(CNN)There's no end in sight for one of the largest prescription drug recalls in recent memory. The US Food and Drug Administration is continuing an investigation and recall of a class of drugs used by millions that began last summer, yet there's still "more to find," an agency director says.
FDA official says ongoing blood pressure drug investigation will probably uncover more tainted pills
Starting in July, separate lots of blood pressure medications from various companies were pulled from pharmacy shelves. They're known as angiotensin II receptor blockers or ARBs and contain either valsartan, losartan or irbesartan. The reason? These blood pressure drugs contained impurities that pose a cancer risk to users.
"The investigation isn't concluded," Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, told CNN this week. Working with regulators from around the world, she said, she anticipates more tainted drug lots will be found.
Woodcock said the problem appeared to occur sometime after 2010, when a Chinese manufacturer made changes to its synthetic processes.
A spokeswoman for the agency later said that, based on available information in this ongoing investigation, the FDA estimates the first possible appearance of NDMA was in 2014.
Yet the FDA did not begin its recall of the drug until July 13, one week after 22 other nations had already pulled the plug on specific manufacturers of valsartan pills to safeguard patients. In fact, two months earlier, European Union regulators had initiated a review following reports that valsartan-containing drugs imported from Zhejiang Huahai Pharmaceuticals were tainted by an impurity known as NDMA (N-nitrosodimethylamine).
Used to make liquid rocket fuel, NDMA is a byproduct from manufacturing some pesticides, yet it can also be unintentionally introduced through certain chemical reactions.
Nitrosamines are genotoxic, meaning they affect DNA replication and possibly cause cancer, Woodcock explained. Testing a variety of ARB drugs, the FDA found additional lots made by several manufacturers that had been tainted by NDMA and, in some cases, another nitrosamine known as NDEA (N-Nitrosodiethylamine).
The search for a cause suggests that these impurities were generated by specific chemical reactions in the manufacturing process of the active pharmaceutical ingredient, Woodcock said. The FDA believes that contamination might have resulted, in part, from reusing materials, such as solvents, during the process.
It's also possible "some of the source material may have had some of this in it," Woodcock said, adding that "it isn't something that would be easy to find," because the low-level impurities are measured in parts per million. When the issue was discovered, the FDA had to develop a test capable of identifying nitrosamine in the blood vessel-widening drugs.
There are FDA safeguards in place to prevent drug contamination, said Maisha Kelly Freeman, a professor and director of Samford University's Center for Healthcare Innovation and Patient Outcomes Research. Manufacturers are compelled to report impurities, for example, and the agency inspects factories on a risk-prioritized basis. However, there's a catch.
"Obviously, if they're not looking for it, they don't really know that it's occurring," Freeman said. And that's what happened in the case of tainted ARBs. "Before they found this particular compound, they didn't even know there could be a chemical reaction that could produce the compound," she said.
"The significance of this recall is that it's one of the major drugs that are dispensed in US pharmacies," Freeman said.
Losartan was the No. 9 most dispensed drug in the country based on 2016 data. Valsartan was No. 92, and irbesartan was No. 171. In a single year, then, 49 million patients were dispensed losartan, 8 million valsartan and 3 million irbesartan, Freeman said, noting that the total 60 million American patients does not include hospitals and the VA systems, only patients purchasing from community pharmacies. These are brick-and-mortar operations supervised by pharmacists and include chain stores but not hospital or online pharmacies.
At a glance, the risk of these patients developing cancer appears low. "If 8,000 patients take a contaminated product over the course of four years, only one will develop the cancer," Freeman explained. "That's the worst-case scenario if someone took the affected product each and every time they got it filled."
Patients affected by the recall may not have been continuously taking a tainted product, because pharmacies often buy the same drug from different manufacturers.
"The impact is supposed to be relatively small," Freeman said. Of course, if a patient is your own loved one and he or she developed cancer, you might not think so, she said.
Woodcock said the FDA oversees manufacturing processes at facilities around the world and noted that the agency does find that some manufacturers "cut corners."
"We are well aware that not everybody is on the up and up," she said, adding that "the vast majority of places we inspect are found to be satisfactory." The agency has a range of actions, including warning letters and consent decrees, for bringing manufacturers "back into compliance."
Some manufacturers that fail inspections voluntarily take steps to improve their operations, while others require "official action," such as the FDA refusing to grant new approvals for the plant "until it's fixed up," Woodcock said. Some domestic factories have been ordered to clean up their acts under supervision of a judge.
"For foreign sites, we're able to put in import alerts, and they can't import anything into the US," she said. "So we have pretty good hammers for the foreign sites if they're doing something wrong."
In a study published in 2016, Freeman evaluated FDA recalls over a 30-month period ending December 31, 2014.
"There are so many FDA recalls over the course of a year, it's kind of difficult to really characterize why they are occurring," she said.
During the study period, about 3,000 recalled products were analyzed by Freeman and her colleagues. A total of 348 manufacturers were associated with recalled drug products, they found, while the most common reasons for recalls were contamination, mislabeling, adverse reaction, defective product and correct potency.
"Obviously, there are so many manufacturers that are out there, it would be difficult for the FDA to visit each and every site at a regular interval to be able to make sure this kind of thing doesn't happen," Freeman said.
The FDA inspects before production begins, and then, once runs are in full swing, it inspects on a "risk-based prioritization" basis, Woodcock said. How long ago a factory has been inspected is factored into risk and helps guide the FDA.
Nathan Cortez, a professor and associate dean for research at SMU Dedman School of Law, wrote in an email that "These supply-chain problems come up periodically for products imported from China -- sometimes for drug products, sometimes for food products."
Cortez said that with so many US imports coming from China, "it's hard to say whether periodic problems are inevitable or are the result of lax domestic oversight there. Either way, the FDA does perform foreign inspections occasionally with the permission of the Chinese government."