Impurities Workshop - Part II: Mutagenic Impurities

Programme

Mutagenic Impurities – requirements, authorities expectations and case studies
General documents and Guidelines for the assessment of mutagenic impurities
The assessor’s approach: principles of toxicological assessment
The TTC concept
Structural alerts
Limits and Permitted Daily Exposure
The ALARP principle
Applicability of the EU “Guideline on the Limits of Genotoxic Impurities”
Examples of low daily dose drug substances
Impurities derived from alkylating agents (mesilate, besilate, tosilate, diisothionate); examples
Potential mutagenicc residual solvents
Impurities derived from metal catalysts

ICH M7 Guideline – Mutagenic Impurities: overview of key aspects
Applicability of the M7 Guideline
General principles
Modified Limits based on patient population / unmet medical need
Considerations for marketed products

ICH M7 Guideline – practical implementation: a quality and safety perspective
Drug substance and drug product impurity assessment
Hazard assessment elements
Computational toxicology assessment
Structure activity relationships
Process related impurities
Control strategy approaches
Lifecycle management
Considerations for clinical development
In vivo relevance of in vitro mutagens
Linear extrapolation from TD50; calculation examples

Workshop: Compound-specific risk assessment for mutagenic impurities
In this Workshop participants will be shown the basis of how safety data can be effectively utilised to calculate compound specific limits. How the data can be interpreted, based on mechanistic action, to define the most appropriate approach (permissible daily exposure (PDE) or linear extrapolation) and how this was used to define the ICH M7 addendum.