How to Prepare an ICH M7 Risk Assessment Report in 3 Steps

Tox by Design ICH M7 mutagenic impurities toxicological characterisation reports are developed in compliance with current ICH M7 (R2) guidelines:

Step 1 − Identification of Active Substance Synthesis or Degradation Impurities

  • Actual synthesis or degradation impurities
  • But even also all potential impurities

Step 2 − Hazard Assessment

Which involves:

  • An initial analysis of actual and potential impurities by conducting database and literature searches for carcinogenicity and bacterial mutagenicity data, in order to classify them in Class 1, 2 or 5 (Table 1).

Sources: PubMed, Toxline, IPECS, IARC, etc…

  • If data for such a classification is not available, a computational toxicology assessment should be performed using (Q)SAR methodologies that predict the outcome of a bacterial mutagenicity assay. This could lead to a classification into Class 3, 4 or 5 (Table 1).

Sources (Q)SAR: Instem, VEGA, DQD, Toolbox, ToxTree, EPA TEST, etc…

As requested in ICH M7 (R2) section 6, two (Q)SAR prediction methodologies that complement each other should be applied. One methodology should be expert rule-based and the second methodology should be statistical-based. The absence of structural alerts from two complementary (Q)SAR is sufficient to conclude that the impurity is of no mutagenic concern, and no further testing is recommended (Class 5 in Table 1)

  • In case of a relevant structural alert (Class 3 in Table 1), a bacterial mutagenicity assay with the impurity alone can be conducted.

The toxicological evaluation may end with the Hazard Assessment or have to continue until risk characterisation is completed in order to determine a threshold value (PDE, TTC, etc…).

Step 3 − Classification

As a result of hazard assessment, each impurity will be assigned to one of the 5 classes of Table 1, giving impurities classification with respect to Mutagenic and Carcinogenic Potential and Resulting Control Actions:

Table 1: Impurities Classification with Respect to Mutagenic and Carcinogenic Potential and Resulting Control Action


Proposed action for control

(details in ICH M7 (R2) Section 7 and 8)

1Known mutagenic carcinogensControl at or below compound-specific acceptable limit
2Known mutagens with unknown carcinogenic potential (bacterial mutagenicity positive*, no rodent carcinogenicity data)Control at or below acceptable limits (appropriate TTC)
3Alerting structure, unrelated to the structure of the drug substance; no mutagenicity data

Control at or below acceptable limits (appropriate TTC) or conduct bacterial mutagenicity assay;

If non-mutagenic => Class 5

If mutagenic => Class 2

4Alerting structure, same alert in drug substance or compounds related to the drug substance (e.g., process intermediates) which have been tested and are non-mutagenicTreat as non-mutagenic impurity
5No structural alerts, or alerting structure with sufficient data to demonstrate lack of mutagenicity or carcinogenicityTreat as non-mutagenic impurity

*Or other relevant positive mutagenicity data indicative of DNA-reactivity related induction of gene mutations (e.g., positive findings in in vivo gene mutation studies)

You can check Tox by Design methodology for Mutagenic impurities Risk assessment, which are duly validated and signed by an European Registered Toxicologist expert.

In the event you are performing this exercise for innovative compounds GMP scale up manufacturing, please be noted that Tox by Design is duly accredited for the French Research Tax Credit CIR.

Feel free to contact us using the Quotation Request below to receive a quotation for Risk assessment of such Mutagenic impurities present in your drug substances and products.