Recording Online Training: Nitrosamine Impurities

Recording Online Training: Nitrosamine Impurities


ECA-Member*: EUR 990,--
Non ECA Member*: EUR 1190,--
EU/GMP Inspectorates*: EUR 595,--
APIC Member Discount*: EUR 1090,--

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Tel.: +49 (0)6221 / 84 44 0 E-Mail:


Marieke van Dalen, Aspen Oss B.V., The Netherlands
Dr Susanne Glowienke, Novartis, Switzerland
Dr Mark Harrison, Astra Zeneca, United Kingdom
Dr Hiltrud Horn, Horn Pharmaceutical Consulting, Germany
Dr Ulrich Kissel, European QP Association, KisselPharmaConsulting, Germany
Dr Corina Nachtsheim, Quality Assessor, Germany
Dr Andrew Teasdale, Astra Zeneca, United Kingdom


During this conference the relevant aspects of risk mitigation with respect to potential Nitrosamine contamination in drug substan-ces 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,
  • how suppliers for raw materials, solvents and packaging materials should be qualified,
  • what to take into account when risks have to be assessed and communicated to regulatory authorities,
  • which safety aspects need to be considered regarding Nitrosamine Impurities in drug products, 
  • how supply chain quality oversight can mitigate risks of Nitrosamine contamination,
  • which regulatory actions are to be taken in case of Nitrosamine impurities.
You will get advice from industry experts on how to cope with the challenge of performing risk assessments within short timelines.


In June 2018 EU authorities were notified that a Chinese API manufacturer had 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 and to submit these assessments not later than end of March 2020.

Target Group

This conference is of interest to all personnel involved in risk assessments of drug substances and drug products regarding potential Nitrosamine contamination. Scientific staff, Laboratory Managers, Supervisors and Analysts in pharmaceutical quality assurance and quality control departments are addressed. During this event regulatory requirements will be discussed, and hence the event also is applicable to people working in the regulatory affairs area.


Nitrosamine Impurities and the Sartan Cases - Background
  •  Initial cause of Valsartan contamination
  •  Other causes and their implications
  •  Article 31 and its implications
  •  Reflection on alignment with ICH M7
Nitrosamine Impurities and Supplier Qualification
  •  Supplier Qualification: Points to consider
  •  API Manufacturers and Nitrosamines
  •  Responsibilities of the API Manufacturer
  •  Potential Sources of Nitrosamines
  •  Responsibilities of the MAH
  •  Reporting
  •  Practical Example: Risk Assessment
Root causes for Nitrosamine 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
Assessment and Communication of Risks – what regulatory authorities want to see

Ensuring Supply Chain Quality Oversight: How MAHs, finished Product Manufacturers and API Manufacturers should Cooperate
  •  Communication between the parties involved
  •  Who needs to know what
  •  How to cope with the complexity of supply chains
  •  Activities to be shared between the parties involved
  •  The role of the Qualified Person
Regulatory Consequences in Case of a Contamination
  •  Mitigation of risk
  •  Filing  a variation/change
  •  Is a global approach possible?
Assessment and Communication of Risks – what Regulatory Authorities want to see

Safety Aspects of Nitrosamine Impurities in Drug Products
    • Mutagenic and carcinogenic potential
    • Safety threshold, application of ICH M7 principles
    • Human carcinogenic risk assessment in drug substances
Confirmatory Testing: Analytical Methods for Determination of Nitrosamines
      •  Current status of methodology
      •  Analytical challenges
        • Sensitivity
        • Specificity – risk of false positives
Recording from 19.03.2020
Duration of recording: 5 h 16 min.

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