What Are NDSRIs? Nitrosamine Drug Substance-Related Impurities Explained

Scientifically reviewed by: Dr. Anas Alshishani, PhD Analytical Chemistry, Founder & CEO, PharmaPrimes

Short answer: An NDSRI (nitrosamine drug substance-related impurity) is an N-nitrosamine impurity that shares structural similarity with the active pharmaceutical ingredient (API) and is generally unique to that API. NDSRIs can form when a secondary amine or dimethyl tertiary amine in the API, or in an API fragment, is nitrosated, for example by residual nitrite in excipients. Regulators expect manufacturers to assess this risk, confirm it with sensitive testing where needed, and keep each NDSRI at or below its acceptable intake (AI) limit. (FDA, CDER Nitrosamine Impurity Acceptable Intake Limits)

A note on the term: in pharmacology, “NDSRI” is also used for norepinephrine-dopamine-serotonin reuptake inhibitors, a class of central nervous system drugs. This article covers the impurity meaning only.

What makes an NDSRI difficult is that very little transfers between products. The limit, the reference standard and the analytical method are tied to the structure of one API, so each product needs its own assessment. This guide explains what sets NDSRIs apart, how FDA and EMA derive their limits, and what testing and control look like in practice.

NDSRIs vs small-molecule nitrosamines

FDA describes two structural classes of nitrosamine impurities. Small-molecule nitrosamines do not share structural similarity with the API and are found in many different drug products. NDSRIs share structural similarity with the API and are generally unique to each API. (FDA, Control of Nitrosamine Impurities in Human Drugs, Rev. 2, Sept 2024)

How NDSRIs form

Three conditions usually come together:

• A nitrosatable amine. FDA notes that NDSRIs can form by nitrosation of APIs and API fragments containing secondary amine or dimethyl tertiary amine centres. (FDA)
• A nitrosating agent. Nitrosamines form by reaction between amines and nitrous acid, that is, nitrite salts under acidic conditions. (FDA)
• Enabling conditions. Formation can occur during formulation and manufacture, for example through residual nitrites in excipients. Packaging leachates may also contribute nitrosamines or nitrites. (FDA)

Two points are often misread. An API appearing on FDA’s list of hypothetical NDSRIs does not confirm that an NDSRI is present in a product containing it. And the list is not exhaustive, because other formation routes are possible. (FDA) Risk has to be established product by product.

How FDA and EMA set NDSRI acceptable intake limits

The Carcinogenic Potency Categorization Approach (CPCA)

Most NDSRIs have no carcinogenicity data. The CPCA predicts carcinogenic potency from the structure of the N-nitrosamine and assigns it to one of five potency categories, each linked to an AI limit. (FDA, CPCA model description) Where data on a specific substance are insufficient, the EMA Q&A states that the CPCA should be used to establish the AI. (EMA/CMDh Q&A, Rev. 23, Q10)

Source: FDA’s CPCA model description gives category 1 as 18 or 26.5 ng/day depending on the regulatory region, and 100, 400, 1,500 and 1,500 ng/day for categories 2 to 5. (FDA) The practical consequence is that a category 1 NDSRI carries a lower limit in the EU than in the US.

What an AI limit represents

FDA’s recommended lifetime AI limits approximate an increased cancer risk of one additional case in 100,000 people, assuming daily exposure for 70 years. For products intended for shorter treatment, less-than-lifetime (LTL) adjustment factors may be applied, consistent with ICH M7(R2). FDA added LTL information for nitrosamine impurities to its AI page on 24 September 2026. (FDA)

When the CPCA is not the final word

• Compound-specific data or read-across. Where FDA recommends an AI based on compound-specific data or read-across from a surrogate, the CPCA-based limit should generally not be applied. (FDA)
• Enhanced Ames test (EAT). Under the EMA Q&A, a negative result in a GLP-compliant enhanced Ames test allows the N-nitrosamine to be controlled at 1.5 µg/day. A positive result means the AI is set by the other options in Q10. (EMA/CMDh Q&A, Rev. 23) FDA also publishes recommended safety testing methods for nitrosamine impurities on its AI page. (FDA)
• Each authority keeps its own list. FDA publishes recommended AIs in tables on its AI page, and EMA publishes established AIs in Appendix 1 of its Q&A. (FDA; EMA) Check the current list of every authority where the product is marketed.

How NDSRI testing works

Where a risk assessment identifies a risk, FDA recommends confirmatory testing with sensitive and appropriately validated methods, and its AI page lists recommended analytical methods for certain nitrosamines. (FDA) The EMA Q&A sets out how confirmatory tests should be conducted (Q8) and what the analytical methods must achieve (Q9). (EMA, Rev. 23)

The AI is a daily exposure, so it has to be converted into a concentration limit for the method, based on the maximum daily dose. The method’s limit of quantification (LOQ) must sit comfortably below that limit.

Practical challenges specific to NDSRIs

• Reference standards: because each NDSRI is product-specific, a standard often has to be synthesised and characterised before validation can start.
• Selectivity: the NDSRI is structurally close to an API present at far higher concentration, so chromatographic separation and ion suppression drive method development.
• Technique: LC-MS/MS is commonly used for NDSRIs, which are typically non-volatile, while GC-MS/MS is often used for volatile small-molecule nitrosamines. The analyte, matrix and required limit decide the choice.
• Artefactual formation: sample preparation should be designed so that the method does not itself generate nitrosamines.
• Shelf life: whether an NDSRI can form during storage matters as much as its level at release. FDA’s 2025 progress-update expectations refer to whether NDSRIs can form under forced degradation. (FDA Law Blog)

How NDSRIs are controlled

FDA’s nitrosamine guidance describes a three-step process: assess the risk, perform confirmatory testing if a risk is identified, and report changes made to prevent or reduce nitrosamines. (FDA, Recommended AI Limits for NDSRIs)

• Detected at or below the AI: FDA still expects an appropriate control strategy. (USP Quality Matters)
• Detected above the AI: root-cause investigation and mitigation are needed. Reformulating an approved US product to meet the AI will likely be a major change requiring a prior approval supplement. (USP Quality Matters) FDA’s guidance also describes an alternative bioequivalence approach for products reformulated to mitigate nitrosamines. (FDA) In the EU, Q22 of the EMA Q&A covers how to control an N-nitrosamine that exceeds the AI while corrective actions are implemented. (EMA, Rev. 23)

Key milestones

How PharmaPrimes supports NDSRI programmes

PharmaPrimes provides nitrosamine and NDSRI risk assessment, LC-MS/MS and GC-MS/MS method development and validation, confirmatory and routine testing of drug substances, finished products and stability samples, and root-cause investigation with mitigation support. See our NDSRI and nitrosamine testing services.

Frequently asked questions

What is an NDSRI?

A nitrosamine impurity that shares structural similarity with the API and is generally unique to it. It usually forms by nitrosation of an amine in the API or an API fragment.

What is the difference between NDSRIs and other nitrosamine impurities?

NDSRIs are one class of nitrosamine impurity. Small-molecule nitrosamines such as NDMA are unrelated to the API and can appear in many products. NDSRIs are API-specific.

What are the FDA recommended acceptable intake limits for NDSRIs?

There is no single NDSRI limit. FDA recommends an AI for each compound, either from compound-specific data or from its CPCA potency category: 26.5, 100, 400, 1,500 or 1,500 ng/day for categories 1 to 5. Check FDA’s current tables for the specific compound.

How are NDSRIs formed?

Typically by nitrosation of a secondary amine or dimethyl tertiary amine in the API or an API fragment, for example through residual nitrite in excipients during manufacture or storage.

How do you test for NDSRIs?

With a sensitive, validated, compound-specific method, most often LC-MS/MS, whose LOQ is set below the concentration limit derived from the AI and the maximum daily dose.

Are NDSRI limits the same in the US and the EU?

The CPCA categories are largely aligned, but category 1 differs (26.5 ng/day at FDA, 18 ng/day at EMA), and each authority maintains its own compound list.

Plan your NDSRI testing

If your risk assessment has flagged a potential NDSRI, our analytical team can discuss reference standard sourcing, method development, validation and confirmatory testing for your product. Request an NDSRI confirmatory testing quote.

References

1. FDA. CDER Nitrosamine Impurity Acceptable Intake Limits (updated 24 Sept 2026). https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits
2. FDA. Control of Nitrosamine Impurities in Human Drugs, Rev. 2, Sept 2024. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs
3. FDA. Recommended Acceptable Intake Limits for NDSRIs, Aug 2023. https://www.fda.gov/media/170794/download
4. FDA. CPCA model description. https://fda.gov/media/183710/download
5. EMA/CMDh. Q&A on nitrosamine impurities, EMA/409815/2020 Rev. 23, 10 Oct 2025. https://www.ema.europa.eu/system/files/documents/opinion-on-any-scientific-matter/nitrosamines-emea-h-a53-1490-qa-art-53-rev-23-en.pdf