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
Analytical method validation for Impurity 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
- 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 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
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 subsequent plenary workshop will provide the opportunity to discuss 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.
Unexpected Impurities: approaches for investigation and determination
- 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?
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
Analytical methods to determine elemental 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)
Mutagenic Impurities: how to develop suitable analytical methods for detection
- Challenges associated with MI analytical method development
- Class based methods vs individually designed messages
- Technologies
- GC-vs LC
- Chromatography vs NMR
- Validation requirements
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.
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
- Nitrosamines – the Valsartan case
- Potential mutagenicc residual solvents
- Impurities derived from metal catalysts