Genotoxic Impurities in Pharmaceuticals Summit 2019

Tentative Schedule:

08:00 Registration and Welcome Coffee

08:30 Opening Address from the Chairman

08:40 ICH M7 and extractables & leachables: understanding control, analysis and regulations of E&L.

• What are extractables and leachables
• What are the similarities and differences between E and L and genotoxic impurities
• What are the regulations that are applicable, specifically M7

Andrew Feilden,
Director Analytical Sciences, Bicycle Therapeutics, Shawbury, United Kingdom

09:15 Speed Networking

09:55 Examples of use of ICH M7 in early and late drug development including pediatrics.

• ICH M7 in use for drugs along the development phase - specific examples
• ICH M7 use on the context of pediatric/rare disease development
• Group limits versus individual limits
• Differentiation between impurities and metabolites, any differences in the strategy of risk assessment?

Dr. Lutz Mueller,
Toxicology Project Leader – Distinguished Scientist, F. Hoffmann-La Roche Ltd., Basel, Switzerland

10:30 ICH Q3D: safety assessment of elemental impurities in topical drugs. The challange in defining the appropriate scenario of exposure.

• What are elemental impurities
• Establishing Permitted Daily Exposures for topical products
• Focus on the mucosal route
• Defining the appropriate scenario of exposures to set Analytical Limits
• Case studies will be presented

Carla Landolfi, ERT,
European Registered Toxicologist (ERT) R&D, Head of WEP Toxicology - Preclinical Development, Angelini, Pomezia, Italy

11:05 Morning coffee and networking break

11:35 Screening and control of genotoxic impurities – An analytical approach.

A variety of process materials and reactive compounds are involved in the synthesis of pharmaceutical products. As a consequence, residues of such compounds and related degradation products can later be found as drug impurities in API and final formulation Some of those impurities are known to be mutagenic with the potential to cause adverse effects on the human body even when only present at trace level concentrations.

The detection, quantification and evaluation of such impurities is important but can be very challenging since matrix effects often discriminate these compounds. In many cases the route of synthesis allows to predict potential impurities. However, in other cases unexpected genotoxic compounds may be an issue since predictability is limited due to complexity of processes and formulations.

In our presentation we highlight the analytical challenges and propose possible solutions:

• Sources for known and unknown genotoxic impurities
• Reasonable analytical control strategy
• General Screening - choosing the right techniques
• Structure elucidation and quantifications of GI in complex matrices
• Validation and routine monitoring

Case studies and examples

Dr. Stefan Heck,
Business Development Manager Pharma DACH, Intertek (Schweiz)AG, Freiburg, Germany

12:10 Characterization and quantitation of genotoxic impurities using a single platform. The Valsartan case.

To ensure patient safety, regulatory agencies have put in place guidelines which mandate the identification and profiling of impurities in APIs and formulated drug products and sets thresholds at which these impurities must be reported.

The Valsartan case, has shown the need for the implementation of the state of the art technology in the QC/QA laboratories. A creation of a fast, high throughput, robust, and reproducible analytical technology and method (e.g., LC-MS) is critical for increased confidence in impurity identification, detection, and quantification in pharma research to increase the safety of the end product. This critical information speeds drug candidate development from IND-enabling studies to NDA.

In our presentation we show how the combination of the speed, sensitivity and resolution on the latest QTOF technology can help to solve the questions related to the characterization and quantiation of impurities, with a system and solution that:

• Is able to support all workflows to be used in impurity analysis: from impurity profiling to quality control.
• Comes along with all Pharma QC requirements: 21 CFR Part 11 compliance, MS/MSALL SWATHTM, high-resolution mass accuracy, reproducibility and sensitivity to detect smallest traces of impurities.
• Works in a General Unknown Comparative Screening method easy-to-use, considered the ‘Gold-Standard’ workflow in Pharma quality control analysis. It shows significant strengths to monitor batch-to-batch production of active medicinal components.
• Includes Statistical analysis for either in-depth impurity analysis or to obtain information about the origin of active medicinal component.

Axel Besa,
Business Development Manager, SCIEX, Dortmund, Germany

12:45 Business lunch

13:50 ICH Q3D: elemental impurities- an insider’s perspective.

• How did the ICH process work for this quality guideline with a large safety component?
• How were the elements covered in the guideline selected?
• How was relevant literature selected?
• Do the PDE cover pediatric products?
• Can the PDE be exceeded?

Anja Slikkerveer, MD, PhD, ERT,
Scientific Director Translational Science, Astellas Pharma Europe BV, Hague, Netherlands

14:25 What to do if you need to do to propose a regulatory change to a ICH Q3D Elemental Impurity Control Threshold or PDE Limit.

• Examples of reports including toxicology assessment
• Typical data with revised limit calculations
• Example letter to the authorities to request the change

Lance Smallshaw BSc(Hons) PhD EurChem CSci CChem FRSC,
Regulatory Intelligence and External Advocacy (Quality Analytical and Pharmacopoeia), UCB Biopharma sprl., Wallonia, Belgium

15:00 Afternoon coffee and networking break

15:30 Strategies for assessment of impurities and E&Ls.

• Definitions of E&L and impurities
• Qualification thresholds
• Use of QSAR
• Role of API in assessment
• Experience with regulators on PQRI proposals

Prof. Dr. Johannes Harleman
Independent Consultant, , Darmstadt, Germany

16:05 Use of the Bacterial Reverse Mutation (Ames) Test to Evaluate Impurities.

• Background and application
• Case study
• Use of miniaturized Ames assays to assess potential genotoxic impurities
• Update on the OECD review of miniaturized bacterial mutagenicity assays

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

16:40 Challenges calculating compound-specific exposure limits.

• ICH M7 guideline status
• Key principles of the guideline
• Key publications and their impact
• Valsartan and beyond

Patricia Parris,
Project Toxicologist (RIA Safety), AstraZeneca, Royston, United Kingdom

17:15 Panel Discussion

17:40 Chairman’s closing remarks and end of day one

19:00 Business dinner