should be that pharmacists comply "when practical." She said the board would still have the power to conduct inspections and find operations as being negligent under that standard. 

But Greenwell said that would be a difficult dynamic.

"If we're saying they have the ability to choose really what they are and aren't compliant with, then we're also setting them up for potential disciplinary action that they may view that they shouldn't be subject to, because they've been told they have the professional ability to choose where they are or aren't compliant," Greenwell said.

The regulator did include a provision that will allow compounding pharmacies to request a waiver ahead of time from parts of the rule. Those waivers would be considered by the KBP, and Greenwell said the board planned to allow time for such waiver requests before the rule is put in place.

While the KPA opposed the changes, other pharmacist groups and individual pharmacists in attendance spoke in favor of the more stringent regulation. Seth DePasquale, a compounding pharmacist at BET Pharm, a Lexington compounder that mixes medications used in equine reproduction, favored the change. 

He said BET Pharm, which operates in 45 jurisdictions, has made improvements, "not only because it's the right thing to do," but also to meet the standards of California, Florida, and Texas. He said in recent years those states have raised the bar and several have special licenses required for compounding pharmacies.

Many states strengthened their oversight of compounders following the 2012 outbreak of fungal meningitis that was linked to injections prepared by a Boston compounding pharmacy. According to the New York Times, in all 64 people died and 732 others were sickened by meningitis and other infections.

The Kentucky Society of Health-System Professionals supported the Kentucky regulatory change. 

"I personally do not want to be on the witness stand when somebody is asking me ... about the 10 people and their families that, because of something I did, are no longer with us," Policastri said. "I do feel strongly about the care we give to our patients. In health systems we absolutely see the sickest and most critical patients. For me, it is so important that we do have a high standard."

DePasquale believes most compounders operate responsibly, but he understands the increased public concerns following some of the problems. He added that Kentucky has made improvements in its regulation of the industry and he was glad the KBP didn't take a step backward Wednesday.

"While it would be great if every pharmacist just performed and compounded quality formulations for the sake of making quality products, this is not the world we live in," DePasquale said. "I'm not oblivious to the fact that some players in the compounding industry without scruples are compounding duplicates of existing products commercially manufactured and selling them at a cheaper cost, and who knows what corners they're cutting to bring them to the public.

"Since the death of the horses, because of a major compounding error on the part of Wickliffe, I feel Kentucky has made great strides in trying to raise the bar for compounding pharmacies and hospitals alike."