Impurity & Risk Studio

1. What this module does

The module writes 3.2.S.3.2 or 3.2.P.5.5 and three standalone reports: the ICH M7 mutagenic impurity assessment, the nitrosamine risk assessment and the ICH Q3D elemental impurities risk assessment.

Limits are calculated from the maximum daily dose, the treatment duration and the route: the M7 acceptable intake for class 1 to 3 impurities, nitrosamine limits from the published intake or the CPCA category, and Q3D concentrations from the PDE and the daily intake of drug product.

What you get

• Word or PDF files for the impurities section and the three risk assessment reports.
• A summary file for the QOS Composer & Dossier Assembler.

2. Before you start

Have these ready. You can still start with the example data and replace it piece by piece.

• Maximum daily dose of drug substance, daily intake of drug product (g/day), route and treatment duration.
• Organic impurities with origin, maximum found and where each is controlled.
• For M7: each potentially mutagenic impurity with its class, (Q)SAR results from two complementary methods, levels found, control option and, for Option 4, the level at introduction and predicted purge factor.
• The nitrosamine risk factors, and any nitrosamines tested with their CPCA category or published name.
• Elements found (or calculated from components) and their sources.

3. Step by step with the example

Open the tool at app.cmcfy.com/app/impurity-risk-studio.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.

1. Enter dose, route and duration

   Choose the section and enter the doses, route and Treatment duration (ICH M7). The headline gives the M7 limit for a class 1–3 impurity: 15.0 ppm (1.5 µg/day at 100 mg/day for lifetime use).

   

2. Enter organic and mutagenic impurities

   For each mutagenic impurity choose the M7 class and the control option. For Option 4, give the level where it enters the process and the predicted purge factor; the tool calculates the predicted level and the purge ratio.

3. Tick the nitrosamine risk factors

   Tick each factor that applies. In the example the drug substance has a secondary amine (NDSRI risk) and the blister lidding has nitrocellulose. Enter each nitrosamine assessed with its CPCA category; the tool adds up the fractions of the acceptable intake (0.04 here).

   

4. Enter elemental impurities

   Enter each element with its level in the drug product. Each is compared with its permitted concentration for the route and with the 30% control threshold.

5. Resolve alerts

   The example has a major alert because two complementary (Q)SAR methods are not documented for one impurity, and a minor alert for a known mutagen without batch data.

   

6. Preview and download

   Preview the CTD section and each report, check the review 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, dose and route

2 · Organic impurities

3 · Mutagenic impurities (ICH M7)

Class 1–3 need control to the acceptable intake. For Option 4, give the level where the impurity enters and the predicted purge factor.

4 · Nitrosamines

5 · Elemental impurities (ICH Q3D)

Give the highest level found in the drug product, or the level calculated from component data (Option 2a, 2b or 3).

5. Checks and alerts

Calculations and pass/fail outcomes always come from fixed rules, never from AI. The tool checks:

• Every organic impurity has an origin and a fate or control.
• Process-related impurities have an M7 assessment and class; class 3 impurities have two complementary (Q)SAR methods; class 1–3 impurities have a control option and levels within the limit; Option 4 has purge data and the predicted level is below the limit.
• When risk factors are ticked, nitrosamines are assessed; an amine in the drug substance needs an NDSRI assessment; each nitrosamine has an intake basis and a result; levels against the limit (critical above, major above 10% of it); the sum of fractions of the acceptable intake.
• Q3D: daily intake given; elements recognised; intentionally added elements have a level; levels against the permitted concentration (critical above) and the 30% control threshold.

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: Organic impurities: origin and fate; Mutagenic impurities (ICH M7); Nitrosamine risk assessment; Elemental impurities risk assessment. 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

1. 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.
2. 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).
3. Click a finding to jump to the place in the preview. Fix it in the tool, then preview again.
4. 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.
5. 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

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 mode cites the FDA guidance on nitrosamine impurities and the FDA acceptable intake limits for NDSRIs. EU mode cites the EMA Article 5(3) nitrosamine outcomes and the EMA question-and-answer document. Both use the CPCA approach for nitrosamines without a published limit. ICH M7 and Q3D apply in both.

8. Working with other modules

• Impurity limits in the specification are written by the Specification Builder.
• Elemental contributions from excipients connect with the statements in the Excipients Writer module.
• Packaging nitrocellulose and leachables are covered in the Container Closure & E&L.

9. Common pitfalls

• Choosing the wrong duration: most marketed products are lifetime (1.5 µg/day).
• Claiming Option 4 without a purge factor or the level at introduction.
• Ticking a risk factor but entering no nitrosamine assessment.
• Entering element levels in ppm of drug substance instead of µg/g of drug product.

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.

1. Change the treatment duration

   Set Treatment duration (ICH M7) to "≤ 1 month (120 µg/day)".

   Expected resultThe headline note gives the M7 limit as 1200.0 ppm (120 µg/day at 100 mg/day).

2. Remove the nitrosamine assessment

   Clear the Nitrosamines assessed or tested table.

   Expected resultA major alert says risk factors are present but no nitrosamine is assessed or tested.