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Potential for Nitrosamines in Medical Device Combination Products - Letter to Industry

April 16, 2026

Dear Medical Device Manufacturers:

The U.S. Food and Drug Administration (FDA), through the Center for Devices and Radiological Health (CDRH), is issuing this letter to provide manufacturers of CDRH-led combination products with information related to potential nitrosamine impurities.  This letter describes manufacturer responsibilities and highlights resources that may assist in identifying and managing potential nitrosamine impurities in these products.

Background

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. As part of this ongoing work, CDRH has become aware that 1-methyl-4-nitrosopiperazine (MNP), a nitrosamine drug substance–related impurity (NDSRI), has been detected in certain CDRH-led combination products containing the drug rifampin. At this time, CDRH is not aware of adverse events associated with nitrosamine exposure from CDRH-led combination products.

Considerations for Manufacturers of CDRH-led Combination Products

Potential sources of nitrosamines in CDRH-led combination products may include the drug product itself or the manufacturing process for the finished combination product. Manufacturers are responsible for understanding the risks of any impurities, including nitrosamines, that may be present in their final products as part of their overall biocompatibility/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 to nitrosamines.  Additional information on biocompatibility assessments can be found in FDA guidance Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process, including Section III (Risk Management for Biocompatibility Evaluations) and Attachment A (Evaluation Endpoints for Consideration).

Information regarding potential sources of nitrosamines and recommended limits can be found in the following FDA guidance documents and resources for Center for Drug Evaluation and Research (CDER)-led products:

CDRH is highlighting these resources to assist manufacturers of CDRH-led combination products in identifying and managing risks of nitrosamine impurities in products currently on the market as well as those seeking FDA marketing authorization. Manufacturers may review these resources to determine whether to conduct further nitrosamine risk assessment for their CDRH-led combination product. Such a risk assessment may include:

  • Consulting FDA guidance and communications regarding active pharmaceutical ingredients (APIs) or drug products with a higher risk of nitrosamine contamination.  
  • Reviewing FDA-published acceptable intake limits for nitrosamines.
  • Collaborating with API or drug product manufacturers to identify conditions that may increase nitrosamine formation.
  • Evaluating pathways that could introduce nitrosamines during manufacturing, assembly, sterilization, or storage of the finished combination product; including raw materials, manufacturing aids, packaging, sterilization processes, storage conditions, or other factors that could degrade the API and produce additional or new nitrosamines.

If there is a potential nitrosamine risk, the FDA guidance document on Control of Nitrosamine Impurities in Human Drugs recommends assessing whether nitrosamine limits are exceeded through gathering compositional or manufacturing information and/or analytical testing by directly comparing observed levels with FDA-published daily acceptable intake limits.  If manufacturers determine that nitrosamine limits are exceeded, may potentially be exceeded, or are considering use of alternative limits (for example, comparing the amount in their device to a higher, short-term limit or any published interim limit), they can consider using the Q-Submission process to engage with the appropriate CDRH review office.

CDRH Actions

CDRH continues to investigate the root cause and scope of nitrosamine impurities in CDRH-led combination products. These activities include:

  • Evaluating the potential use of interim or alternative limits for certain products.  
  • Working with manufacturers to better understand potential causes of nitrosamine formation.

CDRH encourages manufacturers to help ensure the continued safety and effectiveness of CDRH-led combination products and to engage with the FDA through the Q-Submission process to address potential risks related to nitrosamine impurities.

Questions?

If you have questions, contact CDRH's Division of Industry and Consumer Education (DICE).

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