Impurities Workshop - Part I and II
Im Auftrag der European Compliance Academy

Programm

Part I

Analysis and qualification of Impurities in Drug Substances and Drug Products – general overview
Impurity profiling in synthetic drug substances
Qualification of impurities
Degradation studies
Identification of chiral impurities, polymorphic phases and new impurities
Residual solvents
Impurities in starting materials and intermediates
Pharmacopoeial tests and acceptance criteria
Drug product specifications and parametric release
Inorganic impurities

Practical aspects of method validation for impurity determination
Important ICH and FDA guidelines
Quantitation of impurities
How to define an impurity profile (stress tests)
Reference substances
Validation of methods at various development stages
Statistical approaches to method validation (LOD & LOQ)

Presentation and Workshop: Analytical techniques for determination and qualification of impurities in Starting Materials and Intermediates
Purity analysis by HPLC, impurity profile
Residual solvents by GC
Inorganic impurities (heavy metals, sulphated ash)
For chiral compounds in addition: enantiomeric purity and proof of the absolute configuration

In the Workshop, the participants will learn which activities are necessary to characterise drug substances taking into account the following aspects:
Analytical procedures are necessary for the characterisation
Experiments necessary to check the downstream impurities in order to justify acceptance criteria for the respective impurities
Other impurities have to be taken into account
Experiments to be performed in order to get a stability-indicating analytical procedure

Presentation and Workshop: Leachables and Extractables
Why should Extractables & Leachables be assessed?
Regulatory requirements in the EU and US
Compendial requirements and industry standards
Safety qualification of Leachables and Extractables

The Workshop will provide the opportunity to work on case studies about Leachables and Extractables regarding detection and safety qualification. It will seek, through a practical exercise, to examine the steps involved in a comprehensive E&L evaluation.

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.