Impurities Workshop - Part II and III

Programme

Part II

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.


Part III
Implementation of ICH Q3D in the European Pharmacopoeia
History of heavy metals tests
General texts on elemental impurities in Ph. Eur.
Implementation strategy for Ph. Eur. after adoption of ICH Q3D

Analytical methods to determine metallic impurities
Principles and characteristics of the most common spectrometric techniques AAS, ICP-OES, ICP-MS
Compound methods (sample preparation plus spectrometric detection and quantification)
Special considerations for trace-elemental analysis
Application-based approach for choice of methodology
Analytical process (method development, validation strategy, routine testing)

Control Strategies for Elemental Impurities in final dosage forms – Case studies
Utilisation of Data as part of an Integrated EI Risk Assessment Process
Potential Sources of Elemental Impurities in the Finished Product
- API
- Equipment
- Container-closure system
- Excipients
Conclusions

Workshop: Conducting a risk assessment
In this Workshop the participants will work on several case studies and perform a risk assessment for different scenarios taking into account e.g. manufacturing equipment, dosage form of the drug product etc.

QC lab infrastructure and equipment for metal impurities analytics
Process-oriented laboratory design
Basic components of a trace elemental laboratory
Approaches for contamination control
Handling of highly active pharmaceutical compounds in a trace elemental laboratory: operator protection versus product protection?
Accessories for interference control in ICP-MS