The FDA found unsanitary conditions and sloppy procedures at 60 specialty pharmacies. Behind each one of these pharmacies, known as compounders, independent testing laboratories were affirming that the drugs were safe, sterile and mixed at the proper strength, FDA records show.
The FDA cited five labs for more than 70 safety problems, including one case in which the repeated appearance of bacteria in a so-called clean room where sterile drugs were being tested called into question the integrity of the testing procedures.
The five laboratories conduct testing for about 90 percent of the nation’s large-scale specialty pharmacies, which mass-produce custom-mixed drugs and other medical solutions for doctors, clinics and hospitals.
Dozens of types of medications, packaged in thousands of IV bags, syringes and vials, have been recalled as a result of FDA inspections at the compounding pharmacies and the laboratories they use.
One of the labs, Oklahoma-based Analytical Research Laboratories (ARL), reported favorable test results for medications for the now-shuttered NECC, which produced the steroids that federal health officials say killed 64 people and sickened 686 other people last fall.
Another facility, DynaLabs in Missouri, tested and reported that a calcium gluconate solution, made by Texas-based Specialty Compounding, was safe and effective. Federal authorities said they believe the solution supplied by Specialty Compounding was contaminated with bacteria. Dozens of batches of that solution, commonly used to stabilize calcium levels in heart patients, were recalled by the pharmacy in August after the Centers for Disease Control and Prevention linked it to two deaths and 13 illnesses at two Texas hospitals.
The FDA has not assigned blame for the contaminated medications exclusively to the labs but said they must play an essential role in ensuring public safety.
“They were supposed to be a safety net, but no one has been policing the labs,” said Eric Kastango, a national expert on compounding and compounding industry consultant.
Unlike small pharmacies that custom mix medications based on an individual patient prescription, large-scale compounding firms make their custom-mixed products in sizable quantities and often ship them across state lines.
These large firms, like NECC, began routinely turning to independent laboratories for outside validation a decade ago. The move followed a series of scandals, including one in 2001 where thousands of cancer patients were given chemotherapy treatments by a Kansas City compounder who had diluted them to 40 percent below their prescribed strength.
To validate the sterility and potency of medical products, laboratories rapidly expanded their operations, and new laboratories began springing up, offering certificates that compounders provide to clients showing that products passed external testing.
Although court cases have produced conflicting rulings about which regulators have authority over the compounders — state pharmacy boards or the FDA — no one has ever claimed full authority over laboratories that contract with the specialty pharmacies.
Compounding experts say state pharmacy boards have neither the legal authority nor expertise to inspect the facilities. And the FDA, which lacks clear oversight authority, has rarely gone in unless there is a reported problem or if the lab has voluntarily registered with the agency.
Late last month, House and Senate committees agreed on legislation that would give the FDA greater authority over large-scale compounding pharmacies, but agency officials said the bill does not address the testing labs.
In the wake of the meningitis crisis, the FDA has come under pressure from Congress and government watchdog groups to increase oversight of the compounders since dozens of compounding pharmacies are functioning like manufacturers, mixing large batches of medications without prescriptions for specific patients.
“We saw a number of concerning practices that cast a lot of doubt on the validity of their sterility and other test results,” said Howard Sklamberg, director of compliance for the FDA’s Center for Drug Evaluation.
In interviews, officials with three of the laboratories cited by the FDA defended their practices. They also asserted that they do not fall under the FDA’s authority and that they and their clients should not be judged by the standards that apply to manufacturers.
“We think compounders should test, absolutely,” said Jennifer Travis, co-owner of Front Range Laboratories in Colorado. “We want safer drugs, too, but we don’t think those standards apply to us. The biggest problem right now, though, is we are operating in a crazy gray area.”
After the meningitis outbreak, the FDA conducted inspections of 66 compounders, leading to 22 recalls overseen by the agency and five more by state health officials. This level of activity is a dramatic escalation for the FDA, which had conducted an average of 20 inspections of compounders a year and rarely inspected the labs they use.
The FDA’s first laboratory inspection came last October, days after the FDA officials saw filthy conditions at Massachusetts-based NECC that included visible mold in injectable steroids that ended up being fungus, FDA records show. The agency also found vermin in rooms where sterile drug products were being made at NECC’s sister company, Ameridose, which has also since closed.
Both compounders used the ARL lab, and within days of the outbreak, FDA officials were at the ARL facility in Oklahoma City. The agency cited the lab for failing to keep records for much of the bacterial and fungal testing it performed for NECC and Ameridose. Among other things, FDA inspectors could not determine how tests were performed or which ARL employees did the tests, information that allows labs to perform internal audits when problems arise.
ARL spokesman Brent Gooden said in a statement that the company “promptly addressed each observation listed during the recent inspection, which were primarily focused on increasing documentation.” In a written statement, the lab also said that after it reviewed the FDA’s inspection reports for NECC and Ameridose, lab officials concluded that the two companies had sent them partially processed steroid products and that contamination was likely introduced at a later stage of production.
Two weeks after FDA inspectors visited ARL, a different team of federal inspectors arrived at DynaLabs. In its report, the FDA cited the laboratory for not having basic procedures in place that would “prevent microbiological contamination of drug products purporting to be sterile.”
Russell D. Odegard, managing partner with DynaLabs, said the company has “implemented the necessary improvements” in response to the FDA visit and is addressing the “quality concerns” raised by inspectors.
The laboratory tested the calcium gluconate solution that was made by Specialty Compounding, which the Centers for Disease Control and Prevention linked this summer to the deaths and illnesses in Texas. Specialty Compounding spokesman David Ball said the company thinks the testing was reliable and that contamination could have been introduced at some other point.
Also last fall, FDA officials examined Boston Analytical in Salem, N.H. A November report shows the FDA faulted the lab for failing to investigate client complaints in a timely manner and for failing to use testing methods that reliably assess the “strength, quality and purity” of products.
Officials from Boston Analytical did not return calls seeking comment.
In June, FDA inspectors examined another laboratory, Eagle Analytical Services in Houston. Two weeks later, the agency issued a report that said the lab did not have “scientifically sound” testing procedures in place and had poor record keeping and inadequate staff training.
No products were recalled as a result of this inspection. FDA officials said their investigation into Eagle is continuing and would not comment on it.
Eagle’s general manager said he does not think the company should have to conform to legal safety standards that apply to drug manufacturers — called Good Manufacturing Practices — but that in most cases, the company has agreed to make the changes recommended by the FDA.
“We are using good science,” J.D. Willey said. “For the things that made sense for us to change, we changed them, but for others we did not.” For example, in its written response to the FDA, Eagle said it would not start asking clients for information regarding the batch size of medications it is testing for them.
The FDA cited three labs — ARL, DynaLabs and Eagle — for failing to ask their clients for batch size information, which is used to calculate how much product should be tested. Such data are important, federal regulators say, if labs are to produce scientifically reliable test results.
Labs say they traditionally rely on the compounding pharmacies to supply the proper amount of material for testing.
The latest laboratory to face FDA scrutiny is Front Range Laboratories. The August inspection produced a highly critical report, prompting the recall of products by at least four compounders that used Front Range. There have been no reports of patient illnesses or deaths associated with any of the medications.
The agency issued a public alert Aug. 21, telling the 100 pharmacies in 32 states that use the lab to “not use this firm for sterility and other quality attributes testing at this time.”
In its report, the FDA said Front Range’s testing methods were “not scientifically valid.” It also cited concerns about how the company was disinfecting a room where sterile products were being tested since the company’s own data showed a reoccurrence of multiple strains of bacteria surfacing in the room.
Travis, the company’s co-owner, said many of the problems were being corrected when the FDA showed up and were caused, in part, by the company’s move three weeks earlier to a bigger building to keep pace with the growing demand from compounders.
“We were just getting our systems up and running when they showed up,” Travis said. “I also believe we looked worse than our competitors because we kept better data, and it was used against us.”