Name: 3rd Annual Genotoxic Impurities in Pharmaceuticals Virtual Summit
Start: 2023-03-09T09:00
End: 2023-03-10T17:00
Location: ZOOM

Conference Overview

For the transformation of starting material into the product is needed API synthesis, which involves multiple reaction steps, including reagents, intermediates, catalysts, solvents and others. As a result, low levels of by-products may appear in API as impurities. This impurity may have toxicity, incl. carcinogenicity and genotoxicity, what may cause mutations, potentially leading to cancer. Due to this fact and focusing on ensuring safety of public health is critical to identify, monitor, analyse and control genotoxic impurities and strive to their minimum level. This has led to the crucial need in the development and improvement of analytical methods.

The Genotoxic Impurities in Pharmaceuticals Summit 2023 is focusing on overcoming challenges and barriers, sharing knowledge, strategies, best techniques and new methodologies in GTI predictions, analysis and control during the drug development process, overview and practical implementation of GTI guidelines and regulations (ICH M7 and ICH Q3D), risk assessment, exposure limits calculation and predictions' empowerment through in silico.

The featured talks on:

Analytical approaches to cover potentially harmful Impurities in drug formulations
Exploring the scale of potential nitrosamine risk associated with existing approved APIs
Development of a drug product workflow for nitrosamine risk assessments?
Quantitative analysis of in vivo mutagenicity dose-response data for risk assessment and regulatory decision-making: a case study of alkylnitrosamines.
Technologies for Optimising Performance, Minimising Risk and preparing for the Future in Trace Impurity Quantification
Setting Limits for Complex Nitrosamines (NDSRIs)
Incorporating Nitrosamine Risk Mitigation Activities Across a Diverse Development Portfolio
Inhibition of Nitrosamine Formation in Drug Products
Impact of different rat or hamster S9 fractions on the metabolic activation of low-molecular-weight N-nitrosamines – a comparative analysis
Analytical testing and control approaches for GTIs in drug substance
Case Studies of Nitrosamines in Pharmaceuticals
Recent updates on Nitrosamine Impurities by EMA & FDA
Enhancing nitrosamines analysis: a focus on complex nitrosamines (NDSRIs or NO-APIs)
How Sanofi scientists streamlined their in silico hazard assessment of potential genotoxic impurities by collaborating with Discngine
Development of in silico systems for expert review under ICH M7 guideline: increasing efficiency through automated arguments
Expert Review of In Silico Mutagenicity Predictions
Analytical Strategies for Enhancing Selectivity and Sensitivity of Genotoxic Impurities
A review of ongoing efforts to optimize the Ames assay by the HESI-GTTC Nitrosamine Mechanismbased Genotoxicity Risk Assessment (NA-MGRA) Subgroup
Applications of computational methods in the assessment of extractables and leachables

Who You Will Meet

By Seniority Level

C-Level, Presidents, Chairs, Members of the Board & VPs
Directors, & Heads
Leaders & Managers
Fellows, Principals & Scientists
Toxicologists & Chemists
Advisors, Coordinators, Auditors & Consultants
Other Professionals, Experts & Specialists

By Division

ADME
Analytical Chemistry
Analytical Development
Analytical R&D
Analytical Science
Analytical Science & Technology
Analytical Sciences
API
Biocompatibility
Chemical Toxicology
CMC
Compound Safety
Computational Toxicology
Data Sciences & Artificial Intelligence
Drug Development
Drug Safety
Drug Safety Research & Evaluation
Genetic Toxicology
Genetics & Mutagenesis
Genotoxicity
GMP
GTIs
Impurities
In Silico Toxicology
Metabolism
Mutagenicity
Pharmaceutical Sciences
Pharmacokinetics
Pharmacology
Pharmacovigilance
Process Chemistry
Process Development
QbD
Quality Assurance & Operations
Quality Control
Regulatory Affairs & Compliance
Research & Development
Risks Assessment
Small Molecules
Toxicology
Toxicology Discovery
Validation

By Company Type

Pharmaceuticals
Biotechnology
CRO
CMO
Technologies & software providers
Equipment providers
Regulatory agencies
NOP
Other

By Region

Central and Eastern Europe
North America
Middle East and Africa
Asia-Pacific
Other

Conference Programme

Day One - Thursday 09, March 2023

Tentative Schedule:

Central European Time (CET, Prague, UTC/GMT +1 hour)

10:00

10:40

11:10 To Be Announced

Dr. Andrew Teasdale,
Senior Principal Scientist / Head of Impurity Management & CMC Strategy, AstraZeneca, UK

11:50 Analytical approaches to cover potentially harmful Impurities in drug formulations

Despite the guidance about assessment of genotoxic impurities in ICH M7 there are still difficulties when it comes to analytical screening and characterization of such compounds.

Frequently, the interference of drug matrix components makes impurity analysis quite difficult. Moreover, in case of presence of substances of the cohort of concern the analytical limits are often extremely low and could hardly be reached with current methods or instruments.

In this presentation the following topics will be covered:

Sources and kind of potential impurities
General screening strategies to cover the risks
Case studies about characterization and quantification of impurities
Importance of structure elucidation
Special considerations for substances of cohort of concern not suitable for TTC approach

Dr. Tino Otte,
Senior Scientific Consultant, Intertek (Schweiz) AG, Basel-Landschaft, Switzerland

12:30 Exploring the scale of potential nitrosamine risk associated with existing approved APIs

Assessing the true scale of potential impact on pharmaceutical supply using existing drug databases
Identifying trends of nitrosamines that may theoretically form
Provide some context for ongoing activities relating to nitrosamines

Dr. Michael Burns,
Principal Research Scientist, Lhasa Limited, United Kingdom

13:10

13:30 Development of a Drug Product workflow for Nitrosamine Risk Assessments

Mike Urquhart,
Scientific Director, GlaxoSmithKline, Stevenage, United Kingdom

14:10 Quantitative analysis of in vivo mutagenicity dose-response data for risk assessment and regulatory decision-making: a case study of alkylnitrosamines

Nitrosamine impurities are detectable in some pharmaceutical products.
Risk assessment of nitrosamine impurities can be carried out using genetic toxicology data.
Benchmark dose metrics can be calculated from in vivo gene mutation data which are used to calculate permitted daily exposures (PDE).
A threshold mechanism’ must be defined before the PDE can be used.
Adjustment/uncertainty factors used in the PDE may differ when using genetic toxicity data compared to when using cancer bioassay data.

Dr. George Johnson,
Associate Professor in the Institute of Life Science, Swansea University, United Kingdom

14:50 Technologies for Optimising Performance, Minimising Risk and preparing for the Future in Trace Impurity Quantification

Quantification of GTIs can be challenging particularly when considering the complex and diverse matrices, combined with ever changing and extremely low limits of quantification. Continuing with the theme of evaluating risk, I am going to expand this to considering the risk to analytical integrity, presenting the methodologies developed to quantify genotoxic impurities including nitrosamines and boronic acids. I’ll discuss a systematic approach to quantitative method development, some of the analytical issues that can arise, and share some of the latest waters technologies that are used for low level quantification of GTIs and explain how their inclusion in the analytical workflow can help mitigate predicted and unforeseen analytical errors and issues.

Antonia Wierzbicki,
Principal Pharma Market Development Manager EMEA, Waters Corporation, UK

15:50

16:10 Setting Limits for Complex Nitrosamines (NDSRIs)

Differences between ICH M7 and nitrosamine guidances
Setting AIs for NDSRIs using SAR/read-across
Case studies - De-risking of NDSRIs of drug classes (Ca channel blockers, β-blockers, ACE inhibitors)

Raphael Nudelman, Ph.D., ERT,
Senior Director Impurity Expert, Teva Pharmaceutical Industries Ltd., Israel

16:50 To Be Announced

Mark Harrison,
Principal Analyst, AstraZeneca, Sheffield, United Kingdom

17:30 Panel Discussion:

The HAs timing on issuing an official Acceptable Daily Intake Limit AI or ADI Limit.
Interpretation on the interim limit proposed by eg EMA 178ng/day. Lack of acceptance HAs of the bacterial reverse mutation test / Ames test for mutagenicity.
Lack of guidance on alternatives like the Comet Assay or the In-vivo rodent Assay / transgenic rodent assay.
Use of in vivo mutagenicity testing for impurities and advances in technology.
The applicability of Ames testing for nitrosamines.
Best practices deriving SAR for Nitrosamine drug substance related impurities.
Use of in vivo mutagenicity testing to derive permitted daily exposures.
Learnings from confirmatory testing outcomes on NDSRIs (nitrosamine drug substance related impurities).
Current regulatory positions on NDSRIs.
Assigning limits for NDSRIs.
What does the future state of pharmaceuticals look like with regards to nitrosamines.

Lance Smallshaw,
Regulatory Intelligence and External Advocacy (Quality Analytical and Pharmacopoeia), UCB Biopharma sprl., BE

Olivier Dirat,
Senior Director, Pfizer, UK

Dr. Alexander Amberg,
Head of In Silico Toxicology, Sanofi Aventis Deutschland GmbH, DE

Dr. M. Vijay Reddy,
Senior Principal Scientist in the department of Genetic Toxicology, Merck & Co., Inc., USA

Dr. George Johnson,
Associate Professor in the Institute of Life Science, Swansea University, United Kingdom

Marina Couva,
QPPV, Medochemie Ltd, CY

Raphael Nudelman, Ph.D., ERT,
Senior Director Impurity Expert, Teva Pharmaceutical Industries Ltd., Israel

Dr. Joel Bercu PhD, MPH, DABT,
Sr. Director in the Nonclinical Safety and Pathobiology, Gilead Sciences, USA

18:10 Incorporating Nitrosamine Risk Mitigation Activities Across a Diverse Development Portfolio

Jared Fennell,
Senior Scientist, Eli Lilly and Company, Indiana, United States

18:50 Inhibition of Nitrosamine Formation in Drug Products

Steven Tignor,
Senior Scientist, Merck & Co., Inc., New York, USA

19:30

Day Two - Friday 10, March 2023

Tentative Schedule:

Central European Time (CET, Prague, UTC/GMT +1 hour)

09:20

09:30 Impact of different rat or hamster S9 fractions on the metabolic activation of low-molecular-weight N-nitrosamines – a comparative analysis

Compare metabolic activation of short-chain alkyl nitrosamines at various concentrations of rat or hamster-derived S9 fractions
Does the inducing agent (Aroclor vs phenobarbital/beta-naphthoflavone) play a role?
Comparative Cyp isoform protein expression analysis of various S9 fractions

Dr. Stephanie Simon, PhD,
Head, Genetic Toxicology, Merck Healthcare KGaA, DE

10:10 Analytical testing and control approaches for GTIs in drug substance

Tom van Wijk,
Principal Scientist, Analytical Science and Technology Team lead Pharmaceutical analysis, Abbott Healthcare Products B.V., Weesp, The Netherlands

10:50 To Be Announced

Jason Creasey,
Managing Director, Maven E&L Ltd, Stevenage, United Kingdom

11:30

11:50 Case Studies of Nitrosamines in Pharmaceuticals

NDMA in Metformin DP
Analytical challenges
Some NDSRI(s)

Dr. Joerg Schlingemann,
Director, Principal Expert Quality Control Systems, Merck Healthcare KGaA, DE

12:30 Recent updates on Nitrosamine Impurities by EMA & FDA

Background on Nitrosamine impurities
The updates introduced in FDA and EMA regulations
Risk assessment, Confirmatory Testing and Control Strategy
Regulatory considerations
New frontiers in techniques and technologies in Nitrosamine impurities quantification
Analytical methods development, validation, and testing – Practical challenges and suggested solutions
Walkthrough of compendial testing requirements
Uncertainties, misalignment, investigations, observations, and experiences related to nitrosamine impurities
How to write comprehensive risk assessment reports?

BM Rao, Ph.D,
VP & Head – Emerging Markets, Analytical Science & Technology & Corporate Quality control, Dr. Reddy’s Laboratories, India

13:10

13:30 Enhancing nitrosamines analysis: a focus on complex nitrosamines (NDSRIs or NO-APIs) - Part 1: General considerations and challenges

With more than 15 years’ experience on nitrosamine analysis, Mérieux NutriSciences enjoys sound experience in the implementation and validation of nitrosamine impurities target research methods with a special focus on NDSRIs / NO-APIs:

Nitrosamines global experience in the key industrial sectors and regulatory updates
Testing strategies and analytical challenges for QC & skip/waiving approaches

Sergio Fasan,
Business Director – Pharma, Healthcare & Cosmetics, Mérieux NutriSciences Italy, IT

13:50 Enhancing nitrosamines analysis: a focus on complex nitrosamines (NDSRIs or NO-APIs)

With more than 12 years’ experience on nitrosamine analysis, Mérieux NutriSciences’ Pharmaceutical and R&D Divisions enjoy sound experience in the implementation and validation of nitrosamine impurities target research methods with a special focus on NDSRIs / NO-APIs:

Nitrosamines global experience in the key industrial sectors and regulatory updates
Testing strategies and analytical challenges for QC & skip/waiving approaches
Analytical issues for the determination of specific NDSRIs / NO-APIs
Case studies

Emiliano De Dominicis,
Chemistry Research Director, Mérieux NutriSciences Italy, IT

14:30 How Sanofi scientists streamlined their in silico hazard assessment of potential genotoxic impurities by collaborating with Discngine

Streamlining of the hazard assessment process, leading to a 25% decrease in cycle time
Covering ICH M7 value chain from early research team to CMC follow-up activities
Tried and tested approach to delivering impurity management platforms from inception to maintenance

Sébastien Conilleau, PhD,
Customer Success and Delivery Manager, Discngine, FR

15:10 Development of in silico systems for expert review under ICH M7 guideline: increasing efficiency through automated arguments

Robert Foster,
Senior Scientist, Lhasa Limited, United Kingdom

15:50

16:10 Expert Review of In Silico Mutagenicity Predictions

Case studies demonstrating the different features of review
Discrepant in silico predictions and results
Assessment of misclassified, unclassified, and out of domain structures
Using chemistry rationales for supporting classifications
Confirming Ames test results when there are potential risks for false positives or false negatives

Alyssa Musso,
Senior Scientist, Drug Safety Research and Development, Global Risk Assessment Services Toxicologist, Pfizer, USA

16:50 Analytical Strategies for Enhancing Selectivity and Sensitivity of Genotoxic Impurities

C. J. Venkatramani,
Senior Principle Scientist, Genentech, USA

17:30 A review of ongoing efforts to optimize the Ames assay by the HESI-GTTC Nitrosamine Mechanism-based Genotoxicity Risk Assessment (NA-MGRA) Subgroup

Leon F. Stankowski,
Senior Scientific Director, Genetic and In Vitro Toxicology, Charles River Laboratories, Chicago, USA

18:10 Applications of computational methods in the assessment of extractables and leachables

Use of in silico approaches supporting the assessment of Extractables and Leachables (E&L)
Prevalence of predicted mutagens and potent sensitizers in large representative databases of E&L
Use of in silico models to assess leachable reactivity with biomolecules
Biomolecule reactivity in silico workflow

Dr. Candice Johnson,
Senior Research Scientist, Instem, Ohio, United States

18:50

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