Impurities Forum 2019 - Part I and II
Im Auftrag der ECA Academy

26/27 June 2019

Praha, Czech Republic

Seminar Nr. 16956

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

Sprecher

Dr Gisela Fontaine, Solvias AG, Switzerland
Dr Gerd Jilge, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Grace Kocks, Lhasa Limited, United Kingdom
Dr Corina Nachtsheim, Quality Assessor, Germany
Dr Xaver Schratt, GBA Pharma GmbH, Germany
Dr Andrew Teasdale, AstraZeneca, United Kingdom
Dr Lise Vanderkelen, Nelson Labs, Belgium

Zielsetzung

Part I

Part I of the Impurities Forum will provide an opportunity to reinforce and expand your knowledge of the general area of impurities in chemical entities from initial development to the market with emphasis on

Detection, profiling and control of impurities in drug substances, intermediates and drug products
Practical aspects of method validation for impurities Determination
Analytical techniques used for detecting and qualifying impurities
Extractables and Leachables as a source of impurities
“Unexpected Impurities” – lessons learned from the Valsartan case

This event is designed to provide a comprehensive review of impurities analysis and characterisation in drug substances and drug products and their recording and reporting.

Part II

In Part II of the Impurities Forum the key principles of the ICH Q3D Guideline will be highlighted. You will get to know the essential aspects and approaches of determining and controlling elemental impurities in drug products. You will learn

which are the principles of the elemental impurities risk assessment process,
factors that affect the limits – route of administration and also duration of exposure.
how to implement risk-based strategies to control elemental impurities,
how to develop suitable analytical methods for genotoxic impurities determination,
regulatory filing: what do regulatory authorities expect?

Moreover you will hear about recent developments regarding the control of Mutagenic Impurities according to ICH M7

Hintergrund

Part I

Setting specifications for impurities are one of the most critical topics in the development of new drug products. Impurities analysis in drug substances and drug products and their recording and reporting is quite often a challenge for the scientific experts in routine production and quality control. This challenge is even bigger when profiles of unknown impurities in complex matrices have to be established. The recent Valsartan case made clear the importance of a thorough process understanding.

Part II

In November 2014 the ICH Q3D Guideline for Elemental Impurities was published as Step 4 document. This document outlines

• the evaluation of the toxicity data for potential elemental impurities
• the PDEs for each element of toxicological concern
• the basis for an EI risk assessment and the key factors for evaluation.
• the development of controls designed to limit the inclusion of elemental impurities in drug products to levels at or below the PDE

Meanwhile ICH Q3D was revised twice, regarding Cadmium Inhalation PDE (ICH Q3D(R1); Step 2 document) and cutaneous and transdermal products (ICH Q3D(R2); Concept Paper).

Equally the ICH M7 Guideline for Assessment and Control of DNA reactive (mutagenic) impurities has undergone a twofold revision: ICH M7(R1) (Step 4 document) being completed by an Addendum containing a summary of known mutagenic impurities commonly found or used in drug synthesis and ICH M7(R2) (Concept Paper) where PDEs for new DNA reactive (mutagenic) impurities have been incorporated.

Zielgruppe

Part I

This conference addresses all personnel involved in development of drug substances and drug products from scientific staff to laboratory heads involved in R&D. The needs of Laboratory Managers, Supervisors and Analysts in pharmaceutical quality assurance and quality control departments will also be covered. This event will also address regulatory requirements and hence is applicable to people working in the regulatory affairs area.

Part II

The conference addresses all personnel involved in development of drug substances and drug products from scientific staff to laboratory heads involved in R&D. The needs of Laboratory Managers, Supervisors and Analysts in pharmaceutical quality assurance and quality control departments will also be covered.

Programm

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

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Impurities Forum 2019 - Part I and IIIm Auftrag der ECA Academy