FDA’s New Guidance on Nitrosamine and Nitrosamine

Drug Substance Related Impurities and Recommended Acceptable Intake Limits

The FDA has recently published a Recommended Acceptable Limit guidance document for nitrosamine impurities in drug products. The guidance is based on a risk-based approach to nitrosamines and provides manufacturers with timely information on the recommended acceptable intake limits. By August 2025, manufacturers must ensure that any nitrosamine drug-related contaminants in their products adhere to the FDA’s approved Acceptable Intake level.

Nitrosamines are a group of organic chemical compounds that have a nitroso (-NO) functional group bonded to an alkyl or aromatic amine. These compounds are formed by the reaction between nitrates or nitrites in the presence of precursor amines or amides under acidic conditions. Nitrosamines are unintentional by-products found in processed meats, cosmetics, tobacco products, pharmaceuticals, and other materials, but typically at very low concentrations. The commonly found nitrosamines are N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodipropylamine, and N-nitrosomorpholine. Nitrosamines vary widely in their level of toxicity, but several are classified as Group 2A or 2B carcinogens (probable or possible) by the International Agency for Research on Cancer and have been a subject of concern for regulatory agencies and health organizations. Manufacturers in various industries are continuously making efforts to control and reduce nitrosamine formation and minimize potential health risks.

The presence of nitrosamine drug substance-related impurities is a significant concern for the pharmaceutical industry as well as in herbal supplements. There is a lack of clarity over the source of nitrosamine and the acceptable limits for certain nitrosamines in drug products. Numerous manufacturers conduct unnecessary studies or prematurely remove their products from the market. Determining an acceptable intake limit is challenging because of the limited toxicological information or absence of any existing safety data (rodent carcinogenicity or absence of chronic toxicity data) for some of the nitrosamines.

The general mechanism of toxicity of nitrosamines is the metabolic activation of the amine group through alpha-hydroxylation, resulting in an intermediate product that can react with DNA. To predict the risk from a given nitrosamine, the FDA guidance uses structural information (whether there is a potential metabolic activating or deactivating feature present) to assign a carcinogenic potential category to the chemical. The potency score of a nitrosamine is the sum of the alpha-hydrogen score, deactivating feature score, and activating feature score. Based on the chemical’s resulting carcinogenic potency category the recommended acceptable limits can be determined. The table below provides a summary of the FDA Recommended Acceptable Intake Limits.  If the chemical contains two N-nitroso groups, the group with the highest carcinogenic potency category should be considered for risk estimation.

Table 1: FDA Recommended Acceptable Intake Limit based on Nitrosamine Potency Category

It is vital to engage toxicologists as early as possible in the regulatory process to identify and manage any hazards before they present risks. MED Institute has unique regulatory expertise with strong biocompatibility and toxicology experience. Whether you need to estimate a potency score, or risk assess nitrosamines in a final product, MED Institute can help you.

To learn more about how new FDA guidance may impact your medical product and regulatory submission please contact us today 855.463.1633 | askmed@medinstitute.com | medinstitute.com.