The Ben Venue facility in Bedford, Ohio has spent more than $300 million to upgrade the plant.
Quality lapses as big drug companies show that contamination and shoddy practices go well beyond the loosely regulated compounding pharmacies that have attracted attention because of their link to an outbreak of meningitis..
Weevils have been found floating in vials of heparin as well as morphine cartridges that contain up to twice the labeled dose. There are manufacturing plants with rusty tools, mold in production areas and — in one memorable case — a barrel of urine.
In the last three years, six of the major manufacturers of sterile injectable drugs — which are subject to rigorous inspections by the federal government, as opposed to compounding pharmacies, which are generally overseen by the states — have been warned by the Food and Drug Administration about serious violations of manufacturing rules. Four of them have closed factories or significantly slowed production to fix the problems. Nearly a third of the industry’s manufacturing capacity is off line because of quality issues, according to a Congressional report.
The shutdowns have contributed to a shortage of critical drugs, and compounding pharmacies have stepped into the gap as medical professionals scramble for alternative sources. But several serious health scares have been traced to compounding pharmacies in recent years. Authorities said 19 people had died from meningitis in an outbreak traced to a contaminated steroid made by the New England Compounding Center in Massachusetts. Supplies of the steroid, methylprednisolone acetate, became short earlier this year after two generic manufacturers, Teva and Sandoz, stopped making it.
“In the industry, everyone knows that all of the factories are in terrible shape,” said Erin Fox, manager of the Drug Information Service at the University of Utah, which tracks drug shortages. But the public, she said, is still in the dark. “I think people think this is a foreign outsourcing problem, but these factories are in our own country.”
Regulators and manufacturers note that most sterile injectable drugs — products like chemotherapy drugs and anti-seizure drugs like diazepam — sold in the United States are safe and of high quality. Still, several industry observers and former plant employees said that the recent quality issues were troubling and that manufacturers had been reluctant to fix problems because stopping production was simply too costly in a business where profits were driven by volume. Many basic drugs sell for less than a dollar a vial and are made in batches of tens of thousands of vials, run on lines that can operate up to 24 hours at a time.
Manufacturers reject descriptions of their factories as deteriorating and say they are investing hundreds of millions of dollars to make improvements.
“When you read and or hear different people in the industry saying that these are old, dilapidated, rundown facilities — absolutely not true,” said David Gaugh, a senior vice president for the Generic Pharmaceutical Association, an industry trade group. Mr. Gaugh was previously vice president and general manager for Bedford Laboratories, a unit of the manufacturer Ben Venue. He likened some of the older, 1970s-era plants to vintage Camaros or Mustangs, noting that while some old cars are indeed falling apart, others are tended with pride.
“That’s what these facilities are,” Mr. Gaugh said. “They’re maintained muscle cars.”
The manufacturing process garnered more attention in 2009, when Dr. Margaret Hamburg took over as commissioner of the F.D.A. and pledged to get tougher on plant inspections. That year, the F.D.A. cited Teva, the large generic drug maker, for several violations at its injectable drug plant in Irvine, Calif., including that it had failed to catch bacterial contamination of propofol, the anesthesia drug, before it left the factory.
Hospira, the leading manufacturer of injectable drugs, has been a major target of quality complaints. Since 2009, federal regulators have outlined failures in quality control at its plants in North Carolina, California and Costa Rica, leading to several major recalls of products as diverse as faulty infusion pumps and overfilled morphine vials. The company has slowed production at its largest factory in Rocky Mount, N.C., which had the most extensive problems.
Hospira’s manufacturing issues became public months after the company began in 2009 a two-year initiative called Project Fuel, designed to save more than $100 million a year by, for example, shrinking the work force 10 percent.
Critics, including a group of shareholders who have filed a lawsuit against Hospira, claim that Project Fuel led to deep cuts in quality control, including the dismissal of seasoned employees and the failure to maintain equipment. In comments to investors last year, a Hospira executive acknowledged the company had gotten “a little lazy” and was “skating behind the puck.”
Stacey Eisen, a Hospira spokeswoman, said the company supported the F.D.A.’s recent focus on manufacturing quality. “We support the agency in this respect, as we, too, consider the quality of our products to be of paramount importance, and we’re working closely with the agency on all aspects of our quality efforts,” Ms. Eisen said. She said Project Fuel was not about cost-cutting but about reducing complexity across the company and improving productivity.
Late last year, Ben Venue, a division of the German drug maker Boehringer Ingelheim, shut its plant in Bedford, Ohio, after the F.D.A. visited the facility. Agency inspectors reported rusty tools, mold and a barrel of an “unknown liquid” later determined to be urine; the report did not make it clear what the barrel was doing there. Three other companies that make injectable drugs — Sandoz, Luitpold Pharmaceuticals and A.P.P. Pharmaceuticals — have also received warning letters. Earlier this year, Sandoz slowed production at a plant in Quebec to fix problems identified by the agency. All the companies said they took quality seriously and were either working with the agency to address its concerns or had already resolved the issues.
In a particularly vivid lapse, agency inspectors cited the failure to investigate a number of reported problems at A.P.P.’s plant outside of Buffalo, including complaints of human hair and fungal growth in vials.
One former supervisor at the plant said his managers were reluctant to stop the production lines. “It’s like trying to fix your car when you’re driving down the Thruway,” said the former employee, who was recently terminated and said he did not want to be identified because he feared retaliation. Managers ordered shortcuts that compromised quality, he said, and skimped on cleaning to shorten the turnaround time between batches. Afterward, centipedes and spiders were spotted in manufacturing areas, he said.
F.D.A. inspectors cited internal reports of infestations, including a spider and weevils inside vials.
Matthias Link, a spokesman for Fresenius Kabi, the German drug maker that owns A.P.P., said the company was committed to making high-quality medicines and was addressing the inspectors’ concerns. He said Fresenius Kabi had already planned to spend $38 million on improving and expanding the plant before the agency’s warning letter.
The F.D.A. says it has stepped up its efforts to work with manufacturers, hosting conferences to exchange ideas and starting a program with its European counterpart about expectations.
Many of the manufacturers are spending hundreds of millions of dollars to address the problems. Ben Venue has spent more than $300 million to upgrade its factory in Ohio and is opening a new plant that will manufacture cancer drugs. It said on Tuesday that it had resumed some production.
Hospira, whose chief executive has likened its remediation process to “draining the swamp,” expects to spend up to $375 million to address the agency’s concerns. Teva has reopened its factory in Irvine, though it has not yet resumed full production.
The investments are real, said Dr. Sandra Kweder, deputy director of the F.D.A.’s Office of New Drugs. “I would say we are encouraged,” she said. “But we also know it takes three to five years to get one of these plants up and running.”
Via New York Times