Dr. Andrew Teasdale
Astra Zeneca
Referent:innen
Dr Ulrich Rose
Straßburg
Dr. Karel Haesevoets
Nelson Labs
Dr. Xaver Schratt
GBA Pharma
Dr Gerd Jilge
Formerly Boehringer Ingelheim
Dr Cornelia Nopitsch-Mai
formerly Quality Assessor
Dr. Reinhard Stidl
Safetree Consulting
All times mentioned are CET
Zielsetzung
Part I of the Impurities Forum will provide an opportunity to reinforce and expand your knowledge of the general area of impurities in chemical entities from initial development to the market with emphasis on
- Detection, profiling and control of impurities in drug substances, intermediates and drug products
- Important monographs and chapters in Ph. Eur. for control of impurities
- Practical aspects of method validation for impurities Determination
- Analytical techniques used for detecting and qualifying impurities
- Extractables and Leachables as a source of impurities
- Approaches for investigation and determination of unexpected impurities
This Live Online Training is designed to provide a comprehensive review of impurities analysis and characterisation in drug substances and drug products and their recording and reporting.
In Part II of the Impurities Forum 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, you will be informed about the European Pharmacopoeia activities on Nitrosamines and other mutagenic impurities.
Hintergrund
Part I
Setting specifications for impurities are one of the most critical topics in the development of new drug products. Impurities analysis in drug substances and drug products and their recording and reporting is quite often a challenge for the scientific experts in routine production and quality control. This challenge is even bigger when profiles of unknown impurities in complex matrices have to be established. The Valsartan case made clear the importance of a thorough process understanding.
Part II
Mutagenic substances as impurities in drug substances or drug products are of big concern as they have the potential to alter or damage human DNA. Among these species Nitrosamines and elemental impurities have triggered various regulatory activities and initiatives. Since September 2019, Marketing Authorisation Holders are requested to evaluate the risk of the presence of Nitrosamine impurities in human medicinal products containing chemically synthesised APIs. In case of a contamination with Nitrosamines, MAHs are requested to file a variation application. The deadline for submission of variations has been extended once again and needs to be filed within 2023.The ICH Q3D Guideline for Elemental Impurities was published as Step 4 document and has meanwhile been revised twice, regarding Cadmium Inhalation PDE and cutaneous and transdermal products.
Zielgruppe
The Live Online Training 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 Live Online Training will also address regulatory requirements and hence is applicable to people working in the Regulatory Affairs area.
Technical Requirements
We use WebEx for our live online training courses and webinars. At https://www.gmp-compliance.org/training/online-training-technical-information you will find all the information you need to participate in our trainings and you can check if your system meets the necessary requirements to participate. If the installation of browser extensions is not possible due to your rights in the IT system, please contact your IT department. WebEx is a standard nowadays and the necessary installation is fast and easy.
Programm
Gesamtes Programm als PDF herunterladen
Part 1
Impurities Analysis and Qualification of Impurities in Drug Substances and Drug Products – General Overview
- Impurity profiling in synthetic drug substances
- Qualification of impurities
- Degradation studies
- Identification of chiral impurities, polymorphic phases and new impurities
- Residual solvents
- Impurities in starting materials and intermediates
- Pharmacopoeial tests and acceptance criteria
- Drug product specifications and parametric release
Control of Impurities in Ph.Eur.
- Which impurities are controlled?
- General texts/monographs/ICH Guidelines
- Organic impurities in Ph. Eur.
- Specification Setting
- Validation
- Elemental impurities
Analytical Method Validation for Impurities
Determination at Various Development Stages
Determination at Various Development Stages
- Quantification of impurities
- How to define an impurity profile (stress tests)
- Reference substances
- Validation of methods at various development stages
- Statistical approaches to method validation (LOD & LOQ)
Presentation and Workshop: Analytical Techniques for Determination and Qualification of Impurities in Starting Materials and Intermediates
Applying an example of an API synthesis the participants will learn in the Workshop which activities are necessary to characterize drug substances taking into account the following aspects:
Applying an example of an API synthesis the participants will learn in the Workshop which activities are necessary to characterize drug substances taking into account the following aspects:
- Analytical procedures are necessary for the characterization
- Experiments necessary to check the downstream impurities in order to justify acceptance criteria for the respective impurities
- Other impurities have to be taken into account
- Experiments to be performed in order to get a stability-indicating analytical procedure
Extractables and Leachables – What is Expected from Packaging Materials for Drug Products?
- Why should Extractables & Leachables be assessed?
- Regulatory requirements and guidelines in the EU and US and pitfalls
- General flow and critical aspects of Extractables & Leachables studies
- Safety qualification of Extractables and Leachables
How to Avoid Unexpected Impurities: Approaches to Establish a Holistic Understanding of Impurity Risks
- Is there such a thing as ‘unexpected impurities” or is there a lack of process understanding?
- Valsartan – overview of Events
- Source of contamination
- Mechanistic understanding
- Examination of risk within other Sartans – overview of how to conduct a risk assessment and to identify key factors
- Are there other mutagenic impurities related risks?
Part 2
European Pharmacopoeia Activities on Nitrosamines and other Mutagenic Impurities
- 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
Safety Qualification of Impurities - Current Principles and Methods
- General approaches and regulatory framework for impurity qualification by safety threshold Derivation
- Generic and substance specific safety thresholds
- Threshold of Toxicological Concern (TTC) - different Scenarios
- Derivation of Permitted Daily Exposure (PDE) Limits
- Acceptable exposure calculations based on TD50 and their limitations
- Approaches for data poor substances: (Q)SARs and read-across
- Route-to-route considerations for safety thresholds
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 mutagenic residual solvents
- Impurities derived from metal catalysts
Workshop: Conducting a Nitrosamine 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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This course is part of the GMP Certification Programme "ECA Certified Quality Control Manager"
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