Module 3 sections · Training guide
Nitrosamine Risk Assessment
Write the three-step nitrosamine report: risk evaluation, confirmatory testing, and changes and control. Acceptable intakes come from published values or the CPCA potency category.
Open the tool at https://app.cmcfy.com/app/nitrosamine-assessment.html. This guide is also online at https://cmcfy.com/guides/nitrosamine-assessment.html
1. What this module does
You tick the risk factors that apply, and enter each nitrosamine with its root cause and either a published acceptable intake (AI) or the CPCA inputs: α-hydrogen counts on each side, deactivating and activating feature scores, and whether there is a tertiary α-carbon.
The tool works out the CPCA category and AI, converts the AI to a limit at your maximum daily dose, and checks each result, the sum across nitrosamines, the LOQ, the batches and the control strategy.
What you get
- A Word or PDF report: Nitrosamine risk assessment (steps 1 to 3).
2. Before you start
Have these ready. You can still start with the example data and replace it piece by piece.
- The maximum daily dose of the drug substance.
- The structure of each nitrosamine (for the CPCA) or its published AI.
- Confirmatory test results, the LOQ and the batches tested.
3. Step by step with the example
Open the tool at app.cmcfy.com/app/nitrosamine-assessment.html. The example is loaded when the page opens, so every panel already has realistic data. Follow the steps to see how it works, then replace the example with your own data.
Describe the product
Enter the product, the maximum daily dose and the regulations. In the EU the category 1 AI is 18 ng/day; in the US it is 26.5 ng/day.
Evaluate the risk
Tick each risk factor that applies and describe your evaluation.
Enter the nitrosamines
One row per nitrosamine. Write the α-hydrogen counts as "2;3". Leave the published AI empty to use the CPCA.
AIs, limits and results. Resolve alerts and download
A result above the AI, or a total above 1, is critical. Missing tests, an LOQ that is too high, and results above 10% of the AI without a control are flagged. Then preview and download.
4. Field reference
Every input in the tool, panel by panel. Tables accept rows pasted straight from Excel, comma-separated text, or a loaded file; check the columns after loading a file. Fields marked “when it applies” appear only for the choices that need them.
1 · Product
| Field | What to enter |
|---|---|
| Product | Type it in. |
| Regulations | Choose one: US: FDA nitrosamine guidance; EU: EMA nitrosamine Q&A; Both US and EU. |
| Maximum daily dose of the drug substance (mg/day) | Type a number. |
| Report number | Type it in. |
| Product stage | Choose one: Marketed or in an application; Clinical development. |
2 · Step 1: risk evaluation
Tick every factor that applies to the drug substance, the drug product or the packaging.
| Field | What to enter |
|---|---|
| The drug substance, an intermediate or an impurity has a secondary or tertiary amine (NDSRI risk) | Tick the box if it applies. |
| Excipients, process aids or degradants contain amines | Tick the box if it applies. |
| Nitrite may be present (excipients, water, reagents) | Tick the box if it applies. |
| Nitrosating agents are used or formed in the process (nitrite, nitrous acid, NOx) | Tick the box if it applies. |
| Recovered solvents, reagents or catalysts are used | Tick the box if it applies. |
| Starting materials or reagents come from processes with a known nitrosamine risk | Tick the box if it applies. |
| Packaging contains nitrocellulose or amines (for example blister lidding) | Tick the box if it applies. |
| Formation on storage is possible (amine and nitrite together in the drug product) | Tick the box if it applies. |
| Evaluation of the risk factors | Type or paste text. |
3 · Step 2: confirmatory testing
One row per nitrosamine. Give a published AI, or the CPCA inputs (α-hydrogen counts on each side, deactivating and activating scores, tertiary α-carbon). Results in ppm (µg/g of drug substance).
| Field | What to enter |
|---|---|
| Nitrosamines | Write results below the LOQ as "<0.01". They count as 0 in the total. A table. Columns: Nitrosamine | Root cause | Published AI (ng/day) | α-H counts (e.g. 2;3) | Tertiary α-carbon (yes/no) | Deactivating score | Activating score | Max found (ppm) | LOQ (ppm) | Batches tested. Paste rows from Excel, type comma-separated rows, or press Load file (Excel, CSV, Word, PDF or a scan). |
| Method | Type it in. |
| Method validated | Tick the box if it applies. |
| Batches tested | Type or paste text. |
4 · Step 3: changes and control
| Field | What to enter |
|---|---|
| Control strategy | Choose one: No routine test: consistently below 10% of the AI; Specification test on the drug substance or drug product; Control upstream (raw material or intermediate test); Skip testing after consistent results. |
| Proposed specification limit for the controlled nitrosamine (ppm) when it applies | Type a number. |
| Mitigation and changes | Type or paste text. |
5. Checks and alerts
Calculations and pass/fail outcomes always come from fixed rules, never from AI. The tool checks:
- CPCA category and AI for each nitrosamine.
- Each result and the sum of fractions against the AI.
- LOQ, batches, method validation and control strategy.
How to resolve alerts
- Critical alerts block the download and must be fixed in the data. A failing result can instead be linked to an investigation: type the investigation reference and outcome and press Record.
- Major alerts block the download until you fix them or type a justification and press Accept justification.
- Minor alerts do not block anything. They are listed in the documents so the reviewer sees them.
- Some alerts have an Apply fix button that makes the change for you. Reopen undoes a justification.
Narratives
This module writes: Step 1: risk evaluation; Step 2: confirmatory testing; Step 3: changes and control strategy. Each narrative is written by fixed rules from your data. You can edit it in the box. Rewrite with AI (where your plan includes AI) rewrites it in regulatory style; every number in the text is checked against your data, and a number that does not match is flagged under the box and blocks the download until you correct it. Reset to rule-based text brings back the original.
6. Preview, gap review and download
- Press Preview next to a section, or Preview and download all. The document opens in a preview window, exactly as the Word file will read.
- The left side lists the review, run on your device: gaps in the data (missing values, open alerts), gaps in the report (missing content the guidance expects, placeholders such as [site] or TBD left in the text) and, if you load the approved protocol under Compare with the protocol, differences from the protocol (requirements, criteria, batches or time points it plans that the report does not show).
- Click a finding to jump to the place in the preview. Fix it in the tool, then preview again.
- Optional AI review: a second read for contradictions, claims without data and vague wording. The report text is sent to Claude only when you press it, and only where your plan includes AI. Check every AI finding; AI can be wrong.
- Press Download Word (.docx) or Download PDF. With several documents open, All as Word (.zip) and All as PDF (.zip) download the set. The download buttons stay disabled while a blocking alert is open; the preview still works.
Documents this module produces
| Section | Document |
|---|---|
| Report | Nitrosamine risk assessment |
Use Save project to keep your work as a file on your computer, and Open project to continue later. Start blank clears every field; Load example brings the example back. Nothing is stored on CMCfy servers.
7. US and EU submissions
US follows the FDA nitrosamine guidance (Rev. 2, 2024) and the NDSRI AI guidance. EU follows the EMA nitrosamine Q&A (EMA/409815/2020) and its Appendix 2 (CPCA).
8. Working with other modules
- The nitrosamine section of the drug substance and product impurity profile is in the Impurity & Risk Studio.
9. Common pitfalls
- Forgetting the NDSRI from the drug substance itself.
- An LOQ too high to show results below 10% of the AI.
10. Practice exercises
Each exercise starts from the example (press Load example to reset). We run these on every update of this guide, so the result you see should match.
Exceed the AI
Change the N-nitroso-CMX-201 result from 0.32 to 3.1 ppm.
Expected resultThe headline shows one nitrosamine above the AI.