Impurities Workshop Part I - III
Im Auftrag der ECA Academy

30 June - 2 July 2020

Heidelberg, Germany

Seminar Nr. 17869

Unser Seminarservice

Kosten

ECA-Member:	EUR 2070,--
Non ECA Member:	EUR 2270,--
EU/GMP Inspectorates:	EUR 1135,--
APIC Member Discount:	EUR 2170,--

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Zur Anmeldung

Rückfragen unter:
Tel.: 06221 / 84 44 0 E-Mail: info@concept-heidelberg.de

Sprecher

Dr Gerd Jilge, Boehringer Ingelheim, Germany
Jürgen Martin, Martin-Consulting
Dr Lutz Müller, F. Hoffmann-La Roche, Switzerland
Dr Corina Nachtsheim, Quality Assessor, Germany
Dr Ulrich Rose, EDQM, France
Dr Xaver Schratt, GBA Pharma GmbH, Germany
Dr Andrew Teasdale, Astra Zeneca, UK
Dr Lise Vanderkelen, Nelson Labs, Belgium

Programm

Part I: Impurities

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 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

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?

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
- API
- Drug Product
- Packaging

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

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.

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

Part III: Elemental Impurities

European Pharmacopoeia Activities (Policy) on Elemental Impurities – an Update

Implementation of Q3D in Ph. Eur.
Changes in individual and general monographs
Harmonisation of general chapter 2.4.20
Second phase for revision of excipient monographs

Risk Based Approach for Elemental Impurities in the Supply Chain

APIs, excipients, packaging materials impacting the purity profile
Evaluation of supply chain processes
Risk analysis as evaluation tool
Audits- and monitoring programs as important sources
Testing strategies

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