Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses

Area of Science:

• Pharmaceutical Chemistry
• Computational Toxicology
• Regulatory Science

Background:

• The International Council for Harmonisation (ICH) M7 guideline provides a framework for managing mutagenic impurities in pharmaceuticals.
• Controlling these impurities is crucial for mitigating potential carcinogenic risks in drug products.
• Regulatory submissions require robust data to support impurity hazard classifications.

Purpose of the Study:

• To outline principles and procedures for generating (Quantitative) Structure-Activity Relationship ((Q)SAR) assessments compliant with ICH M7.
• To guide the integration of (Q)SAR methodologies for regulatory impurity qualification.
• To describe the role of expert review in validating (Q)SAR predictions.

Main Methods:

• Utilizing complementary (Q)SAR methodologies to derive initial hazard classifications in the absence of experimental data.
• Incorporating expert review to assess and validate (Q)SAR predictions.
• Documenting (Q)SAR methodologies, expert review findings, and supporting arguments for regulatory submissions.

Main Results:

• A systematic approach for applying (Q)SAR to mutagenic impurity assessment under ICH M7 is presented.
• Scenarios benefiting from expert knowledge in (Q)SAR assessment are elucidated.
• The manuscript demonstrates how to construct a robust (Q)SAR-based argument for impurity qualification.

Conclusions:

• The described principles and procedures facilitate consistent and reliable (Q)SAR assessments for pharmaceutical impurity control.
• This approach supports regulatory compliance and enhances the safety profile of pharmaceutical products.
• Expert judgment plays a vital role in refining and substantiating (Q)SAR-driven impurity assessments.