Valsartan, ranitidine, metformin. These are ubiquitous, FDA-approved drugs that have been on the market for years and that consumers have assumed were safe within their known limits. But for two years, the industry has been figuring out things have not been what they seemed.
The suspected carcinogen N-nitrosodimethylamine (NDMA) first cropped up in valsartan and then ranitidine and DFM, a common solvent used across the industry. The FDA is now testing metformin for it as well. The FDA acknowledges that with new, more sophisticated testing, it's a problem that will continue to unfold in drug manufacturing for the foreseeable future, creating uncertainty for consumers and the industry alike.
The discovery of NDMA, sometimes related to manufacturing, has led to the recall of hundreds of thousands of bottles of drugs, eating up costs and time—and leaving the industry unsure how to move forward.
While the FDA has assured consumers the risk of developing cancer from an impurity in their drugs is less than the risk of quitting their medications, the new threat has left many wary. And the problem only looks to get worse before it gets better.
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“I am confident there will continue to be issues in the near future in drug products and the extent of the ones we are looking at, particularly Zantac (ranitidine), are yet unknown. Our view is that it is a really serious problem,” says David Light, founder and CEO of Valisure, an online pharmacy attached to a sophisticated drug-testing company.
Light and his partner and friend from Yale University, Adam Clark-Joseph, landed in the middle of the matter after testing that Valisure does for every batch it sells turned up NDMA in ranitidine, the active ingredient in popular stomach acid drugs like Zantac.
New Haven, Connecticut-based Valisure also filed a citizen petition arguing the FDA needs to investigate a solvent often used in drug manufacturing, N,N-Dimethylformamide (DMF), because it ranks as a Class 2 carcinogen.
The pharmacy contends DFM use is responsible for much of the NDMA found in the pharma supply chain. The petition says the FDA should lower the acceptable level of DFM use in the U.S. drug supply and requested the FDA seek to recall all drugs where it's found in levels that exceed its guidance.
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The FDA, which was initially caught unawares by the NDMA problem, pointed out in an emailed statement that it continues to test drugs whose manufacturing increases the risk of forming nitrosamine impurities, including ARBs, ranitidine and metformin. The agency says it will look deeper if new issues arise and will have drugmakers test for other impurities, or for known impurities in other drugs, as the science dictates.
One reason this problem was only discovered within the last couple of years, the FDA says, is that newer, more sophisticated testing methods can now detect even trace amounts of impurities. These previously unknown risks can be found and mitigated, but it can’t all be done overnight, it says.
“The FDA’s advisories are rooted in evidence, and gathering data takes time. ... We will continue to investigate and work to ensure these types of impurities do not exceed acceptable limits so that patients can continue taking their medicines without concern,” the agency said in its emailed statement.
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Light agrees that the system is working for the most part. Most of the drugs it tests for its pharmacy are fine. But with generics making up 90% of the drugs prescribed in the U.S.—and many of them approved years ago—he believes the industry needs to do deeper testing of every drug it makes. And meanwhile, he argues, the oversight system needs to be overhauled.
While the FDA has sometimes dismissed Valisure as an independent, third-party laboratory, Light argues that is exactly the point.
“We have to admit there is a problem. We can’t keep saying everything that has ever been approved is perfect,” said Light. "An important part of this is adjusting, working outside of just drug manufacturers and the FDA.”