Wednesday, 19 October 2022 9 .00 - 16.30 h
Dr Karl Abele, Solvias AG, Switzerland
Dr Cornelia Nopitsch-Mai, BfArM, Germany
Dr Ulrich Rose, Formerly EDQM, France
Dr Andrew Teasdale, Astra Zeneca, UK
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.
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.
This Live Online Training is addressed to 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 training will also address regulatory requirements and hence is applicable to people working in the regulatory affairs area.
Part II: Nitrosamine Impurities
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
- Drug Product
Analytical Solutions for Monitoring Presence/Formation of N-Nitrosamines within APIs and Drug Products
- Detection limits requested by in Article 5(3) of Regulation EC (No) 726/2004
- Techniques used for analysis of non-API related N-Nitrosamines
- Formation of N-nitrosylated APIs in drug products
- Analytical methods used for quantification of N-nitrosylated APIs in drug products
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.
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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