ICH M7 Guidelines: Assessment and Control of Genotoxic Impurities

ICH M7 Guidelines: Assessment and Control of Genotoxic Impurities

Key Takeaways

Scope and Applicability of ICH M7(R1)

What ICH M7 Covers

ICH M7 applies to new drug substances and new drug products during clinical development and marketing authorization. The guideline covers:

• Actual and potential impurities in drug substance synthesis (process impurities, intermediates, by-products)
• Degradation products in drug substance and drug product that are DNA-reactive
• Impurities in marketed products when significant manufacturing changes occur

Explicit Exclusions

When ICH M7 Assessment Is Required

ICH M7 assessment is expected at several points in product development:

The Threshold of Toxicological Concern (TTC)

The TTC is the central risk management concept in ICH M7. It defines an acceptable daily intake below which the lifetime risk of cancer from a mutagenic impurity is considered negligible.

TTC Derivation

The TTC of 1.5 mcg/day is derived from a statistical analysis of carcinogenicity data for a large set of known carcinogens:

1. TD50 values (dose inducing tumors in 50% of test animals) were compiled from the Carcinogenicity Potency Database (CPDB)
2. Linear extrapolation from the TD50 to a theoretical 1-in-100,000 lifetime cancer risk level was performed
3. The distribution of calculated acceptable intakes was analyzed
4. The TTC was set at a level protective against the vast majority of compounds in the dataset

The math:

The 50,000 safety factor corresponds to a 1-in-100,000 cancer risk over a 70-year lifetime. For the most potent carcinogens in the dataset, this yields approximately 1.5 mcg/day.

Compounds Excluded from TTC (Cohort of Concern)

Certain structural classes are considered too potent for the standard TTC to provide adequate protection. These "cohort of concern" compounds require compound-specific risk assessment:

For nitrosamines specifically, the default TTC does not apply. Instead, compound-specific AI limits are used when carcinogenicity data is available, or a lower default of 18 ng/day (the "cohort of concern" TTC) applies when compound-specific data is unavailable.

Staged TTC: Less-Than-Lifetime Adjustments

ICH M7 permits higher daily intake limits for treatments of limited duration, based on the rationale that shorter exposure periods proportionally reduce cumulative cancer risk.

The 5-Class Mutagenic Impurity Classification System

ICH M7 categorizes impurities into five classes based on the availability of mutagenicity and carcinogenicity data. Classification determines the control strategy.

Classification Decision Tree

Classification Workflow

The classification of an impurity follows this sequence:

1. Literature search: Check published data for known mutagenicity and carcinogenicity
2. In silico SAR assessment: Run computational models to identify structural alerts (minimum two complementary methodologies required)
3. Expert review: Evaluate SAR predictions with scientific judgment
4. Bacterial mutagenicity assay (if needed): Ames test (ICH S2(R1) compliant) for Class 3 compounds
5. Final classification: Assign class based on all available data

Key decision points:

• If both in silico systems predict "no alert" and expert review concurs: Class 5 (no further action needed)
• If either in silico system predicts "alert" but Ames test is negative: Class 4 (non-mutagenic controls apply)
• If Ames test is positive but no carcinogenicity data exists: Class 2 (TTC controls apply)
• If Ames test is positive and carcinogenicity data exists: Class 1 (compound-specific AI)

In Silico Assessment Requirements

ICH M7 requires two complementary computational methodologies for SAR assessment:

Both systems must be evaluated. Results are interpreted as follows:

Acceptable Intake Calculation

For Class 1 Impurities (Known Carcinogens)

Class 1 impurities have compound-specific AI limits derived from carcinogenicity data:

This yields a lifetime cancer risk of 1 in 100,000. If multiple TD50 values exist (from different species, sexes, or tumor sites), the most conservative (lowest) value is used.

For Class 2 and Class 3 Impurities

In the absence of carcinogenicity data, the TTC of 1.5 mcg/day applies for lifetime exposure, with staged TTC adjustments permitted for shorter treatment durations.

Converting AI to Specification Limits

To set specifications in drug substance or drug product, the AI must be converted to a concentration limit:

Example: For an impurity with AI = 1.5 mcg/day in a drug product with maximum daily dose of 0.5 g:

Control Strategies

ICH M7 defines three control approaches based on impurity classification and process understanding:

Option 1: Control by Specification (Testing)

• Set specification at or below the acceptable limit
• Validate analytical method to required sensitivity (LOQ ≤ 30% of specification)
• Test each batch of drug substance or drug product
• Appropriate when impurity level is close to the limit or variable

Option 2: Control by Process Parameters (No Testing)

• Demonstrate through process understanding that the impurity is consistently controlled below limits
• Requires process validation data showing impurity levels well below the limit (typically < 30% of specification)
• May use process analytical technology (PAT) for in-process monitoring
• Appropriate when the impurity is a synthetic intermediate or is consistently purged

Option 3: Upstream Control (Purge Factor Approach)

• Calculate the predicted purge of the impurity across downstream process steps
• If the calculated purge reduces levels to well below the limit, testing at drug substance level is unnecessary
• Requires experimental or scientifically justified purge factor data for each downstream step
• ICH M7(R1) Addendum provides a framework for purge factor calculation

Purge factor calculation:

If predicted level at drug substance is < 30% of the specification limit, control by upstream processing is considered justified.

Lifecycle Approach

ICH M7(R1) emphasizes a lifecycle approach to mutagenic impurity management, recognizing that impurity knowledge evolves throughout development.

Lifecycle Assessment Stages

When Reassessment Is Required

• Change in synthetic route introducing new impurities or intermediates
• Change in starting material specification or supplier
• New degradation products identified during stability studies
• Change in drug product formulation affecting degradation pathways
• Regulatory intelligence indicating new mutagenicity data for existing impurities

Key Takeaways

References