ICH M7 Overview
What is ICH M7?
ICH M7 is the ICH guideline on DNA-reactive (mutagenic) impurities in pharmaceuticals. It gives a practical framework for identifying, categorising, qualifying and controlling these impurities so that their potential carcinogenic risk stays negligible. It complements ICH Q3A(R2), Q3B(R2) and M3(R2) [1]. The current version is M7(R2). It has three parts: the Step 4 guideline (2023), an Addendum of compound-specific acceptable intakes, and a Questions & Answers document.
Approach: I read the M7(R2) guideline, Addendum and Q&As in the ICH guidelines collection.
Scope
-
What it covers: new drug substances and new drug products, both during clinical development and in marketing applications [1].
-
Marketed products: it applies only when a change triggers it:
- a synthesis change that introduces new impurities or raises acceptance criteria;
- a formulation or process change that creates new degradation products;
- a change in indication or dosing that significantly affects the acceptable cancer risk.
It is not applied retrospectively to products marketed before it was adopted [1].
-
What it excludes:
- biological/biotechnological, peptide, oligonucleotide and radiopharmaceutical products;
- fermentation, herbal and crude animal or plant products;
- products for advanced cancer indications within the scope of ICH S9;
- excipients in existing marketed products, flavours, colourants and perfumes;
- leachables from packaging (the guideline is not intended to apply to them) [1].
-
Semi-synthetic substances: these are in scope when manufacturing steps could introduce mutagenic impurities [2].
How M7 works
- Hazard assessment: search databases and literature for carcinogenicity and bacterial mutagenicity (Ames) data. Where no data exist, run two complementary (Q)SAR predictions, one expert rule-based and one statistical. If neither method finds a structural alert, the impurity is of no mutagenic concern [1].
- Classification into five classes [1]:
| Class | Definition | Control |
|---|---|---|
| 1 | Known mutagenic carcinogens | At or below a compound-specific limit |
| 2 | Known mutagens, carcinogenic potential unknown | At or below the TTC-based limit |
| 3 | Structural alert unrelated to the drug substance, no data | TTC-based limit, or run an Ames test (negative moves it to Class 5, positive to Class 2) |
| 4 | Alert shared with the drug substance or related compounds that tested negative | Treat as non-mutagenic |
| 5 | No alert, or enough data showing it is not mutagenic or carcinogenic | Treat as non-mutagenic |
- Risk characterisation:
- Default limit (TTC): 1.5 µg per person per day, which corresponds to a theoretical excess lifetime cancer risk below 1 in 100,000. It is used for Class 2 and 3 impurities [1].
- Class 1 impurities: the limit is compound-specific, by default derived from the TD50 (the dose giving a 50% tumour incidence) by linear extrapolation [1].
- "Cohort of concern": aflatoxin-like, N-nitroso and alkyl-azoxy compounds are potent enough that intakes even below the TTC could carry significant risk [1].
- Control and lifecycle: the guideline sets out control strategies and how to reassess impurities after approval. New Class 1 or 2 hazard data, or a newly found Class 1 or 2 mutagen in a marketed product, triggers a fresh evaluation [1].
The Addendum
The Addendum gives acceptable intakes for specific Class 1 chemicals.
- TD50 route: most limits come from dividing the TD50 by 50,000 and scaling to a 50 kg person. For example, bis(chloromethyl) ether comes out at 4 ng/day.
- PDE route: where a non-mutagenic mode of action is shown, a permitted daily exposure (PDE) is used instead. Examples are hydrogen peroxide and aniline.
- Upper limit: compound-specific intakes are capped at 0.5%, for example 500 µg in a drug with a maximum daily dose of 100 mg [3].
Points clarified in the Q&As
- Impurities that are carcinogenic but not mutagenic are outside M7. Mutagens shown to be non-carcinogenic go into Class 5 [2].
- If an impurity is Ames-negative but positive for clastogenicity, it is Class 5 for M7 purposes; the clastogenicity result falls outside M7's scope [2].
- An out-of-domain result from one (Q)SAR model is not enough on its own for Class 5; expert review is needed [2].
How does it handle nitrosamines?
ICH M7(R2) puts N-nitroso compounds (nitrosamines) in the "cohort of concern", a group of highly potent mutagenic carcinogens. Because of that, the default limits that cover other mutagenic impurities do not apply to them. M7 sets no nitrosamine limit of its own. Instead it calls for a case-by-case acceptable intake, for example one based on carcinogenicity data from closely related structures. It also keeps nitrosamines under control in situations where other alerting impurities would be ignored.
Approach: I read the M7(R2) guideline, Addendum and Q&As in the ICH guidelines collection, and searched regulator datasets for nitrosamine-specific follow-up guidance. The EMA's own nitrosamine guidance is not in the datasets I can search; Australia's TGA notices are.
What M7(R2) says
Why nitrosamines are treated differently
- The 1.5 µg/day default limit (the TTC) corresponds to a theoretical 10⁻⁵ lifetime cancer risk. Some structural groups are potent enough that intakes even below that level could carry a significant cancer risk. This "cohort of concern" is defined as aflatoxin-like, N-nitroso and alkyl-azoxy compounds [1].
How limits are set (Section 7.5)
- When these compounds turn up as impurities, their acceptable intakes "would likely be significantly lower" than those in the guideline.
- The principles of M7 still apply, but a case-by-case approach, using for example carcinogenicity data from closely related structures where available, "should usually be developed to justify acceptable intakes" in both development and marketed products [1].
Where nitrosamines stay in scope when other alerts don't
| Situation | Treatment of the cohort of concern |
|---|---|
| Marketed products (Section 4.4) | A structural alert alone does not trigger follow-up, unless the structure is in the cohort of concern [1] |
| Phase 1 trials up to 14 days (Section 7.3.1) | Under the alternative approach, only Class 1, Class 2 and cohort-of-concern impurities must be controlled; Class 3 alerts are treated as non-mutagenic [1] |
| Clinical trial applications (Section 9.1) | For Phase 1 trials of 14 days or less, the application should describe how mutagenic-impurity risks are being reduced for Class 1, Class 2 and cohort-of-concern impurities [1] |
| Post-approval changes (Q&A 7.4) | Finding a structure in the cohort of concern is listed among the triggers for applying M7, alongside newly discovered Class 1 or 2 impurities and new hazard data [2] |
Other points
- Adjusting the limit for shorter treatment: the Q&As allow the less-than-lifetime (LTL) adjustment for limits based on the TTC or on a compound- or class-specific acceptable intake. They do not allow it for PDEs [2]. The texts I read do not address how this applies to cohort-of-concern compounds specifically.
- No nitrosamine monographs in the Addendum: the M7(R2) Addendum contains no compound-specific acceptable intake for any nitrosamine. Nitrosamines appear there only in cited references, such as diethylnitrosamine and dimethylnitrosamine in the acetaldehyde and hydrazine monographs [3].
Where the actual nitrosamine limits come from
Because M7 leaves the limits case by case, regulators publish nitrosamine-specific acceptable intakes outside the guideline. Australia's TGA is one example:
- August 2026: the TGA updated its nitrosamine information "consistent with recent EMA updated information". The update added "recently internationally determined AI limits for numerous nitrosamine impurities". The TGA expects sponsors and manufacturers to know the current limits for both nitrosamines and other nitroso-structure impurities, which it keeps as two separate lists [4].
- Earlier updates: similar updates appeared in November 2025 [5] and January 2026 [6].
I can pull the EMA's or the FDA's nitrosamine acceptable-intake framework from their official websites if you'd like the regional detail.
What's the acceptable intake limit?
Under ICH M7(R2), the default acceptable intake for a mutagenic impurity is 1.5 µg/day for lifetime exposure, the TTC. It rises in steps for shorter treatment: 10, 20 and 120 µg/day. Nitrosamines are the exception. As cohort-of-concern compounds, M7 says their acceptable intakes "would likely be significantly lower" than these values. They need a case-by-case limit, and M7 itself gives no nitrosamine figure [1].
Approach: I read the M7(R2) guideline and its Q&As in the ICH guidelines collection. The compound-specific nitrosamine limits come from regional regulators (EMA, FDA, TGA), and I found none of those figures in the datasets I can search.
Single impurity (Table 2)
The 1.5 µg/day lifetime limit equals a cumulative dose of 38.3 mg (1.5 µg × 25,550 days). For shorter treatment, that dose is spread over the actual number of exposure days [1].
| Treatment duration | < 1 month | > 1 to 12 months | > 1 to 10 years | > 10 years to lifetime |
|---|---|---|---|---|
| Acceptable intake (µg/day) | 120 | 20 | 10 | 1.5 |
- Intermittent dosing: use the total number of dosing days, not the calendar span. For example, a drug given weekly for 2 years (104 dosing days) is allowed 20 µg per dose [1].
- Risk levels in clinical development: the adjusted values keep a 10⁻⁶ risk in early development and a 10⁻⁵ risk in later stages [1].
Three or more Class 2 or 3 impurities (Table 3)
| Treatment duration | < 1 month | > 1 to 12 months | > 1 to 10 years | > 10 years to lifetime |
|---|---|---|---|---|
| Total acceptable intake (µg/day) | 120 | 60 | 30 | 5 |
- With two Class 2 or 3 impurities, only the individual limits apply. Class 1 impurities and degradation products in the drug product are left out of the total [1].
- The Q&As say the specification should list both an individual limit (for example, no more than 1.5 µg/day for lifetime use) and a total limit (for example, no more than 5 µg/day) [2].
Compound-specific limits (Class 1)
- Duration scaling: a compound-specific intake can be scaled for shorter duration in the same proportions, capped at 0.5% of the dose, whichever is lower.
- M7's worked example: a lifetime limit of 15 µg/day becomes 100 µg/day for > 1 to 10 years, 200 µg/day for > 1 to 12 months and 1,200 µg/day for < 1 month. For a 100 mg/day drug, though, the < 1 month value is held at 500 µg [1].
Nitrosamines
- No M7 default applies. For aflatoxin-like, N-nitroso and alkyl-azoxy compounds, M7 does not supply 1.5 µg/day or any other figure.
- How a limit is set instead: a case-by-case acceptable intake, for example based on carcinogenicity data from closely related structures, "should usually be developed" for both development and marketed products [1].
- Where the numbers come from: the actual ng/day limits for individual nitrosamines are set by regulators outside M7. As covered last time, the TGA keeps separate lists of nitrosamine and nitroso-impurity acceptable intakes, aligned with the EMA's updates [4].
I can pull the current EMA or FDA nitrosamine acceptable-intake list from their official sites if you want the limit for a specific nitrosamine.