Impurities Workshop - Part I and II
Im Auftrag der ECA Academy

Impurities Workshop - Part I and II Im Auftrag der ECA Academy

Heidelberg, Germany

Seminar Nr. 17397



ECA-Member: EUR 1590,--
Non ECA Member: EUR 1790,--
EU/GMP Inspectorates: EUR 895,--
APIC Member Discount: EUR 1690,--

Alle Preise zzgl. MwSt.

Rückfragen unter:
Tel.: 06221 / 84 44 0 E-Mail:


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, Germany
Dr Andrew Teasdale, AstraZeneca, United Kingdom
Dr Lise Vanderkelen, Nelson Labs, Belgium


Part I

Part I of the Impurities Workshop 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
  •  Approaches for investigation and determination of unexpected impurities
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 Workshop the relevant aspects of root cause analysis and risk assessment with respect to potential Nitrosamine contamination in drug substances and drug products will be discussed. You will hear what you need to know about the required risk assessments for medicinal products containing chemically synthesized APIs. In particular you will learn
  •  which root causes for Nitrosamine Impurities should be considered,
  •  which practical approaches can be applied to assess the risks related to potential Nitrosamine contamination,
  •  which safety aspects need to be considered regarding Nitrosamine Impurities in drug products,
  •  which regulatory actions are to be taken in case of Nitrosamine Impurities and what authorities expect in these cases.
You will get advice from industry experts on how to cope with the challenge of performing risk assessments. Furthermore a representative of the EDQM will inform you about the European Pharmacopoeia activities (policy) on mutagenic impurities with focus on Nitrosamines.


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 Valsartan case made clear the importance of a thorough process understanding.

Part II

In June 2018 EU authorities were notified that a Chinese API manufacturer has detected the presence of N-nitrosodimethylamine, NDMA, in batches of Valsartan. NDMA is a genotoxic and carcinogenic agent in animals and is classified as a Class 2A carcinogen to humans. After a referral under Article 31 of Directive 2001/83/EC triggered by the European Commission the CHMP assessed the impact of the presence of this impurity on the benefit-risk balance of valsartan-containing drug products and issued a recommendation whether the concerning marketing authorisations can still be maintained or should be suspended.
Meanwhile different Nitrosamines (NDMA, NDEA and others) were detected in almost every drug product which contains a Sartan derivative as an API. In an EMA Questions & Answers Document various potential sources of Nitrosamine contaminations are described. In September 2019 EMA published a press release where pharmaceutical companies were advised on steps to be taken to avoid nitrosamines in human medicines. In another document which appeared at about the same time Marketing Authorisation Holders are requested to evaluate the risk of the presence of Nitrosamine impurities in human medicinal products containing chemically synthesised APIs. As a consequence in case of contamination with Nitrosamines Marketing Authorisation Holders are requested to file a variation application. All regulatory activities with regard to such cases have to be completed within a 3 years period (end of march 2022).



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.


Part I
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
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
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


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