US FDA Guidance on Nitrosamine Impurities

News & Events

December 22, 2020


US FDA Regulations, Pharmaceuticals,
Drug Impurities, Nitrosamine, Risk Assessment


US FDA Guidance on Nitrosamine Impurities in Drugs Outlines Strategy for Detection, Prevention, and Risk Management

In September 2020, the US FDA issued guidance for industry on the detection, prevention, and risk management of potentially carcinogenic nitrosamine impurities in drug products (US FDA, 2020a). This guidance was issued in response to recent findings that nitrosamines were present at unexpected levels in diverse classes of drugs such as angiotensin receptor II blockers (losartan), antidiabetics (metformin), and antacids (ranitidine) (US FDA, 2020b). Approximately 149 million drug prescriptions were issued for these three drugs in 2019 in the United States alone (ClinCal DrugStats Database, 2020). Drug manufacturers voluntarily recalled losartan, and the US FDA requested a recall of all ranitidine containing drugs from the US market on April 1, 2020. The US FDA continues to investigate nitrosamines in metformin containing drugs.


Nitrosamines have long been flagged as “cohort of concern” constituents that may be highly potent genotoxic carcinogens (ICH, 2020; US FDA, 2018). However, nitrosamines can vary significantly in their chemistry and toxicity profiles. Furthermore, the likelihood of nitrosamines occurring in a drug product depends on the manufacturing process. As a result, only certain drugs might contain nitrosamines, and even then, the potential health risks are compound specific.

The recently issued US FDA guidance recommends that all drug manufacturers conduct a risk assessment for nitrosamine impurities for both approved and investigational drugs. Highlights include:

  • For approved or marketed drug products, manufacturers are requested to conduct a nitrosamine risk evaluation by March 2020.
  • A recommendation by the US FDA to prioritize risk evaluations based on maximum daily dose, treatment duration, therapeutic indication, and number of patients.
  • For investigational drugs, sponsors are requested to provide a risk assessment in the application.

The guidance was immediately effective, though US FDA is still receiving public commentary under the provisions of 21 CFR 10.115, the agency’s good guidance practices (GGP) regulation. Comments may be submitted electronically via


See US FDA website for information regarding nitrosamines in pharmaceuticals.


Gradient works with drug manufacturers to identify and qualify potential safety concerns and can partner with certified analytical labs to offer services for the entire product assessment process. Contact us if you would like to discuss your needs.



Joel M. Cohen, Sc.D., DABT
Senior Toxicologist


Tom A. Lewandowski, Ph.D., DABT, ERT, ATS



Isaac Mohar, Ph.D., DABT

Senior Toxicologist



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