Scientifically reviewed by: Dr. Anas Alshishani, PhD Analytical Chemistry, Founder & CEO, PharmaPrimes
Short answer: A nitrosamine risk assessment is a documented, science-based evaluation of whether nitrosamine impurities could be present in, or form in, an API or drug product. FDA describes it as the first of three steps: (1) assess the risk, (2) perform confirmatory testing if a risk is identified, and (3) implement and report changes that prevent or reduce nitrosamines. (FDA, Recommended AI Limits for NDSRIs) In Saudi Arabia, the SFDA dossier requirements ask for a comprehensive N-nitrosamine risk assessment for the drug substance and a risk assessment report for the drug product. (SFDA, Data Requirements for Human Drugs Submission V4.0)
The concept is simple. What delays reviews is an assessment that cannot be followed: sources skipped, conclusions without evidence, and no clear link between the risk found and the testing or control chosen. This guide walks through the steps, gives a source-by-source checklist, and shows how to structure the report.
Who needs a nitrosamine risk assessment?
FDA’s guidance covers chemically synthesised APIs, drug products that contain them or their fragments, and products at risk through other factors described in the guidance. (FDA, Control of Nitrosamine Impurities, Rev. 2) SFDA V4.0 requires the assessment for “substances for human use” and does not limit it to the manufacturing process. (SFDA V4.0, 3.2.S.3.2)
Step 1: Evaluate the risk
The assessment must cover nitrosamines carried in from materials and nitrosamines that could form during manufacture or storage. SFDA’s wording is explicit: the evaluation should address the manufacturing process, materials introduced in manufacture, and other sources such as starting materials, reagents, solvents, recovered materials, equipment and degradation. (SFDA V4.0, 3.2.S.3.2)
Source-by-source checklist
| Area | Question to answer | Typical evidence |
|---|---|---|
| API structure | Does the API or any fragment contain a secondary or dimethyl tertiary amine that could be nitrosated? | Structural review; FDA list of APIs at hypothetical risk |
| API synthesis | Are nitrite or other nitrosating agents, and vulnerable amines, present in the route? | Route of synthesis; DMF/CEP information; supplier statement |
| Starting materials, reagents, solvents | Could nitrosamines or precursors be carried over, including from recovered solvents? | Supplier questionnaires; specifications; test data |
| Excipients | Could residual nitrite react with the API in the product? | Supplier nitrite data; literature; product testing |
| Water | Is nitrite or nitrate in process water relevant? | Water quality data |
| Manufacturing process | Do steps such as wet granulation or drying favour nitrosation? | Process description; development data |
| Packaging | Could packaging introduce nitrosamines or nitrites? | Material review; extractables and leachables data |
| Storage and stability | Could levels rise over shelf life? | Stability data; stress studies |
SFDA lists drug substance, excipients, water, solvents, manufacturing, packaging and stability as sources for the drug product report. (SFDA V4.0) FDA notes that packaging leachates may be a source of nitrosamines or nitrites. (FDA) Where the API carries a nitrosatable amine, identify the possible NDSRI and its acceptable intake (AI) limit at this stage.
How industry structures the evaluation
The EFPIA/IQ workflows (version 3.0, 2024) are widely used to organise this step. They are industry tools, not regulatory requirements. (EFPIA, Nitrosamine Risk Management Workflows, 2024)
- Drug substance workflow: sources of nitrosating agents; indirect risks such as recovered solvents and shared equipment; sources of amines; the applicable AI; formation, fate and purge in the process; whether the nitrosamine can actually form; and the action after confirmatory testing.
- Drug product workflow: risk carried in from drug substance, excipients and water; vulnerable amines; the applicable AI; whether the predicted level reaches 10% of the AI; whether the nitrosamine can form; which strengths and time points to test; the control strategy; and packaging, including nitrocellulose-containing inks and films.
- Working assumptions: the workflow uses a typical default of 1 ppm nitrite in excipients and 2 ppm as a conservative default, and treats a predicted level below 10% of the AI as negligible risk.
If you adopt these thresholds, state that they come from the industry workflow, and confirm they are acceptable to each authority you submit to.
Conclude every line of risk
For each source, record one of three outcomes:
- no plausible risk, with the reason;
- a risk controlled by an existing measure, with the evidence;
- a risk that needs confirmatory testing.
A bare “no risk identified” statement is the weakest part of most reports.
Step 2: Confirm with testing where a risk is identified
FDA recommends confirmatory testing with sensitive and appropriately validated methods when a risk is identified. (FDA) The EMA/CMDh Q&A sets out how confirmatory tests should be conducted (Q8) and what the analytical methods must achieve (Q9). (EMA/CMDh Q&A, Rev. 23) A testing plan should state:
- which nitrosamines are tested, and why;
- the acceptance limit for each, derived from the AI and the maximum daily dose;
- the method’s limit of quantification relative to that limit;
- which batches, strengths and stability time points are tested.
Step 3: Implement controls and report changes
- At or below the AI: FDA still expects an appropriate control strategy. (USP Quality Matters)
- Above the AI: investigate the root cause and implement corrective and preventive actions (CAPA). In the US, reformulating an approved product will likely be a major change requiring a prior approval supplement. (USP Quality Matters) In the EU, Q22 of the Q&A covers how to control an N-nitrosamine exceeding the AI while CAPAs are implemented. (EMA, Rev. 23)
- Keep it current: revisit the assessment when the API source, an excipient supplier, the process or the packaging changes.
Where the assessment goes in the dossier
| Authority | What is required | Source |
|---|---|---|
| SFDA (Saudi Arabia) | Drug substance: comprehensive N-nitrosamine risk assessment under 3.2.S.3.2 Impurities, with a control strategy if a risk is found. The applicant completes this section even when a DMF is used. Drug product: risk assessment report under 3.2.P.5.5 Characterisation of Impurities | SFDA V4.0 (3 Aug 2025) |
| SFDA | Risk assessment studies requested in the initial registration submission for innovative and generic products | SFDA circular as reported by USP Nitrosamines Exchange |
| EMA/CMDh (EU) | Approach for new and ongoing applications (Q14); when a nitrosamine test belongs in the dossier (Q15); MAH responsibilities for APIs with a CEP or ASMF (Q16) | EMA Q&A, Rev. 23 |
| FDA (US) | Assess risk as early as possible in development, and submit the risk assessment and confirmatory testing with the original application when feasible | The FDA Group summary of FDA guidance |
How to structure a nitrosamine risk assessment report
No region mandates one template. This structure covers what the documents above ask applicants to address:
- Scope: product, strengths, API sources, manufacturing sites, packaging.
- Method: the approach and references used, such as FDA guidance, the EMA Q&A, SFDA V4.0 and any industry workflow.
- Source-by-source evaluation: the checklist above, with a conclusion for each line.
- Identified nitrosamines: including any potential NDSRI, with the applicable AI and its basis.
- Confirmatory testing: method, validation summary, LOQ, batches tested and results.
- Conclusion and control strategy: specification, supplier controls or CAPA.
- Re-assessment triggers.
Gaps that commonly delay review
- Excipient nitrite is mentioned but not evaluated against the specific API.
- Packaging and storage are left out.
- The API supplier’s assessment is relied on without a drug product assessment.
- Test limits are given without showing how they were derived from the AI.
- The method’s LOQ is close to, or above, the acceptance limit.
How PharmaPrimes supports nitrosamine risk assessment
PharmaPrimes evaluates potential nitrosamine formation across nitrosating agents, API structure, amine-containing impurities, synthetic pathways, manufacturing, formulation, storage and packaging, and runs confirmatory testing with LC-MS/MS and GC-MS/MS through its nitrosamine testing service. Dossier work is supported by our CTD documentation support team.
Frequently asked questions
What is a nitrosamine risk assessment?
A documented evaluation of whether nitrosamines could be present in, or form in, an API or drug product, covering every potential source and ending with a decision on testing and control.
What are the FDA recommendations for nitrosamine risk assessments?
Assess the risk, perform confirmatory testing with sensitive validated methods if a risk is found, and implement and report changes that prevent or reduce nitrosamines.
Does SFDA require a nitrosamine risk assessment at registration?
Yes. SFDA’s dossier requirements V4.0 place the drug substance assessment in 3.2.S.3.2 and the drug product report in 3.2.P.5.5, and SFDA has requested the studies in the initial registration submission.
What should a nitrosamine risk assessment report include?
Scope, method, a source-by-source evaluation, identified nitrosamines with their AI, confirmatory test results where applicable, the control strategy, and re-assessment triggers.
What is the ICH guideline for nitrosamines?
Nitrosamines belong to the “cohort of concern” in ICH M7, the guideline on DNA-reactive (mutagenic) impurities. Nitrosamine-specific expectations come from regional documents such as FDA guidance and the EMA Q&A.
Book a risk assessment review
Preparing a submission for Saudi Arabia, the EU or the US? Our scientists can review your existing assessment, close the gaps and plan confirmatory testing. Book a nitrosamine risk assessment review.
References
- SFDA. Data Requirements for Human Drugs Submission, V4.0 (3 Aug 2025). https://www.sfda.gov.sa/sites/default/files/2026-04/Data-Human-Drugs-SubV4.pdf
- 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
- FDA. Recommended Acceptable Intake Limits for NDSRIs, Aug 2023. https://www.fda.gov/media/170794/download
- EMA/CMDh. Q&A on nitrosamine impurities, 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
- EFPIA/IQ. Nitrosamine risk management workflows, v3.0, 2024. https://efpia.eu/media/tkbnsicy/efpia-nitrosamines-risk-management-workflows-jun-24-udpate.pdf