This is a horror story about the medications we have to take. No one is tracking where the ingredients are manufactured or what quality standards exist for those manufacturers.
Many come from third world countries where standards are very different than ours and the FDA is overwhelmed by the number of inspections, which are backlogged for years.
Despite the jackhammer-like rhythm of a mechanical ventilator, Alicia Moreno had dozed off in a chair by her 1-year-old’s hospital bed, when a doctor woke her with some bad news: The common stool softener her son, Anderson, was given months earlier had been contaminated with the bacterium Burkholderia cepacia.
Suddenly, Anderson’s rocky course made medical sense. B. cepacia was the same unusual bacterium mysteriously found in the boy’s respiratory tract, temporarily taking him off the list for a heart transplant.
The same bacterium resurfaced after his transplant and combined with a flu-like illness to infect his lungs. He’s been on a ventilator ever since.
The tainted over-the-counter medicine, docusate sodium, routinely prescribed to nearly every hospitalized patient to avert constipation, caused Anderson to suffer “serious and dangerous life-threatening injuries,” a lawsuit filed by his family alleges.
The drug was eventually recalled, but only after a Texas hospital staff noticed an uptick in B. cepacia infections, prompting a six-month investigation that led back to the tainted drug and its Florida manufacturing plant.
Since the start of 2013, pharmaceutical companies based in the U.S. or abroad have recalled about 8,000 medicines, comprising billions of tablets, bottles and vials that have entered the U.S. drug supply and made their way to patients’ medicine cabinets, hospital supply closets and IV drips, a Kaiser Health News investigation shows.
The recalls represent a fraction of the medicines shipped each year. But the flawed products contained everything from dangerous bacteria or tiny glass particles to mold — or too much or too little of the drug’s active ingredient.
Over the same period, 65 drug-making facilities recalled nearly 300 products within 12 months of passing a Food and Drug Administration inspection — as was the case with the stool softener, according to a KHN analysis of recall notices and inspection records kept by the FDA.
The medicine alleged to have sickened Anderson Moreno seriously infected at least 63 other people in 12 states, according to reports by the FDA and Centers for Disease Control and Prevention. The drug was made at a PharmaTech plant in Broward County, Fla. That same plant passed an FDA inspection even while it was making bacteria-laced products, according to a KHN review of the inspection records.
But veteran industry consultant John Avellanet, who has trained FDA inspectors, questions how effective the FDA’s drug plant inspections actually are.
“It’s so easy” for FDA inspectors to miss things because they’re working with confusing regulatory terms and standards that are often decades out of date, Avellanet said.
Just how often people are sickened or die from tainted drugs is next to impossible to determine. No government agency tracks cases unless they’re linked to a major outbreak among hospital patients.
And sudden, seemingly random illnesses in disparate places are notoriously hard to link to a tainted drug.
That’s in part because drugmakers don’t have to divulge which products are made in which manufacturing plants, since that is regarded as proprietary information.
The result: Even someone who buys drugs for a major hospital can’t track down where a potentially dangerous product came from, said Erin Fox, who purchases medicines for University of Utah Health hospitals.
The PharmaTech Story
How Tainted Drugs Slip Through the Cracks
The FDA is supposed to inspect all factories, foreign and domestic, that produce drugs for the U.S. market. But a KHN review of thousands of FDA documents — inspection records, recalls, warning letters and lawsuits — offers insight into the ways poorly manufactured or contaminated drugs reach consumers:
- Inspectors miss serious hazards.
- Drugmakers fail to meet standards even after the FDA has taken enforcement action.
- Hundreds of plants haven’t been inspected for years, if ever.
Last July, for example, the FDA announced the first of many voluntary recalls of the blood pressure medicine valsartan because some tablets contain a cancer-causing impurity called N-nitrosodimethylamine (NDMA). They would later find a similar carcinogen, N-nitrosodiethylamine (NDEA), in valsartan pills. Over the prior two years, investigators had detected worrisome problems in two overseas factories involved in the manufacturing of the drug.
In 2017, FDA investigators found rust, chipping paint and deteriorating equipment at a plant run by Zhejiang Huahai Pharmaceutical Co. in Zhejiang, China. Plant staffers weren’t properly testing and investigating “anomalies” in their drugs, dismissing problematic test results, the FDA said at that time. Inspectors also found “black metallic particles” and other problems in some unidentified drugs
The FDA put the facility on import alert in late September and issued a warning letter in November detailing deficiencies, including “Failure of your quality unit to ensure that quality-related complaints are investigated and resolved.”
At a facility of Hetero Labs in India, in 2016, FDA inspectors found
- colored and white residue in components,
- some of the factory’s tablets were twice as thick as others, and
- employees were shredding documents in the middle of the night.
The FDA issued a warning letter to the company as a result of the inspection.
Plants making drugs for U.S. consumers are supposed to be inspected every few years, according to a risk-based system. However, in the past decade more than 2,500 facilities, both foreign and domestic, have gone more than five years without an FDA drug-quality inspection, a KHN analysis found.
The FDA has no drug-quality inspection records over the past decade for more than 1,200 domestic plants and nearly 400 foreign plants, excluding those that make animal drug products, according to the analysis.
At best, the inspections are a snapshot in time, and involve looking at processes rather than evaluating the drugs themselves, said drug-quality specialist Dinesh Thakur, who has worked for drugmakers. The inspections might take place while the facility is making only one of a dozen or so drugs that it usually manufactures.
“The implicit assumption … is that if the [manufacturing] processes are sound, the product will be of good quality,” said Thakur, who raised the alarm about quality-control problems at generics drugmaker Ranbaxy, resulting in a 2013 guilty plea and a $500 million settlement. “Your data tells us this is not true.”
Many inspections, he said, are “stage-managed,” so that factories pass on the appointed day, but “once the inspectors leave, it’s a completely different story.”
David Gortler, a former FDA medical officer, said most drug plant inspections involve looking over paper records and trusting that they’re real, instead of randomly testing medicines.
“Anybody can write down anything on a piece of paper,” said Gortler, who is now a consultant at FormerFDA.com. He added that FDA inspectors aren’t reprimanded — or even told — if they’ve passed a plant that issued a recall shortly thereafter.
How Things Can Go Wrong
The FDA has issued thousands of enforcement actions against drug plants over the years, citing safety violations, issuing warning letters and blocking imports from certain foreign plants. In rare cases, the FDA can also seize drug products and has done so 23 times in the past decade. The last drug seizure was more than two years ago, according to FDA records.
But the system can be stymied or gamed and the FDA’s enforcement abilities are limited. For instance, it doesn’t have the power to issue a mandatory recall, and manufacturing citations don’t come with fines.
Many cases come to light only when a whistleblower sounds an alarm.
Thakur, the Ranbaxy whistleblower, said officials in other countries sometimes tip off plants about “surprise” FDA inspections.
And FDA inspectors often have to rely on translators hired by the drug companies, said Avellanet, who has been a drug facility inspection consultant for more than 20 years.
At Nippon Fine Chemical in Japan, employees stood “shoulder-to-shoulder” to keep an FDA official out in December 2015, according to an enforcement letter sent to the plant and published online.
Less than a year later, Vikshara Trading & Investments Ltd. in India allegedly faked a worker strike to block the entrance to the plant, according to an FDA enforcement document that described the manufacturer’s “false statements.” When inspectors were eventually allowed in, the lights were kept off.
“Our investigator had to perform parts of the walkthrough in the dark, using a flashlight,” the FDA warning letter reads, adding that an unidentified powder was “scattered” and “caked on the floor” in production areas and detected on finished drug products.
Two former employees have filed a whistleblower suit against Gilead Sciences, alleging it lied to the FDA about using a drug-manufacturing facility in South Korea, when it was actually using an unregistered facility in China.
According to the civil complaint filed in September 2014 in U.S. District Court for the Northern District of California, the ingredient produced at Synthetics China and used in HIV drugs Truvada and Atripla contained
- “glass-like shards,”
- “black rubber-like particles,”
- “plastic-like particles,”
- “small stone or pebble-like particles” and
- “metal shards.”
The whistleblowers alleged Gilead’s Alberta, Canada, plant was tasked with sieving contaminants and helping to conceal where the ingredient was made.
Since the FDA has little power to force a drugmaker to fix problems or issue recalls, FDA inspectors often flag the same violations again and again.
Kept In The Dark
About a year after the initial PharmaTech recall in 2016, the FDA announced another recall for the same drugs and the same bacterium: B. cepacia.
When Erin Fox saw the second recall, she thought it was a mistake. The alert said to avoid drugs made by PharmaTech under several labels “and possibly [products from] other companies.”
What other companies? Fox wondered. How could they not know which ones?
Doctors at the hospital asked Fox to remove all PharmaTech-made products from the shelves, but because of lax labeling laws, she said, she couldn’t be sure which those were.
Drug labels need to include only the manufacturer, the packer or the distributor — not all three — so the doctors suggested she call PharmaTech and ask what else it manufactures and for whom.’
“Of course,” Fox said, “they wouldn’t tell us.”