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08:55 09:00 (5 mins)

Main agenda

Chairperson's Opening Remarks

  • David Snodin - Principal, Xiphora Biopharma Consulting, UK

09:00 09:30 (30 mins)

Genotoxic Impurities

Teleconference: Control Options and role of in silico tools in managing risk

  • This will examine, through case study example the practical assessment of MI related risk
  • It will examine how in silico tools can be integrated into a risk assessment one aligned to the principles of both ICH M7 and ICH Q9 Quality risk management
  • The future development of such tools
  • Andrew Teasdale - Principal Scientist, Chair of Impurity Advisory Group, AstraZeneca, UK

09:30 10:00 (30 mins)

Genotoxic Impurities

Prediction of the purging power of a chemical process for genotoxic impurities using the MIRABILIS software

•Experiences when introducing the theoretical purging concept into a chemical development community

•Implementing MIRABILIS into the workflow

•How to integrate theoretical purge factors into an overall control strategy

•How to present the theoretical purge data in a dossier

  • Rolf Schulte Oestrich - Head of Solid State Sciences, F. Hoffmann-La Roche AG, Switzerland

10:00 10:30 (30 mins)

Genotoxic Impurities

Genotoxic Control Strategy for Drug Substance Synthesized using the Coupling Catalyst HOBt

  • Recently the synthetic route for HOBt was requested by the FDA during an IND filing.
  • HOBt is synthesized from hydrazine and 1-chloro-2-nitrobenzene, both of which are AMES positive.
  • This request had wider implications for both clinical and commercial products at BMS as HOBt is a commonly used coupling catalyst.
  • Implementation of a suitable genotoxic control strategy was required to ensure patient safety.
  • Andrew Marriott - Research Investigator, Bristol-Myers Squibb

10:20 11:05 (45 mins)

Main agenda

Morning Coffee and Networking

11:05 11:35 (30 mins)

Genotoxic Impurities

Considerations for the Development of a Robust Analytical Method for Routine Monitoring of Low Level Genotoxic Impurities

The control of genotoxic impurities is crucial for ensuring regulatory compliance, and with the implementation of the ICH M7 guidance for impurity assessment and control, it is more important than ever for drug manufacturers to employ effective strategies for dealing with toxic or mutagenic impurities.

Where there is a risk  that potential genotoxic impurities are likely to still be present in the final drug substance or drug product, then reliable, robust and sensitive methods are required for accurate determination. However, genotoxic impurities and degradants can present specific analytical challenges, for example, containing non-UV chromophores and a wide variety of ionizable groups, etc., which can make method development more challenging. Additionally, with the introduction of the recent M7 guidance and the more precise definition of acceptable intake limits, there may also be a need to achieve lower detection limits during routine testing.

In this work, we present the process of developing a robust, dual-detection UPLC method suitable for the routine testing of esters of benzenesulfonic and p-toluenesulfonic acids. The approach utilizes both UV and mass detection for fast and accurate monitoring and quantitation. The impact of different chromatographic parameters (columns, pHs and organic solvents) on the separation of the sample components will be evaluated and in addition to the chromatographic parameters, we will investigate different factors that can affect the quality of mass information and the sensitivity of the method. The selection of mobile phase, sample diluent and acquisition parameters to optimize the quality and sensitivity of the MS detector results will be discussed and the linearity, sensitivity and specificity of the method will be shown.

Using this approach, we show that the esters of benzenesulfonic and p-toluenesulfonic acids can be accurately measured in the 1.5 to 15 ng/mL range using mass detection, allowing significantly lower detection limits than those achievable using a PDA detector. The additional benefit of this approach is the ease with which methods can be transferred to routine testing labs required to monitor low level genotoxic impurities. This is a result of recent developments in technology and the wider acceptance of the need and benefits of modern technology for ensuring the quality of drug substance and drug product.

  • Stephanie Harden - Small Molecule Pharmaceutical Business Development Manager, Europe, Waters, Switzerland

11:35 12:05 (30 mins)

Genotoxic Impurities

Analytical Strategies for GTIs

  • Cadapakam (CJ) Venkatramani - Senior Scientist, Genentech

12:15 12:55 (40 mins)

Genotoxic Impurities

Round Table Discussion

Thought Leader’s Discussion: Innovation in Analytical Methods

This interactive discussion will allow participants to be guided through innovative and relevant analytical techniques for Genotoxic detection and prediction. 

  • Analytical Strategies 
  • Purge tools
  • Mirabilis software

  • Rolf Schulte Oestrich - Head of Solid State Sciences, F. Hoffmann-La Roche AG, Switzerland
  • Cadapakam (CJ) Venkatramani - Senior Scientist, Genentech
  • Andrew Marriott - Research Investigator, Bristol-Myers Squibb

12:45 14:00 (75 mins)

Main agenda

Lunch and Networking

14:00 14:30 (30 mins)

Genotoxic Impurities

Regulatory Best Practice

  • Overview on Regulatory Guidelines
  • Identification and characterization of genotoxic impurities
  • Relevance of genotoxic impurities in different medicinal products
  • Regulatory requirements to minimize the risk associated to the genotoxic impurities
  • Massimiliano Sarra - Preclinical and clinical assessor, AIFA Agenzia Italiana del farmaco

14:35 15:05 (30 mins)

Genotoxic Impurities

Strategies for assessing potential mutagenic degradation products

- Coverage of degradation products per ICH M7

- Predictive screening analysis

- The potential of semi-targeted approaches

  • Tom van Wijk - Senior Scientist, Analytical Science & Technology, Abbott Healthcare Products B.V., The Netherlands

15:10 15:40 (30 mins)

Genotoxic Impurities

Genotoxic impurities: a focus on the ICH M7 guideline.

The synthesis of drug substances involves the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids. As a result of chemical synthesis or subsequent degradation, impurities reside in all drug substances and associated drug products. This presentation will focus on the guidance for qualification and control for those impurities that are DNA reactive by working through ICH M7 guidance document in a step-wise approach.

  • Ian Waterson - Non-Clinical Assessor, MHRA, UK

15:40 16:10 (30 mins)

Main agenda

Afternoon Coffee

16:10 16:40 (30 mins)

Genotoxic Impurities

Development and future outlook of an in silico tool for reactivity-based purge prediction

In this talk, we would describe the development of the science within the Mirabilis software, its scope and limitations, and future outlook..

  • Michael Burns - Knowledge Scientist, Lhasa Limited

16:40 16:45 (5 mins)

Main agenda

Chairperson's Closing Remarks

  • David Snodin - Principal, Xiphora Biopharma Consulting, UK