The Impurities Forum Part I and II - Live Online Training
9/10 November 2023
Course No. 20646
Speakers
Dr. Ulrich Rose
Straßburg
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
Objectives
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.
Background
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.
Target Group
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
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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
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:
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.
This course is part of the GMP Certification Programme "ECA Certified Quality Control Manager" Learn more
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Seminar Programme as PDF