Safety, sanitary problems prompt scores of drug recalls

The infection came out of nowhere, 36 hours after Eloise Soler's heart surgery last summer at the Corpus Christi Medical Center in South Texas. As her fever spiked to 103, other patients developed similar symptoms. Doctors raced to pinpoint the cause.

Tests showed that all of the patients had been sickened by the same bacteria, Rhodococcus equi, which typically infects horses and other grazing animals, and they all fell ill after infusions of the same drug, calcium gluconate.

The drug was made 200 miles away by Specialty Compounding, which sits in a category of pharmacies that mix unique or hard-to-find drugs not only for individual patients, but also in batches for doctors and hospitals. By the time the company recalled the medication days later, investigators believed it had sickened at least 15 people; two had died.

"You think because there are so many controls on drugs that you're not going to be given something that will make you sick," says Soler, 60, who spent months recovering. "I just couldn't believe it."

Two years after contaminated drugs linked to a compounding pharmacy in Massachusetts killed 64 and sickened more than 750 with fungal meningitis, the industry still struggles with serious safety problems affecting thousands of patients, a USA TODAY examination shows. A regulatory crackdown by the U.S. Food and Drug Administration since the outbreak in October 2012 has led to an unprecedented spate of drug recalls by compounding pharmacies — and scores of citations for bad practices.

Compounders say they're being held to new standards that are unfair and unnecessary, threatening an industry that provides hundreds of thousands of patients with critically needed drugs they cannot get from commercial manufacturers. Some compounding pharmacies are cutting services because they can't meet tougher protocols for larger-scale production.

USA TODAY reviewed hundreds of pages of federal records, industry documents and legal filings and discovered:

• Compounding pharmacies have issued more than 50 recalls in the past two years. Most of the recent recalls covered multiple drugs shipped to patients and health care providers nationwide. In a sampling of half the cases, USA TODAY found that 20% involved the most serious recall classification, reserved for "dangerous or defective products that predictably could cause serious health problems or death."

• From October 2012 through September, the FDA performed nearly 150 inspections of compounding pharmacies. In about 90% of those inspections, evaluators identified "objectionable conditions" — typically safety and sanitary problems — that warranted corrective action. They saw everything from workers wearing soiled gloves to visible mold growth in injectable medications.

• Since October 2012, the FDA has issued more than 30 warning letters to compounding pharmacies for "serious" deficiencies. The letters typically are a last-chance notification to pharmacies with sanitary and safety problems that, if not corrected, are likely to trigger enforcement action, potentially including fines or prosecution.

"We are out there doing more inspections … (and) a substantial portion of the recalls are linked to problems we discovered during those inspections," says Ilisa Bernstein, deputy director for compliance at the FDA's Center for Drug Evaluation and Research. Compounding pharmacies got little oversight before the meningitis outbreak, she says, but "the seriousness of the findings (in) the inspection reports we've issued suggests there also were many problems prior to 2012."

They just went undetected.

DEBATE SWIRLS AROUND FDA CRACKDOWN

The definition of what constitutes a compounding pharmacy remains somewhat murky, and it's unclear how many there are, how much medication they produce or where it goes.

Most drugstores and virtually all hospitals do at least some compounding; mixing custom or hard-to-get drugs to fill prescriptions is a standard part of pharmacists' training. Nationwide, 1%-3% of all prescriptions are compounded, according to the International Academy of Compounding Pharmacists, including specialty treatments for everything from cancer to various pediatric conditions.

Recent years have seen considerable growth in pharmacies dedicated almost entirely to compounding. Some make thousands of doses of medications for hospitals and other health care providers, using Internet commerce to build a national client base. The New England Compounding Center (NECC), which made the drugs that federal officials linked to the meningitis outbreak, was such a pharmacy. Like many large-scale compounders, it got little oversight.

"There was a very uncertain legal framework surrounding pharmaceutical compounding," says Elizabeth Jungman, a drug safety expert at the Pew Charitable Trusts. "It made it really difficult for the FDA to exert the oversight over compounding that consumers might expect."

NECC and similar operations fell into a regulatory seam between traditional pharmacies, licensed and overseen by the states, and conventional drug manufacturers, overseen by the FDA. Both the state and the FDA identified problems at NECC before the meningitis outbreak, which was traced to fungal contamination in injectable steroids, and both said they were hamstrung by murky regulatory authorities.

Congress responded by clarifying the FDA's oversight and creating a pharmacy class, called outsourcing facilities, to cover compounders producing drugs in batches for hospitals and other health care providers. Outsourcers must meet "good manufacturing practices" consistent with those covering conventional drugmakers, particularly to ensure the sterility of injectable drugs.

Compounders say the NECC case — and the regulatory changes it triggered — drove the FDA to apply the stricter safety standards in cases where they are unwarranted.

"The FDA was caught by Congress and others for being asleep at the switch in the NECC tragedy. … So (the agency) said, 'OK, we're going to go in and inspect (compounders) as if they're a manufacturer,' " says David Miller, CEO of the International Academy of Compounding Pharmacists. "It's like going to the baseball diamond with your buddies, and the other team shows up wearing helmets, padding and carrying a football."

SEARCHING FOR DEADLY BACTERIA

The FDA showed up at Specialty Compounding a few months before the pharmacy made the medication suspected of sickening Eloise Soler and the other Texas patients.

As usual, the inspection focused on standards for making sterile, injectable drugs. Specialty, like most compounders, was cited for several safety lapses. The report faulted a pharmacist for not changing gloves after going on hands and knees to pick items off the floor in a drug-preparation area. The inspection noted that technicians wiped their faces and didn't change gloves while making sterile medications. And the report criticized Specialty's processes for testing the sterility of its facilities and finished products.

Specialty submitted correction plans, but within weeks, the illnesses emerged in Corpus Christi.

After finding that all of the sick patients were infected by Rhodococcus equi after getting Specialty's calcium gluconate, investigators tested an unopened bag of the solution from the hospital. The result: bacterial contamination consistent with the strain that infected the patients.

Specialty recalled all of its sterile medications — the calcium gluconate, which had gone to physicians and hospitals in Texas, as well as other medications sent directly to patients in nearly every state.

"None of these products should be used," the Centers for Disease Control and Prevention said in a national health alert, warning of "bloodstream infections potentially related to the company's calcium gluconate infusions."

Within days, the FDA launched another, more extensive review of Specialty's operations, resulting in a new list of safety citations. Inspectors noted, among other things, that the pharmacy repeatedly failed to investigate potential problems with medications that had elicited complaints from patients.

Investigators were stymied on the most important issue: the search for Rhodococcus equi.

Specialty's facility showed no sign of the bacteria, typically found in soil. And, while bacterial contamination was found in lots of calcium gluconate that had been recalled, the pharmacy argued that the drugs were contaminated after being set aside, unrefrigerated, to await destruction.

The FDA declined to comment on the ongoing investigation.

Specialty acknowledged many of the problems found in the follow-up inspection and promised again to correct the deficiencies. But the pharmacy insists that if any of its products were linked to the illnesses in Corpus Christi, it was because they were contaminated after they left its facility.

"It remains unclear what the cause of infection is," the company said in one news release, "but very clear that Specialty Compounding is not the source."

90% OF INSPECTIONS FIND SAFETY PROBLEMS

Some compounding is relatively simple — mixing ointments, for example, or liquefying drugs so they are easily swallowed. The challenge is making solutions to be administered in shots or intravenously. They must be made in sterile conditions — with special air filtering equipment, fully gowned workers, quality assurance testing and other precautions — to make sure medications aren't contaminated with bacteria, fungus, mold or other impurities that can cause potentially fatal bloodstream infections.

Of the 54 recalls by compounders since October 2012, at least two-thirds involved sterile medications that were deemed to be contaminated or at risk of contamination. In most of those events, the compounding pharmacy recalled all of its sterile products — in some cases dozens of different drugs — often in the wake of FDA inspections that identified unsanitary production conditions.

"Most of the recall notices have come from larger (volume) pharmacies," says John Voliva, head of legislative relations for the Professional Compounding Centers of America, a company that supplies and advises independent compounding pharmacies. Not all of those pharmacies believe they warrant the new "outsourcer" designation, but many are compounding on a scale where "they're being looked at that way in the FDA's eyes," Voliva says. "And the FDA is finding failures."

Indeed, FDA inspectors are citing the facilities they visit at a far higher rate than in earlier years.

From 2002 through October 2012 (the month of the NECC outbreak), the FDA did 197 inspections at compounding pharmacies, and its investigators documented "objectionable" safety conditions in a third of those reviews, according to FDA data requested by USA TODAY. In the two years since then, the agency did 148 inspections at compounding operations and documented safety problems in nearly nine of 10.

"We unfortunately continue to see compounded drugs being made in poor quality conditions," FDA Commissioner Margaret Hamburg said in a statement to USA TODAY. The agency's stepped-up inspection regimen will continue, she added, with a focus on "identifying potentially dangerous manufacturing practices in compounding facilities producing sterile drugs."

When problems are identified in an inspection, pharmacies are expected to submit plans of correction. If the violations are serious, the FDA typically issues a warning letter threatening enforcement action. In the past year, the FDA has issued 28 of them — more than the previous five years combined.

"A lot of these big compounders are really acting as manufacturers, making 500 doses of something at a time, so a lot of them are expected to follow good manufacturing practices," says Sarah Sorscher, an attorney specializing in drug regulation for Public Citizen's Health Research Group. If they want to avoid those requirements, she says, "they're going to have to change the way they operate and behave more like mom-and-pop drugstores."

A COMPOUNDER FIGHTS BACK

Some larger-scale compounders are shrinking their business to avoid the stricter safety standards, but a few are fighting back.

NuVision Pharmacy in Dallas has refused to recall products the FDA has identified as potentially dangerous. The dispute began after FDA inspectors cited the pharmacy in 2013 for an array of safety problems in its production of sterile medications. The pharmacy initially recalled two injectable drugs based on FDA complaints about potential contamination and reports of bad patient reactions.

When the FDA asked NuVision to recall all its sterile products, the pharmacy refused.

The FDA followed up with another inspection this year and said it confirmed contamination in sterile medications prepared at the facility. Again, the agency asked for a recall of all of the company's sterile products, which are shipped nationwide. Again, the company refused.

"Any products that fail sterility or endotoxin testing are investigated and destroyed. … These products are never dispensed to patients," NuVision wrote in a statement. The company said it has upgraded its facility substantially to assure sanitary conditions, insisting that the improvements "are above and beyond what is legally required."

The FDA won't comment on whether it plans enforcement action against NuVision. More immediately, the agency warns doctors, hospitals and the public to avoid any products from NuVision or Downing Labs, the pharmacy's operator.

"Health care professionals should not use any NuVision/Downing Labs sterile products for their patients because the firm cannot ensure the safety or quality of these products," the agency said in a warning in September. "They pose serious potential risks to patients."

Specialty Compounding's decision to recall all of its products has come with a heavy price.

The company lost about $2 million on the recall, according to spokesman David Ball, and it has suspended all compounding of sterile medications until the FDA approves its plan to resume production. The pharmacy has laid off 40 employees, leaving seven to fill prescriptions for non-sterile products, Ball says, and it has lost money every month since the recall occurred.

Specialty says its hold on making sterile drugs left patients and hospitals scrambling to get needed medication, including parents of children using compounded formulas for autism. When the pharmacy resumes production, it will fill only individual prescriptions, Ball says, noting that Specialty has no plans to be an outsourcing facility.

"Most businesses in our situation would have simply closed down," owner and chief pharmacist Ray Solano says. "It is our commitment to patients and our Texas fighting spirit that keeps us open."

The pharmacy faces a lawsuit filed on behalf of Soler and dozens of patients who say they were sickened by contaminated calcium gluconate. Many of those patients say they, too, feel lasting effects. Specialty declined comment on the suit, which alleges negligence by the pharmacy and seeks unspecified compensation for the patients' impairment, medical expenses and lost wages.

"I was so, so sick … by the second week, honestly, I was ready to go," Soler says. "I had total nausea, I had chills, so my body was shaking, and nobody could figure out what was wrong with me. … When they finally came back and said I had a bacteria that gives horses and goats pneumonia, I couldn't even process it."

When Soler got home after her three-week hospitalization, she had to continue self-administering IV antibiotics and other medications. She worries that the infection could come back and attack the heart valve that was repaired before she fell sick.

"All this could have been prevented," Soler says, "if the company that made those drugs had followed procedures correctly."

Contributing: Alyssa Seidel