Impurities Forum - Part Part II + III

Programme

Impurities Forum - Part II

The new ICH Q3D Guidance on Elemental Impurities – authorities expectations
Scope and applicability of the ICH Q3D guideline
Similarities and differences with the EU-Metal Catalysts guideline
What is the link with the EP and USP monographs?
The classification system of heavy metals and metal catalysts in the proposed guideline, thresholds.
Implications to the API industry – additional requirements – analytical work required – costs
What do authorities expect?

Utilisation of Data as part of an Integrated EI Risk Assessment Process - Role of Industry Collaboration /FDA-IPEC Excipient Study Data
An overview - Utilisation of Data as part of an Integrated EI Risk Assessment Process
Practical Implementation Considerations
Potential Sources of Elemental Impurities in the Finished Product
- API
- Equipment
- Container-closure system
- Excipients
Data sharing - Elemental Impurities Pharma Consortium – current status – future aims
Conclusions

Safety assessment of metallic impurities in oral dosage forms – limits and
Permitted Daily Exposure (PDE)
General principles of safety assessment
How to determine PDEs
Conversion between PDEs and concentration limits
Justification for impurity levels higher than the PDE
Case studies

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)

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

Identification and assessment of potential elemental impurities in pharmaceutical excipients
Potential sources of elemental impurities in pharmaceutical excipients
Important aspects of excipients safety assessment
Excipients supplier qualification
Classification of elemental impurities: examples

An approach to risk assessing for elemental/metallic impurities
ICHQ3D - what’s expected
An example of a Risk Tool Macro
What information is required for Skip Testing – Ph.Eur./ICHQ3D expectations
Regulatory filing – Where do I include information relating to a Risk Assessment

Impurities Forum - Part III

Part III: Genotoxic Impurities
Genotoxic Impurities – requirements and authorities expectations
General documents and Guidelines for the assessment of genotoxic 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”

Case studies for the assessment of potential genotoxic impurities
Examples of low daily dose drug substances
Impurities derived from alkylating agents (mesilate, besilate, tosilate, diisothionate); examples
Potential genotoxic residual solvents
Impurities derived from metal catalysts

ICH M7 Guideline – Mutagenic Impurities: overview of key aspects
Applicability of the M7 Guideline
General principles
Considerations for marketed products

ICH M7 Guideline – practical implementation: a quality perspective
Drug substance and drug product impurity assessment
Hazard assessment elements
Computational toxicology assessment
Structure activity relationships
Process related impurities
Control strategy approaches

ICH M7 Guideline – practical implementation: a safety perspective
Lifecycle management
Considerations for clinical development
In vivo relevance of in vitro mutagens
Linear extrapolation from TD50; calculation examples