By Eliott C. McLaughlin, May 16, 2024
The Safety of Compounding Pharmacies
Should thousands of pharmacies be trusted to mix medications on site?
By the time Jeff Reeh received the letter from Pharm D Solutions, a compounding pharmacy in Houston, he was already battling a "raging infection" that threatened to take his leg. It wasn't the first, or last, letter Pharm D Solutions had to send telling customers to stop using its products — in this case, amino acid injections to help Reeh recover after workouts.
Unlike conventional pharmacies, which mostly dispense premade drugs in standard doses, compounding pharmacies make, or "compound," medications on the premises, according to federal guidelines. For many patients, their medications aren't available any other way.
Recent headlines have raised alarms about compounding pharmacies. In March, a Massachusetts compounding pharmacy owner was sentenced to 10-15 years in prison after pleading no contest to 11 counts of involuntary manslaughter stemming from his pharmacy's contaminated medicine, now estimated to have killed at least 100 people.
News of some compounders making semaglutide (Ozempic, Rybelsus, Wegovy) and tirzepatide (Mounjaro, Zepbound) — sometimes illegally — during widely reported shortages has added to the confusion.
Amid the uncertainty, consumers are unsure what to believe: Are compounding pharmacies safe? Who is watching the bad actors? And who's responsible when something goes wrong?
As he navigated months of surgeries to save his leg, Reeh wished he'd asked more questions before doing business with Pharm D Solutions. "Do your due diligence, beforehand," the Boerne, TX, man says.
Ozempic and Wegovy: When Big Pharma Runs Short
Medication shortages are common. Supply chain problems caused shortages in 2023, as did a tornado that hit Pfizer's Rocky Mount, NC, facility, where more than 150 medicines were made. Compounding pharmacies stepped in, performing their longtime essential role of filling in gaps in production.
When medicines are on the FDA shortage list, the agency lifts many, though not all, restrictions on compounding those medications.
Semaglutide is currently on the shortage list, as is tirzepatide. That means many people with legitimate prescriptions from their doctors were unable to get them, except through a compounding pharmacy.
Properly compounded versions are legal for anyone with a prescription, says Scott Brunner, CEO of Alliance for Pharmacy Compounding (APC), an advocacy organization. (Some states have tried to ban the compounding of semaglutide, but they may be on shaky legal ground due to conflicts with federal law.)
There have been recent bad actors: The FDA issued a warning on compounded semaglutide in December. Europe reported counterfeits in October, prompting a World Health Organization committee to take up the matter. The Partnership for Safe Medicines has reported fakes in 16 countries.
People have confused these counterfeiters, often operating offshore, with legitimate compound pharmacies, says Brunner.
"It's not compounding. It's not even pharmacy. It's illegal activity," he says.
Not Just a Backup
Their role as stopgap is one of many needs compounding pharmacies serve. They also omit ingredients that cause allergic reactions and customize pain medications, cancer drugs, hormone replacements, erectile dysfunction shots, veterinary medicines, and other prescriptions.
In addition, they're often the only source for medications to treat rare conditions, sometimes called "orphan drugs."
Making pills from scratch is just one of the many tasks of a compounding pharmacist.
"Millions depend on compounding pharmacies to live normal lives, and without compounded drugs as a therapeutic option, the American health care system would grind to a halt," says Tenille Davis, PharmD, APC's chief advocacy officer.
One example is kids who can't or won't take their medication and need it in a more palatable "flavored suspension," says Jennifer Baker, PharmD, owner of West Knox Pharmacy in Corbin, KY.
"If we didn't do it, I am not sure where these children would get it," she says.
West Knox sits on the edge of the Daniel Boone National Forest in a rural southeastern part of the state, more than an hour's drive to the nearest big city. It serves thousands of people, she says - people like Scott Fitzgerald, 90 miles north in Lexington.
Two serious auto accidents 17 years apart left the 53-year-old with depression and chronic pain. The accidents damaged Fitzgerald's spine, spleen, and liver, and broke several bones, requiring titanium plates and screws in his face, along with other operations. Pain became a constant companion.
Traditional pain meds weren't an ideal fit for Fitzgerald, and he struggled to find a solution. Then, about 8 years ago, his doctor prescribed a special cream, which West Knox compounds from five drugs, to help with pain and mood. Fitzgerald says it changed his life and made him "feel like the old Scott."
Compounding medications is serious business, Baker says. It requires technical training, specialized laboratory equipment, and strict, detailed procedures. It's easy to get things wrong if you're not paying attention. Injectable medications require special care, she says.
"You are dealing with such minute amounts of drugs, if you got off one decimal point, you can kill somebody," she says. "It's not like you're making hamburgers."
Contamination risk is magnified with injectables. That's why when tests found traces of an airborne pathogen in her area that could contaminate medicines, she stopped making injectables altogether — not because any law demanded it, but because she didn't want to play dice with customers' health, however low the risk.
Though the great majority of compounded medications are consumed without incident, Baker says not all compounding pharmacies are as careful as they should be.
"You have a lot of people out there that — they see dollar signs," she says. "A lot of them do get by with it for a long while, but eventually they'll get caught because they'll end up hurting someone."
'God, Just Get Me Back to Texas'
In 2018, Jeff Reeh had no reason to believe he'd be hurt by the injections his doctor prescribed. His physician recommended Pharm D Solutions, which compounded and mailed them to his business in San Antonio. For more than a year, Reeh gave himself the shots in his thigh twice a week after workouts, without a problem.
But on Jan. 18, 2018, while preparing to head out of town for a work convention, he noticed a bit of leg soreness. He wrote it off to a strained quad. Two days later in Las Vegas, he awoke with a "puddle of water underneath me from fever and sweat," he says. He could barely move. His thigh was swollen, hot to the touch.
"I recall being in the hotel room the night before I was scheduled to come home, and I just laid there and prayed, 'God, just get me back to Texas,'" the 58-year-old says. " 'If I'm going to die, just get me home.' "
Reeh made it home, where, for 153 days, doctors gave him antibiotics and other drugs through a special catheter (PICC line) to his heart to attack the infection (Mycobacterium chelonae-abscessus, a bacteria typically found in dirt and soil). Oral medicines continued for another 94 days.
His doctors had never seen the infection in muscle and eventually suspected the shots. At first, they were at a loss for how to treat it.
"Any drug the bacteria showed some sensitivity to, they were throwing at it," Reeh says.
One of those drugs was the antibiotic amikacin, which can permanently damage hearing. His doctor put it in stark terms: "You can either keep your hearing, or you can keep your leg."
It took 23 surgeries to remove the necrotic tissue from his leg (see slideshow).
It was during this treatment that Reeh got the letter from Pharm D Solutions telling him to stop his amino acid shots "because there might be sterility issues," he recalls.
Reeh was angry. He had spent much of his life striving to keep himself in prime condition. Not long before the infection, he says, he could bench press 225 pounds 24 times in a row (the mark hit by San Diego Chargers All-Pro Joey Bosa at the NFL Combine). Now he was living with the fear and uncertainty of possibly losing a leg.
Not the First Time
It wasn't the first time Pharm D had "sterility issues." In 2015, an FDA inspector cited numerous issues, including problems with the facility's aseptic processing area and failure to establish "procedures designed to prevent microbiological contamination."
In 2016, the FDA sent a letter saying violations went back to 2014, and its "investigator observed serious deficiencies in your practices for producing sterile drug products, which put patients at risk."
Not only was Pharm D Solutions allowed to continue doing business, but Texas renewed its license in 2017, the year before Reeh fell ill.
FDA and state inspectors returned in August 2018, weeks after Reeh's final surgery, and cited issues with quality control, training, and record keeping. The agencies noted the "facilities are not designed to minimize potential contamination and/or mix-ups."
Yet Pharm D Solutions remained open.
The next month, Pharm D Solutions, which served 13 states, followed the FDA's recommendation to recall all sterile drugs because its practices "have the potential to pose a risk of contamination," it said.
Still, the pharmacy was allowed to continue operating.
DQSA: How the Law Regulates Compounding Pharmacies
The 2013 Drug Quality and Security Act, or DQSA, was designed to protect patients from pharmacies like Pharm D Solutions.
Congress passed DQSA after a 2012 meningitis outbreak that sickened almost 800 people and killed more than 100 from epidural injections made by New England Compounding Center (NECC), eventually leading to prison sentences for the Massachusetts pharmacy owner and others.
"It was the most serious in a long history of serious adverse events associated with contaminated, super-potent, mislabeled, or otherwise poor quality compounded drugs," according to the FDA.
The act requires all compounding pharmacies to follow rules set out by US Pharmacopeia, or USP, an independent nonprofit organization that has helped the FDA set quality standards for medicines for more than 100 years.
DQSA has helped a great deal, says Elizabeth Rebello, MD, a pharmacist and professor of anesthesiology at the University of Texas MD Anderson Cancer Center, who sits on the USP committee that makes the rules.
The numbers seem to bear this out, though some experts pointed out problems with the quality of available data.
Before the DQSA, between 2001 and 2013, at least 19 outbreaks linked to compounding pharmacies sickened more than 1,000 people and killed at least 132 across the country (including the NECC outbreak), according to information from the FDA, Journal of Patient Safety and The Pew Charitable Trusts.
After the act, incidents appeared to drop, according to available data. The FDA's "compounding risk alerts," designed to prevent outbreaks like the NECC episode, have been relatively infrequent, and there hasn't been an incident anywhere near the magnitude of the meningitis outbreak, Rebello says. Pew's latest review shows that between 2012 and 2019, there were 400 "adverse events" (more on this below), leading to eight deaths, four of which weren't definitively connected to compounding errors.
DQSA did away with "a system that allowed a bad actor to continue," says Rebello, referring to NECC.
"There is increased scrutiny on the process, which is why you see it happening less frequently," she says. "Not that you'll ever reach zero, but the goal should always be to reach zero."
A Confusing Patchwork of Regulation
So, what then to make of Pharm D Solutions, which continued producing medicines after multiple violations? Or the Illinois pharmacy accused of compounding thyroid medicine 1,000 times stronger than prescribed? Or the Miami pharmacy that allegedly sickened a man with compounded hair-growth medicine? Or the Texas pharmacy that allegedly put one woman in a coma with overly potent medicine and left another with a hole in her arm from a faulty B12 shot?
The rules themselves are not the problem, says Michael Ganio, PharmD, MS. The USP rules "set a high bar for training, competency, environmental surveillance, and quality control," says Ganio, a senior director of pharmacy practice and quality at the American Society of Health-System Pharmacists.
Part of the difficulty is a patchwork of regulation, Ganio says. Not only do states have different rules - and thus, timelines - for adding new USP rules to their own mandates, but there's not always uniformity between the feds and states on enforcement.
This inconsistent and often underfunded regulatory infrastructure puts uneven burdens on pharmacies and has harmed patients, experts say
For example, while the FDA regulates the nation's 76 outsourcing facilities, states require a facility to register with them as well if the facility ships drugs to their residents, Ganio says. However, states vary on whether they must also license out-of-state pharmacists, he says.
With Pharm D Solutions, an outsourcing facility, the FDA documented multiple violations of lab procedures and possible contamination issues for 5 years, the state of Texas continued to license the company and there is no online record of any state discipline against its pharmacists, even after a federal judge shut down the operation.
Leaders and the media liaison for the Texas Board of Pharmacy did not return multiple phone calls and emails seeking comment. Former BOP director Allison Benz told Austin's KVUE in February 2020 that Pharm D Solutions' violations were "procedural" and not sufficient to shut a pharmacy down.
The FDA has cited 51 current outsourcing facilities (more than 65% of them) for "objectionable conditions." Each citation (called an FDA-483), by itself, may not indicate a serious problem, says Ganio, but careful follow-up is essential to be sure. State inspections can also make a difference.
"States that are rigorous in their licensing and enforcement requirements can help supplement FDA inspections and provide more details to purchasers interested in quality assessment," he says.
The FDA requires manufacturers to test ingredients to ensure they meet specifications and are free from contamination, it said in a statement. Ultimately, the agency says, drugmakers — along with distributors, repackagers, relabelers, and importers — "are responsible for the quality of their products."
That the FDA hasn't inspected 22 of the 76 outsourcing facilities could be considered a "regulatory shortcoming," Ganio says, especially when some of the companies registered with the FDA 3-5 years ago.
Asked about those inspections, the agency replied that it conducts inspections on "a risk-based schedule" after it confirms production and distribution have begun, which may come after registration.
FDA domestic drug-quality inspections fell by about half during the first year of the pandemic, and as of 2023, were still about 43% below pre-pandemic levels, according to online data.
But outsourcing facilities are a tiny percentage of the roughly 7,500 other compounding pharmacies in the country. These include your doctor's on-site pharmacy, some chain locations, and mom-and-pop shops, all regulated for the most part by the states.
Jennifer Baker consults with West Knox compounding technician Aaron Money.
At West Knox Pharmacy, for example, inspectors from the Kentucky Board of Pharmacy check personnel levels, testing procedures, potencies, air quality, production surfaces, and the integrity of sterile- and hazardous-drug rooms, among other things, according to owner Jennifer Baker.
Baker values this oversight because she knows improper protocols can cause serious illness or death.
"If you don't put on your gloves correctly, they'll tell you," Baker says. "I welcome it because it lets me know I'm doing everything correctly for the patient."
While the states are the primary regulators of these pharmacies, the FDA will get involved in certain situations. According to FDA guidance, the agency gives "the highest enforcement priority" to violations that "pose the greatest public health risks" but also "emphasizes that it need not identify a particular safety problem before pursuing enforcement."
"Generally, when we do go in, there's been some issue reported to us about an adverse event or a product quality issue," says Gail Bormel, acting director of the FDA's Office of Compounding Quality and Compliance.
An adverse event is any undesirable outcome — including an allergic reaction, seizure, blood infection, or ER visit — that may be linked to the use of a compounded medication.
But with the exception of the nation's 76 outsourcing facilities that compound medications in bulk, there is no across-the-board requirement to report adverse events for the thousands of other compounding pharmacies.
Where there is a state requirement, the type of information required can differ quite a bit. Even in those states, deaths from compounding aren't always brought to light.
"It's a lot like medical errors, in general," Ganio says. "They aren't always reported, and it's hard to estimate how frequently they happen or how severe they are."
The Alliance for Pharmacy Compounding is pushing Congress to update the rules to require reporting, but reporting requirements have to strike a delicate balance, says Ganio.
"If the adverse event reporting results in punitive action, then the number of reports will drop, trust in the system is lost, and the ability to learn from errors and apply them is diminished," he says.
For now, that leaves enforcement at the mercy of the competence and resources of different state agencies — and these can vary, says National Association of Boards of Pharmacy Executive Director Lemrey "Al" Carter, PharmD, MS. Even variation in individual inspectors can be a factor.
"Differences in experiences, knowledge, and longevity within a particular role could be part of the explanation that leads to subtle differences in interpretation," he says.
Asked if variations in enforcement procedures were "an area of concern," Carter replied, "No comment."
Ask Questions and Do Your Research
Reeh's leg is much better. It's "a little bit disfigured, but honestly it's the upper thigh, so it sits behind shorts most of the time," he says. His hearing still frustrates him today, especially in crowded areas.
"The ringing is incessant. I actually hear different tones and hisses in each ear, but it's always the loudest thing that you hear," he says.
On the whole, he's doing much better. He's back to running his health care business, bioworX, and he's working out again. The infection, as well as sports injuries and arthritis, have ended his powerlifting days. Today, he's slimming down and focuses more on core, flexibility, and stability.
Reeh advises anyone using a compounding pharmacy to do their due diligence, conceding that might've helped him avoid disaster, given Pharm D Solutions' history of violations.
"We had no idea the doctor would send us somewhere that wasn't perfectly fine," he says.
"Ask hard questions. It's a lot easier to do your due diligence on the front end rather than suffer the catastrophe that I went through."
"A history of sterility issues should be a huge red flag for any consumer to find another pharmacy to work with."
In May 2019, after years of violations, a federal judge finally ordered Pharm D Solutions shut down. In a news release after the ruling, the FDA said Pharm D Solutions "prepared, packed, or held" medications "under insanitary conditions," which may have led them to be "contaminated with filth or rendered otherwise harmful."
Reeh filed a lawsuit to cover his $1.7 million in medical claims. Pharm D Solutions denied the allegations. The case settled out of court, Reeh says. He isn't at liberty to discuss the settlement amount or whether Pharm D Solutions' owners admitted wrongdoing, he says.
The federal court's 2019 consent decree doesn't bar Pharm D Solutions from reopening or its owners from continuing to work in the industry. It simply gives a laundry list of orders the pharmacy must satisfy before reopening.
Pharm D Solutions, per the decree, is eligible to go back into business this month.
Editor's Note: The FDA forwarded questions on the decree to the U.S. Justice Department, which declined to provide an update. One attorney who represented the pharmacy did not return a call and email, while another said he was unable to comment.