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The investigation into the root cause of the NDMA impurity found in API is still ongoing, but the agency believes the impurities may be caused by specific chemicals and reaction conditions in manufacturing processes.
On January 28, 2019, FDA provided an update on the investigation into the presence of nitrosamine impurities, including N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA), in some generic versions of angiotensin II receptor blocker (ARB) medicines, which treat high blood pressure and heart failure. According to FDA, while the risk to patients is low, these impurities are probable carcinogens and should not be present in drug products.
Since the first discovery of the impurities in 2018 in API manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. (ZHP), in Linhai, Taizhou Zhejiang China, FDA has been investigating the root cause of the problem. The agency believes that the impurities “may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s API, and may also result from the reuse of materials, such as solvents.”
After additional ARB products were identified as containing NDMA and NDEA impurities, the agency placed a ZHP facility on import alert and issued a warning letter to the company. Recalls of ARB medicines that might pose a risk have also been issued, and a recall list on FDA’s website is being continually updated. The agency also plans to incorporate their findings into future impurities policy development.
Because it is difficult to detect NDMA with standard laboratory testing, FDA scientists developed testing methods that specifically detect NDMA and NDEA is ARB drugs. The tests-(GC/MS) headspace method, the combined headspace method, and the combined direct injection method-can be used to test APIs and finished drug products. The agency has posted these methods on its website.
To minimize shortages of valsartan products, the agency has “evaluated safety data for NDMA and NDEA to determine interim acceptable intake levels for these impurities in the ARB class of medicines. While consumers should limit exposure to NDMA and NDEA, these impurities exist in other ingested products, such as some charcoal grilled food items ... We remind patients taking these medications or any recalled ARB to continue taking their current medicine until their pharmacist provides a replacement or their doctor provides an alternative treatment option. It also is important to know not all ARBs contain NDMA or NDEA, so pharmacists may be able to provide a refill of medication not affected by the recall, or doctors may prescribe a different medication that treats the same condition,” the agency stated in a press release.
“While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time. The potential for the development of genotoxic impurities during manufacturing processes is an area of intense focus. We’ll continue to improve our science and standards for detecting and preventing these risks,” the agency stated.