Valisure’s findings suggest the manufacturing of drugs may be more porous than commonly understood.
“Medicines are kind of like used cars: By the time you get it it’s already five or six years old, it’s touched hundreds of hands and it’s got 100,000 miles on it,” Valisure Chief Executive Officer David Light said in an interview.
When drugs are made, the initial raw materials may need to change form before they go into a pill. To break them down, a solvent like DMF may be used, but it’s supposed to largely vanish by the time a pill is put into a bottle for sale. DMF is cheaper than some other solvents, making it appealing for companies coping with the bruising economics of the generic-drug business.
The FDA allows drugs to contain the equivalent of about 8.8 million nanograms of daily exposure to DMF. The agency last revised its allowable solvent levels in 2017; the WHO classified DMF as a probable carcinogen in 2018.
Valisure found DMF in valsartan made by five of the six drugmakers it tested, including Novartis, which makes the brand-name version called Diovan. That drug was first approved in the U.S. in 1996. Diovan’s DMF levels were among the lowest that tested positive.
Novartis doesn’t use DMF in making Diovan and documents provided by suppliers it purchases ingredients from indicate that they don’t, either, said spokesman Althoff. But companies that its suppliers buy from could.
Those suppliers provide components including inactive ingredients, of which Diovan has about eight. The FDA regulates those less stringently than the active ingredients that fight disease. The focus surrounding valsartan has been on the active ingredient, largely supplied to the companies under recall by Zhejiang Huahai Pharmaceutical Co. Ltd. in China and Hetero Labs Ltd. in India.
Valisure filed a citizen petition to the FDA Thursday asking it to lower the amount of DMF allowed in pharmaceuticals and to recall the valsartan found to contain high DMF levels. Valisure runs an FDA registered facility and its results were verified by Emery Pharma, an FDA-registered research lab in Alameda, California.
Valisure asked the FDA to cut allowable DMF to fewer than 1,000 nanograms daily, possibly to as low as the 96 nanograms of NDMA the agency allows, given the similarities between the chemicals. NDMA is commonly found in cooked, cured or grilled meat, such as bacon.
The FDA follows internationally agreed upon guidelines for permitted daily exposure to residual solvents, said Kahn, the agency spokesman. He didn’t say why the DMF guidelines hadn’t been revisited since the WHO carcinogen classification.