The Impurities Workshop Part II and III

The Impurities Workshop Part II and III

Heidelberg, Germany

Course No 17868


Costs

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

(All prices excl. VAT)

If you have any questions, please contact us:
Tel.: +49 (0)6221 / 84 44 0 E-Mail: info@gmp-compliance.org

Speakers

Jürgen Martin, Martin-Consulting, Germany
Dr Lutz Müller, F. Hoffmann-La Roche, Switzerland
Dr Corina Nachtsheim, Quality Assessor, Germany
Dr Ulrich Rose, EDQM, France
Dr Andrew Teasdale, AstraZeneca, UK

Objectives

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 III

In Part III of the Impurities Workshop the key principles of the ICH Q3D Guideline on elemental impurities will be highlighted. You will get to know the essential aspects and approaches of how to assess the risks and control elemental impurities in drug substances, drug products and excipients.

You will learn
  •  what has to be considered with respect to the drug substance monographs of the European Pharmacopoeia,
  •  how to perform a risk assessment in order to establish a control strategy for elemental impurities,
  •  how the route of administration and the duration of exposure affect the limits of elemental impurities,
  •  which potential sources of Elemental Impurities within the supply chain you have to be aware of.

Background

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 III

In November 2014 the ICH Q3D Guideline for Elemental Impurities was published as Step 4 document. This document outlines
  •  the evaluation of the toxicity data for potential elemental impurities
  •  the PDEs for each element of toxicological concern
  •  the basis for an EI risk assessment and the key factors for evaluation.
  •  the development of controls designed to limit the inclusion of elemental impurities in drug products to levels at or below the PDE
Meanwhile ICH Q3D was revised twice, regarding Cadmium Inhalation PDE (ICH Q3D(R1); Step 2 document) and cutaneous and transdermal products (ICH Q3D(R2); Concept Paper)

Target Group

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. This event will also address regulatory requirements and hence is applicable to people working in the regulatory affairs area.

Programme

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
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
Part III
European Pharmacopoeia Activities (Policy) on Elemental Impurities – an Update
  • Implementation of Q3D in Ph. Eur.
  • Changes in individual and general monographs
  • Harmonisation of general chapter 2.4.20
  • Second phase for revision of excipient monographs
Risk-Based Approach for Elemental Impurities in the Supply Chain
  •  APIs, excipients, packaging materials impacting the purity profile
  •  Evaluation of supply chain processes
  •  Risk analysis as evaluation tool
  •  Audits- and monitoring programs as important sources
  •  Testing strategies
Control Strategies for Elemental Impurities in Final Dosage Forms – Case Studies
  •  Utilisation of Data as part of an Integrated EI Risk Assessment Process
  •  Potential Sources of Elemental Impurities in the Finished Product
    • API
    • Equipment
    • Container-closure system
    • Excipients
  •  Conclusions
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.

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