By the PharmaTradz BD Team. Published October 2026.
Nitrosamines have been on regulators' lists since 2018, and the formal deadlines in Europe and the United States have now passed. The work has not finished, though. At CPHI Milan this month, formulation and quality specialists made two practical points. Demanding zero nitrite in excipients is rarely realistic, so limits should be set by risk. And nitrosamine risk has to be judged product by product, not supplier by supplier. For buyers, that changes the questions worth asking before you sign.
What nitrosamines are and why they still matter
Nitrosamines are a family of compounds, several of which are probable human carcinogens. Regulators first focused on small, well-known ones such as NDMA, found in some sartan blood-pressure medicines in 2018. The focus has since moved to nitrosamine drug substance-related impurities (NDSRIs). These form when part of the active ingredient's own molecule reacts with a nitrosating agent, such as trace nitrite from an excipient or water.
That makes NDSRIs a much wider issue than the early cases. One widely cited analysis of more than 12,000 small-molecule drugs found that around 40% have a structure that could, in principle, form one. Not every such product has a problem. But it does mean the question has to be asked about almost every product in a generic portfolio.
Where the regulators are now
- Europe. EMA launched its "call for review" in 2019: assess the risk, test where needed and mitigate. Those deadlines have passed, and EMA now expects the risk to be managed throughout a product's life, including after any change to the process or materials.
- United States. FDA set 1 August 2025 as the date for confirmatory testing and for changes to approved products. Because reformulation can take longer, it now accepts progress reports covering what was found, the root cause and the mitigation plan, with a timeline.
- Both use the same tool for NDSRIs without their own safety data: the Carcinogenic Potency Categorisation Approach (CPCA). It assigns an acceptable daily intake based on the molecule's structure.
| CPCA potency category | Acceptable intake (ng per day) | What it means in practice |
|---|---|---|
| 1 | 26.5 | Highest potency; very tight control needed |
| 2 | 100 | High potency |
| 3 | 400 | Moderate potency |
| 4 | 1,500 | Lower potency |
| 5 | 1,500 | Lowest predicted potency |
The limit applies to the daily dose of the impurity, so the same impurity level can be acceptable in a low-dose product and unacceptable in a high-dose one. This is one reason the assessment has to be done product by product.
What CPHI Milan 2026 added
Two points from the conference are worth carrying into your supplier conversations.
Zero nitrite is not a realistic target. Common excipients, and even purified water, can contain traces of nitrite. Asking every excipient supplier for "nil nitrite" usually produces either a refusal or a certificate that cannot be relied on. The better approach is a scientifically justified, risk-based limit, set for the excipients that matter most in a given formulation.
Assess the product, not just the ingredients. Nitrosation can occur in the finished product even when no nitrite is detected in the starting materials. The pH of the formulation, the manufacturing process (wet granulation and heat, for example) and storage conditions all play a part. A clean report on each ingredient does not prove the finished product is clean.
How manufacturers are reducing the risk
Where a risk is found, the common fixes are well established:
- choosing excipient grades with lower and better-controlled nitrite levels;
- adding a nitrite scavenger, such as ascorbic acid or alpha-tocopherol, where it is compatible with the product;
- adjusting the formulation's pH to slow nitrosation;
- changing the process, for example moving from wet granulation to direct compression;
- improving packaging and storage to limit heat and moisture.
Each of these is a change to an approved product, so it usually needs a regulatory variation. That is why some products are still part-way through mitigation, and why you should ask where a supplier is in that process.
What buyers should ask for
Whether you are registering a product, renewing a registration or bidding in a tender, add these items to your request:
| Document or answer | What to look for |
|---|---|
| Nitrosamine risk assessment for the finished product | Covers the active ingredient, excipients, water, process, packaging and storage, not just a generic statement |
| Confirmatory test results | Batches tested, validated method, results in ng/day or ppm against the acceptable intake |
| The acceptable intake used and how it was set | Compound-specific limit or CPCA category, with the reasoning |
| Excipient nitrite controls | Specifications or supplier data for the higher-risk excipients |
| Mitigation status | What has been changed, what is pending and the expected timeline |
| Regulatory position in reference markets | Whether EU or US authorities have accepted the assessment or progress report |
If a supplier answers with a one-line statement that the product is "nitrosamine-free", treat that as the start of the conversation, not the end. A good supplier will share a structured assessment and real data. Our guide on how to verify pharma suppliers covers the wider checks.
Why this matters for registrations and tenders
Many regulators outside Europe and the United States now ask for a nitrosamine risk assessment as part of a dossier, and missing information is a common reason for questions and delays. If your target market uses the ACTD rather than the CTD format, our comparison of CTD and ACTD shows where this information sits. For more on avoidable delays, see why regulatory filings get delayed.
How PharmaTradz can help
We help importers, distributors and tender agencies find manufacturers whose documentation stands up to regulatory review, including nitrosamine assessments. Our dossier licensing and registration service can support your filing. To get started, send a sourcing request with the product, strength, target market and the documents you need.
This article is general information as of October 2026. It is not regulatory advice; please check current guidance from the authority in your market.
Frequently Asked Questions(FAQs)
What are NDSRIs?
Nitrosamine drug substance-related impurities. They form when part of an active ingredient's own molecule reacts with a nitrosating agent, such as trace nitrite, during manufacture or storage. Several are probable human carcinogens, so regulators set strict daily limits.
What is the CPCA?
The Carcinogenic Potency Categorisation Approach. EMA and FDA use it to assign an acceptable daily intake to a nitrosamine without its own safety data, based on its chemical structure. The limits range from 26.5 to 1,500 ng per day across five categories.
Have the nitrosamine deadlines passed?
Yes. EMA's review deadlines have passed, and FDA set 1 August 2025 for confirmatory testing and changes. FDA accepts progress reports where mitigation takes longer, and both regulators expect the risk to be managed throughout a product's life.
Can excipients be nitrite-free?
Rarely. Many common excipients, and even water, contain trace nitrite. The practical approach is a risk-based limit for the excipients that matter most in a formulation, together with a product-level risk assessment.
What should a buyer ask a supplier about nitrosamines?
Ask for the finished-product risk assessment, confirmatory test results against the acceptable intake, excipient nitrite controls, the status of any mitigation and whether reference-market regulators have accepted the assessment.
