The Impurities Forum Part II - Live Online Training Nitrosamines and other Mutagenic Impurities

The Impurities Forum Part II - Live Online Training

Course No 20647

This course is part of the GMP Certification Programme "ECA Certified Quality Control Manager". Learn more.

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Dr Cornelia Nopitsch-Mai, Quality Assessor, Germany
Dr Ulrich Rose, Former Deputy Head of the European Pharmacopoeia Department, EDQM, France
Dr Reinhard Stidl, Safetree Consulting, Austria
Dr Andrew Teasdale, Astra Zeneca, UK


In Part II of the Impurities Forum 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, you will be informed about the European Pharmacopoeia activities on Nitrosamines and other mutagenic impurities.


Mutagenic substances as impurities in drug substances or drug products are of big concern as they have the potential to alter or damage human DNA. Among these species Nitrosamines and elemental impurities have triggered various regulatory activities and initiatives. Since September 2019, Marketing Authorisation Holders are requested to evaluate the risk of the presence of Nitrosamine impurities in human medicinal products containing chemically synthesised APIs. In case of a contamination with Nitrosamines, MAHs are requested to file a variation application. The deadline for submission of variations has been extended once again and needs to be filed within 2023.The ICH Q3D Guideline for Elemental Impurities was published as Step 4 document and has meanwhile been revised twice, regarding Cadmium Inhalation PDE and cutaneous and transdermal products.

Target Group

The Live Online Training 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 Live Online Training will also address regulatory requirements and hence is applicable to people working in the Regulatory Affairs area.

Technical Requirements

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Part 2
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
    • API
    • Drug product
    • Packaging
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.

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