FDA Alerts Manufacturers to Nitrosamine Impurity MNP in Rifampin Combination Products
The FDA has alerted medical device manufacturers that the nitrosamine impurity MNP was detected in certain combination products containing rifampin. The agency outlined manufacturer responsibilities for assessing and controlling nitrosamine risks and highlighted available guidance documents.
The U.S. Food and Drug Administration alerted medical device manufacturers on April 16, 2026, that the nitrosamine drug substance–related impurity 1-methyl-4-nitrosopiperazine (MNP) has been detected in certain CDRH-led combination products containing the drug rifampin. The agency is not currently aware of adverse events associated with nitrosamine exposure from these products.
Nitrosamine exposure above acceptable levels over long periods of time may increase the risk of cancer. CDRH has been investigating the potential presence of nitrosamine impurities in CDRH-led combination products and issued the letter to provide manufacturers with related information and resources.
Manufacturers of CDRH-led combination products are responsible for understanding the risks of any impurities, including nitrosamines, in their final products as part of their overall biocompatibility and risk assessment. This includes identifying potential nitrosamine impurities originating from pharmaceutical components, evaluating nitrosamines that may arise from manufacturing processes, developing and using suitable analytical methods to detect and minimize nitrosamines when appropriate, and assessing patient exposure. The FDA guidance document Use of International Standard ISO 10993-1 provides additional information on biocompatibility evaluations.
Potential sources of nitrosamines may include the drug product itself or the manufacturing process for the finished combination product. To assist manufacturers in identifying and managing risks, the FDA highlighted several resources developed for Center for Drug Evaluation and Research-led products, including the guidances Control of Nitrosamine Impurities in Human Drugs and Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities, as well as the CDER Nitrosamine Impurity Acceptable Intake Limits database. A nitrosamine risk assessment may involve consulting FDA communications regarding active pharmaceutical ingredients or drug products with a higher risk of contamination, reviewing published acceptable intake limits, collaborating with API or drug product manufacturers to identify formation conditions, and evaluating pathways that could introduce nitrosamines during manufacturing, assembly, sterilization, or storage.
If a manufacturer determines that nitrosamine limits are exceeded or may potentially be exceeded, the FDA recommends assessing whether limits are exceeded by directly comparing observed levels with FDA-published daily acceptable intake limits. If needed, manufacturers can use the Q-Submission process to engage with the appropriate CDRH review office, especially when considering alternative limits.
CDRH continues to investigate the root cause and scope of nitrosamine impurities in CDRH-led combination products, evaluating the potential use of interim or alternative limits for certain products and working with manufacturers to understand causes of nitrosamine formation. The agency encourages manufacturers to help ensure the continued safety and effectiveness of these products and to engage with the FDA through the Q-Submission process as appropriate.