Live Online Training: Nitrosamine Impurities Update

Thursday, 10 June 2021 9 .00 - 16.30 h

Course No. 18895



Dr. Ulrich Rose

Dr. Ulrich Rose


All times mentioned are CEST.


It is the aim of this Live Online Training to provide the latest information on requirements Marketing Authorisation Holders have to meet with respect to Nitrosamine Impurities. Important points to be considered by Quality Assurance and Quality Control departments from manufacturers of APIs and finished products will also be discussed. You will get to know
  •  what regulatory authorities want to see regarding assessment of risks
  •  which European Pharmacopoeia monographs of sartans
  •  how to conduct a significant and comprehensive risk assessment
  •  which quality and safety aspects have to be taken into account for a risk assessment
  •  how to choose a suitable analytical method for determination of Nitrosamines


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 sartan-containing drug products and issued a recommendation whether the concerning marketing authorisations can still be maintained or should be suspended.
Building on this Article 31 referral EMA together with the EU Network and international partners was continuing the review to identify whether there are any consequences for medicinal products apart from the class of sartans. As a result of this the CHMP issued a document entitled “Nitrosamine impurities in human medicinal products” as part of the procedure under Article 5(3) of Regulation EC (No) 726/2004.. This assessment report contains comprehensive recommendations on how to detect and mitigate the risk of Nitrosamine Impurities in human medicinal products containing chemically synthesised APIs as well as biological medicinal products.

In a subsequent assignment the CHMP was requested by the European Commission to assess the impact of the outcome of the Article 5(3) assessment on Nitrosamines regarding angiotensin-II-receptor antagonists (sartans) which resulted in a final assessment report with respect to Candesartan, Irbesartan, Losartan, Olmesartan and Valsartan. This assessment report contains changes to the current conditions to the Marketing Authorisations for sartans such as limits for Nitrosamine Impurities to be implemented for the finished products and deadlines to be met.

As a consequence the five European Pharmacopoeia monographs on sartans with a tetrazole ring, namely Valsartan, Losartan Potassium, Irbesartan, Candesartan ciletexil and Olmesartan medoxomil have been revised to align them with the above mentioned final assessment report. The implementation date of these monographs is 1 April 2021.

Target Group

This Training 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. On this event regulatory requirements will be discussed and hence it is applicable to people working in the regulatory affairs area.

Technical Requirements

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Live Online Training: Nitrosamine Impurities Update

Seminar Programme as PDF

Latest European Pharmacopoeia Activities on Control of Nitrosamine Impurities
  • General principles of control DNA reactive (genotoxic) impurities in the European Pharmacopoeia
  • Update on revisions of monographs on Sartans – Nitrosamine impurities
  • Update on revisions of general monographs
Assessment and Communication of Risks – what Regulatory Authorities want to see. An Update
  • Regulatory Basis
  • Requirements for Nitrosamines
  • Limits and Deadlines
  • Scenarios for implementation
  • Sartans and Non-Sartans
Management of Nitrosamines – Key Quality and Safety Challenges
  • How are Nitrosamines formed and under what conditions
    • Synthetically – API manufacture
    • Within the drug product + other routes
    • How to place risks into context
  • Analysis of Nitrosamines
    • Sensitivity challenges
    • Interference / false positives
  • Safety of Nitrosamines – are all of concern?
    • Factors that impact potency
    • Can Less than lifetime approaches be taken?
    • How to assess – utility of the Ames test – factors for consideration
Nitrosamine Impurities – How to Conduct an Actual Risk Assessment
  • Development of a systematic risk based approach
  • Key factors and the development of a decision tree
    • API
    • Drug Product
Analytical Methods for Determination of Nitrosamines used for Confirmatory Testing
  • Current status of methodology
  • Analytical challenges
  • Sensitivity
  • Specificity – risk of false positives

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