On April 16, 2026, FDA’s Center for Devices and Radiological Health (CDRH) issued a Letter to Industry warning manufacturers of CDRH-led combination products about the potential for nitrosamine impurities and outlining what manufacturers should be doing now to identify and manage the risk.

Why FDA is raising this now

FDA notes that nitrosamine exposure above acceptable levels over long periods may increase cancer risk. As part of its work, CDRH became aware that 1-methyl-4-nitrosopiperazine (MNP), an NDSRI, was detected in certain CDRH-led combination products containing rifampin. FDA states it is not currently aware of adverse events linked to nitrosamine exposure from CDRH-led combination products.

This is a meaningful shift for combination product teams: nitrosamine risk is no longer “just a pharma issue.” FDA is explicitly pointing device-led combination product manufacturers to drug nitrosamine resources and expecting a risk-based, lifecycle approach.

What FDA expects manufacturers to do

CDRH’s message is direct: manufacturers remain responsible for understanding and managing impurity risks, including nitrosamines, as part of the product’s overall biocompatibility and risk assessment.

FDA calls out several potential nitrosamine sources:

• the drug product itself
• the finished combination product manufacturing process
• and potential contributions from raw materials, manufacturing aids, packaging, sterilization, storage conditions, or degradation pathways that could introduce or form nitrosamines.

FDA also points manufacturers to the ISO 10993-1 risk management framework for biological evaluation/biocompatibility work, especially the risk management approach and evaluation endpoints.

Practical “do this now” checklist for CDRH-led combo products

If you make or support CDRH-led combination products, here’s the most efficient way to operationalize the letter:

1) Run a targeted nitrosamine risk assessment

Use FDA’s nitrosamine resources (even though you’re device-led) to determine whether your product warrants deeper evaluation, including reviewing acceptable intake limits and higher-risk APIs or products.

2) Map where nitrosamines could enter or form across the lifecycle

Specifically evaluate:

• API/drug product vulnerabilities (supplier conditions that increase formation)
• assembly and processing steps that could introduce formation pathways
• sterilization and packaging interactions
• storage conditions that may degrade the API and create new nitrosamines

3) Align testing and methods to the risk (and document the rationale)

If risk exists, FDA points to a common approach: gather compositional/manufacturing information and/or perform analytical testing, then compare results against FDA-published acceptable intake limits.

4) Tighten your supplier quality story

This topic is “supplier quality meets impurity control.” CDRH explicitly encourages collaboration with API/drug product manufacturers to identify conditions that may increase nitrosamine formation.

5) Use Q-Sub if limits may be exceeded or you need alternative/interim limits

FDA notes that if you determine limits are exceeded (or may be) or you’re considering alternative limits, you can use the Q-Submission program to engage CDRH early.

What CDRH says it’s doing

CDRH says it is continuing to investigate the root cause and scope, evaluate potential interim/alternative limits, and work with manufacturers to understand causes of nitrosamine formation while encouraging manufacturers to engage through Q-Submissions.

Bottom line

This letter is a signal that nitrosamine risk management is now a combination product quality-system issue. For CDRH-led combination products, the fastest path forward is a disciplined, risk-based approach: identify pathways, validate the data, control the supply chain, and document decisions in a way FDA can follow.