The use of in silico prediction systems has become an essential part of regulatory submissions when assessing the genotoxic potential of chemicals. Guidelines such as those from the EMA, US FDA, and ICH highlight their importance. Most notably, the ICH M7 guidance explicitly requires the application of two complementary quantitative/qualitative structure-activity relationship ((Q)SAR) systems to evaluate the DNA-reactive (mutagenic) potential of pharmaceutical impurities. To complement our expert-based knowledge tool, Derek Nexus, we launched Sarah Nexus in 2013—a statistical prediction tool designed to facilitate ICH M7 assessments. In this blog, we’ll address some of the most frequently asked questions about Sarah Nexus.
1. What is Sarah Nexus?
Sarah Nexus is an in silico statistical tool developed by Lhasa Limited. Sarah Nexus predicts mutagenicity and chromosome damage using fragment-based structural hypotheses derived from a statistically learned self-organising hypothesis network (SOHN). These predictions are based on bacterial reverse mutation, chromosome aberration, and micronucleus assay data, making Sarah Nexus a robust solution for mutagenicity and genotoxicity assessment.
2. How does Sarah Nexus work?
Sarah Nexus employs a SOHN model to statistically analyse structural fragments associated with mutagenicity. By leveraging large datasets, the tool identifies patterns and generates reliable predictions for both mutagenicity and chromosome damage in vitro.
3. What’s the difference between Derek Nexus and Sarah Nexus?
Derek Nexus is an expert rule-based system, while Sarah Nexus uses a statistical approach. Together, they complement each other, providing a full ICH M7 classification to meet the computational toxicological assessment requirements of the ICH M7 guidelines.
4. How can Sarah Nexus help meet ICH M7?
Sarah Nexus, in conjunction with Derek Nexus, fulfils the requirements of ICH M7 to use two (Q)SAR models with complementary methodologies for the prediction of potentially mutagenic impurities. Multiple features of Sarah Nexus are designed to support expert review of predictions as required by the ICH M7 guidelines for assessing the mutagenic potential of impurities. For example, Sarah Nexus includes a heat map feature that indicates which strains have been tested for a compound. This makes it easy to verify whether testing aligns with the five strains recommended by OECD TG 471 or those most likely to detect activity, facilitating compliance with ICH M7 guidelines.
5. What endpoints does Sarah Nexus predict for?
Sarah Nexus makes an overall qualitative prediction for:
- Mutagenicity: A mutagenicity prediction is provided alongside a confidence score to assess mutagenic risk.
- Chromosome damage: As of September 2024, an additional Sarah Nexus model predicts in vitro chromosome damage, including all chromosomal aberrations, based on data from chromosome aberration and micronucleus assays.
6. What data does Sarah Nexus use?
Sarah Nexus is trained using a large data set of bacterial reverse mutation data, in vitro chromosome aberration and micronucleus assay data from public sources. The structures in the dataset are standardised according to a protocol developed by Lhasa Limited to ensure consistency and reliability.
7. Does Sarah Nexus have a training set?
Yes, Sarah Nexus provides access to a comprehensive training set. This is achieved through the exposure of relevant chemical structures in predictions, offering transparency and insight into the decision-making process.
With Sarah Model Building, you can take this a step further, creating tailored Sarah models to meet your specific needs. By incorporating your own data, you can build and export custom models, enhancing prediction accuracy and aligning assessments with your unique requirements.
8. How does Sarah Nexus support genotoxic impurity evaluation?
The chromosome damage model available in Sarah Nexus streamlines candidate screening by identifying high-risk candidates early in the development process. This reduces reliance on costly and time-intensive in vitro or in vivo testing. Additionally, as regulatory bodies increasingly emphasise in silico predictions for pesticide metabolites and impurities, Sarah Nexus becomes a valuable tool for compliance and innovation.
9. How accurate is Sarah Nexus?
Sarah Nexus has undergone extensive external validation using proprietary datasets. In this key publication, Sarah Nexus version 1.1 was evaluated against private datasets provided by nine leading pharmaceutical companies. The evaluation revealed strong performance metrics, particularly in specificity, coverage and balanced accuracy.
10. Are there QMRFs available for Sarah Nexus?
Yes, there are mutagenicity and chromosome damage Quantitative Model Reporting Formats (QMRFs) available for Sarah Nexus, these can be located within the software help centre. Mutagenicity QMRFs are available for versions 2.0 to 4.0, and chromosome damage QMRFs are available starting from version 4.0.
For more information on how Sarah Nexus can support your organisation, get in touch via our contact us page.
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Last Updated on December 10, 2024 by lhasalimited
