Part II: Nitrosamine Impurities
European Pharmacopoeia Activities (Policy) on Mutagenic Impurities with Focus on Nitrosamines
- Ph. Eur. General policy on DNA reactive impurities
- Control of Nitrosamines in Ph. Eur.
- Changes in individual and general monographs following the Sartan case
- New general chapter on control of nitrosamines
Root Causes for Nitrosamine Impurities and Other Mutagenic Impurities – Practical Approaches to Assess the Risks
- Development of a systematic risk based approach
- Key factors and the development of a decision tree
- Drug Product
ICH M7 Safety Risk Assessment and the Cohort of Concern – How to Deal with e.g. Nitrosamines
- Principles of cancer risk estimation in ICH M7
- Why was the cohort of concern excluded from ICH M7?
- Applicability to use ICH M7 based cancer risk assessment to the cohort of concern
- Nitrosamines, why are they in the cohort of concern?
- Major risk factors for sources of nitrosamines in drugs
- Way forward to handle cohort of concern within ICH M7
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.
Nitrosamines and Other Genotoxic Impurities – Authorities' Expectations and Dossier Requirements
- The assessor’s approach: principles of toxicological assessment
- Structural alerts
- Limits and Permitted Daily Exposure
- The ALARP principle
- Examples of low daily dose drug substances
- Impurities derived from alkylating agents (mesilate, besilate, tosilate, diisothionate); examples
- Nitrosamines – the Valsartan case
- Potential mutagenicc residual solvents
- Impurities derived from metal catalysts