Impurities Workshop Part II and III
Im Auftrag der ECA Academy

2/3 December 2020

Heidelberg, Germany

Seminar Nr. 17868

Unser Seminarservice

Kosten

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

Alle Preise zzgl. MwSt.

Zur Anmeldung

Rückfragen unter:
Tel.: 06221 / 84 44 0 E-Mail: info@concept-heidelberg.de

Sprecher

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

Zielsetzung

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.

Hintergrund

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)

Zielgruppe

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.

Programm

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