What are Nitrosamines?

Nitrosamines are impurities that may be found in some drug products. These impurities are not expected to be harmful at low levels, but may increase the risk of cancer when ingested at higher levels over a long period of time. The FDA has set guidelines for over-the-counter (OTC) drug monograph and pharmaceutical companies to detect and control nitrosamine impurities in drugs, including topical drug products, to ensure user safety. Compliance involves thorough risk assessments, testing, and implementing corrective measures. Companies must stay vigilant to meet these requirements and maintain the quality of their drug products.

Drug Assessment Requirements

FDA published guidance for industry in late 2020 entitled “Control of Nitrosamine Impurities in Human Drugs”.   This guidance was published in response to FDA learning in 2019 that some common heartburn products such as those sold under the names Zantac and Axid contained unacceptable levels of a nitrosamine variant.  In 2020, these products were removed from the U.S. market and drug companies have since changed their formulations.  However, FDA published the guidance in October 2020 to ensure the public will not be exposed to nitrosamines in other types of drug products.

The guidance requires all drug manufacturers to assess their raw materials, drug active ingredients (APIs), finished drug products and manufacturing processes for possible nitrosamine impurities. The risk assessment was to be completed by drug companies on or before March 31, 2021.  If the risk assessment identified a possible pathway of nitrosamines, confirmatory testing should have started immediately and was to be concluded as soon as possible.  Any changes in processes, starting materials or other responses to the risk assessment and testing results were to be concluded by October 1, 2023.

Recent Enforcement Trends

SRC monitors FDA cGMP Warning Letters and we are starting to see findings which mention nitrosamines.  It is vital drug companies have in their files the nitrosamine risk assessment which is followed up by any confirmatory testing if required.  The FDA guidance outlines the general root causes of nitrosamines which includes a starting material for quaternary ammonia products such as benzalkonium chloride (BZK) antiseptic handwashes and rubs.  Additionally, a 2010 EU review entitled “Opinion on Nitrosamines and Secondary Amines in Cosmetic Products” lists “chlorohexidine” as a nitrogen containing compound that “can also be rapidly nitrosated to form nitrosamines”.  Therefore, it is especially important for manufacturers of drug products containing this API to have their risk assessments completed and ready to show to FDA cGMP inspectors.

The SRC team stands ready to help both BZK drug product manufacturers and companies with other types of OTC drug products with their risk assessments and any required follow-up confirmatory testing and process changes.  Please contact your SRC consultant for questions regarding nitrosamine compliance.


David Swain 

VP, Regulatory Services

Posted on: 01/22/24