Impurities 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
Control of Impurities in Ph.Eur.
- Which impurities are controlled?
- General texts/monographs/ICH Guidelines
- Organic impurities in Ph. Eur.
- Specification Setting
- Elemental impurities
Analytical Method Validation for Impurities
Determination at Various Development Stages
- Quantification 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
Applying an example of an API synthesis the participants will learn in the Workshop which activities are necessary to characterize drug substances taking into account the following aspects:
- Analytical procedures are necessary for the characterization
- 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
Extractables and Leachables – What is Expected from Packaging Materials for Drug Products?
- Why should Extractables & Leachables be assessed?
- Regulatory requirements and guidelines in the EU and US and pitfalls
- General flow and critical aspects of Extractables & Leachables studies
- Safety qualification of Extractables and Leachables
How to Avoid Unexpected Impurities: Approaches to Establish a Holistic Understanding of Impurity Risks
- Is there such a thing as ‘unexpected impurities” or is there a lack of process understanding?
- Valsartan – overview of Events
- Source of contamination
- Mechanistic understanding
- Examination of risk within other Sartans – overview of how to conduct a risk assessment and to identify key factors
- Are there other mutagenic impurities related risks?
European Pharmacopoeia Activities on Nitrosamines and other Mutagenic Impurities
- 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
Safety Qualification of Impurities - Current Principles and Methods
- General approaches and regulatory framework for impurity qualification by safety threshold Derivation
- Generic and substance specific safety thresholds
- Threshold of Toxicological Concern (TTC) - different Scenarios
- Derivation of Permitted Daily Exposure (PDE) Limits
- Acceptable exposure calculations based on TD50 and their limitations
- Approaches for data poor substances: (Q)SARs and read-across
- Route-to-route considerations for safety thresholds
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 mutagenic residual solvents
- Impurities derived from metal catalysts
Workshop: Conducting a Nitrosamine 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.