ICH M7: Step-by-Step Guide to Controlling Mutagenic Impurities

Introduction

Mutagenic impurities represent one of the most sensitive risks from both a regulatory and toxicological perspective. Unlike classical impurities, even infinitesimal amounts can theoretically increase cancer risk. ICH M7 provides the international framework to identify, classify, and control these impurities. The ICH S Safety Guidelines supply essential examples, templates, and case studies to support rigorous application of the model.

Step 1: Identification of Impurities

The first step is the most critical. The entire API synthesis must be analysed to identify: potentially mutagenic reagents (alkylating agents, nitrosating agents, epoxides), intermediates with reactive groups, known or predictable by-products, and reasonably possible degradation impurities. The guideline emphasises the use of annotated synthesis schemes and decision trees.

Step 2: (Q)SAR Analysis

For each potential impurity without experimental data, two (Q)SAR models must be applied: a rule-based model (e.g., Derek Nexus) and a statistical QSAR model. If both are negative → Class 5. If a positive alert is present → classification into Class 3 or Class 2, depending on supporting literature.

Step 3: Classification into the Five M7 Classes

• Class 1: Mutagenic and carcinogenic (e.g., the most potent nitrosamines)
• Class 2: Mutagenic (Ames positive) without evidence of carcinogenicity
• Class 3: Structural alert with insufficient data
• Class 4: Structural alert but negative experimental data
• Class 5: No structural alert

Step 4: Determination of Limits (AI, TTC, LTL)

ICH M7 introduces the central concept of the TTC (Threshold of Toxicological Concern) = 1.5 µg/day, corresponding to a risk of 1 in 100,000.
The guideline also defines Less-Than-Lifetime (LTL) limits:
• Therapy < 1 month → up to 60 µg/day
• Therapy < 1 year → approx. 20 µg/day
• Therapy 1–10 years → approx. 10 µg/day

Step 5: Control Strategy (4 M7 Options)

Option 1 – Analytical testing in the drug product/API
Option 2 – Demonstrated purging capability
Option 3 – Control of raw materials
Option 4 – Scientific assessment with no testing

The appropriate option depends on the impurity’s position in the synthesis and the process’s ability to remove it.

Points of Attention

Do not focus solely on the API: some impurities form during formulation.
Nitrosamines always require a dedicated assessment.
Avoid generic statements not supported by data.

How to Manage a Non-Conformity

If a mutagenic impurity exceeds its limit (AI/TTC):
• Immediately block the batch
• Assess the real cumulative exposure to patients
• Consult a qualified toxicologist
• Implement CAPA actions on process or controls
• Notify the regulatory authority if required

Common Errors and Solutions

• Error: Assigning classes without QSAR
Solution: Always document both QSAR models
• Error: Applying LTL limits without dosage justification
Solution: Always link therapy duration and SmPC information
• Error: Excessive reliance on purging without data
Solution: Demonstrate purging experimentally

GMP Best Practices

Integrate M7 into change control, review annually in the PQR, and maintain a master file of mutagenic impurities.

Realistic Case Study

An API synthesised using an alkyl halide shows a Class 3 impurity at an estimated level of 0.3 µg/day. Since the value is already below the TTC, the guideline recommends applying the TTC directly without performing an Ames test — the actual risk is negligible.

Conclusion

ICH M7 requires scientific and documentary rigor. Correct implementation of the model helps prevent toxicological risks and critical regulatory inspections. Explore the complete guide at GuideGxP.com.