3rd Annual Genotoxic Impurities in Pharmaceuticals Virtual Summit 2023

Tentative Schedule:

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

10:00 Registration

10:20 Opening Address

10:30 The Need for a Non-targeted Screening Approach to Nitrosamine Analysis

• A look at the issues customers are reporting with the current targeted approach to nitrosamine testing.
• Time consuming due to the number of different samples and sample types.
• Costly due to equipment and resources needed.
• Concerns that not all nitrosamines present are being detected, only the specific ones targeted.
• An overview of the TEA detector and Total nitrosamine analysis
• Performance of the latest versions of the automated total nitrosamine analyser.
• How the system can also be used to screen for nitrating agents

Jonathan Angove,
Senior Applications chemist, Ellutia Limited, United Kingdom

11:10 N Nitrosamines – Complex – API like N Nitrosamines – current realities and threats

• Brief outline of the evolution of issue of N Nitrosamines
• Why the current challenges are very different and more significant than original challenges.
• the shift from synthesis risk to formulation risk.
• Current challenges
• Defining acceptable intakes – a process or roulette?
• Status of the Ames test / other options
• Controlling levels of API like Nitrosamines – we can shift the bar but not move a mountain – the harsh realities
• Analytical challenges – technical risks and capacity
• The near future – the choices and implications for all concerned

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,
Managing Director, 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 Coffee break

13:30 Management of N-Nitrosamines and their risk assessment within GSK R&D

• Nitrosamine risk factors and how to assess products for their presence
• Steps to take if an N-nitrosamine is detected
• Approaches to take for N-nitrosamine remediation within drug products
• Implementation of a pre-clinical N-nitrosamine risk assessment workflow and associated mitigation activities

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 Coffee break

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 Nitrosamines 2.0: The challenge and impact of nitrosamine trace analysis across the pharmaceutical industry

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

• Nitrosamine formation in drug products can be mitigated through the use of inhibitors
• Formulation processing can significantly impact the efficiency of inhibitors in OSDs
• Understanding the benefits and limitations of model compounds used in the solid state

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

19:30 Closing remarks and end of day one