New Haven, Connecticut-based Valisure, an online pharmacy, has submitted a citizen petition to the US Food and Drug Administration (FDA) to request that the FDA take certain actions following the company detecting levels of an impurity, dimethylformamide (DMF), in valsartan products. DMF is classified by the World Health Organization as a probable carcinogen.

In its filling, Valisure said it had tested and detected high levels of DMF, a solvent, in specific lots of valsartan, an angiotensin II receptor blocker. The company said that a switch in pharmaceutical manufacturing to the use of the DMF solvent may be largely responsible for the formation of nitrosamine impurities, such as N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), which have been the subject of recent industry recalls and investigations by regulatory agencies in “sartan” products, including valsartan.

Since last July (2018), the FDA and the European Medicines Agency have been investigating, and working with companies on voluntary recalls due to other potential cacogenic impurities in other products containing “sartan” active pharmaceutical ingredients (APIs). These included impurities of N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA) found in various products containing the APIs valsartan, losartan, irbesartan, candesartan, and olmesartan. Both agencies also issued guidelines regarding acceptable levels of these impurities.

In its citizen petition, the company is asking the FDA take action on five items with respect to the DMF impurity. First it is requesting that the FDA review and “significantly” lower the acceptable intake/permitted daily exposure limit of DMF from its current level of 8,800,000 nanograms as now specified in FDA industry guidance to less than 1,000 nanograms and potentially as low as 96 nanograms.  

Valisure is also asking that the FDA: (1) request a recall of identified lots of valsartan on the basis that, due to contamination with a probable human carcinogen, these drugs are adulterated and misbranded; (2) conduct examinations and investigation regarding these products, their manufacturing processes, and the manufacturer submissions made for FDA approval and effect labeling revisions as needed; (3) provide information to the public regarding these products; and (4) promulgate regulations requiring robust independent chemical batch-level testing and verification of the chemical content of batches of pharmaceuticals of drugs, and while these regulations are pending, issue guidance requesting such testing and verification. The FDA acknowledged receipt of the company’s petition.

Valisure says it will no longer sell the affected lots of valsartan it has acquired from the manufacturers available to it through its distributors. Valisure added that its analysis showed that multiple manufacturers of on-market valsartan have produced lots that do not contain detectable levels of the DMF contaminant, but for affected products, the impact of recalls is “important for public safety and is not expected to create significant drug shortages or otherwise overly burden the US healthcare system.”

Source: FDA, Valisure