Integration of QSAR models with high throughput screening to accelerate the development of polishing chromatography unit operations

IF 3.8 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS Journal of Chromatography A Pub Date : 2025-02-25 DOI:10.1016/j.chroma.2025.465818
Michael Hartmann , Michael Rauscher , Julie Robinson , John Welsh , David Roush
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Abstract

The development of robust polishing chromatographic processes is a critical step in downstream bioprocess development that can be time-consuming and resource intensive. Recently, there has been an increase in diverse protein constructs that are not amenable to platform approaches, increasing the need for novel processes to be developed for effective purification. High throughput screening (HTS) is an important tool to parse chromatographic design space and identify promising conditions to continue development. Despite its utility, HTS capabilities are challenged by tight development timelines, material scarcity, and an increasingly complex pipeline of biotherapeutics. Predictive modeling can augment HTS by leveraging historical screening data to rapidly explore and prioritize process design space, effectively expanding the range of conditions considered without the need for additional experimental screening. Here we present the development of a quantitative structure activity relationship (QSAR) model, trained from internal HTS data, that predicts protein partitioning as a function of resin and mobile phase conditions. The training dataset contains a diverse collection of screening data and has more than 8000 datapoints, covering 29 therapeutic proteins and 44 resins. The model encodes partitioning by building descriptors of the mobile phase, parameters that describe the resin, and biophysical properties of the protein. Overall, the regression model has an R2=0.92 and shows 95% and 93% classification accuracy for predicting elution and strong binding conditions, respectively. Here, we highlight the model predictiveness and describe how in silico screening can be used as a first step in the HTS workflow to reduce design space and accelerate process development.
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来源期刊
Journal of Chromatography A
Journal of Chromatography A 化学-分析化学
CiteScore
7.90
自引率
14.60%
发文量
742
审稿时长
45 days
期刊介绍: The Journal of Chromatography A provides a forum for the publication of original research and critical reviews on all aspects of fundamental and applied separation science. The scope of the journal includes chromatography and related techniques, electromigration techniques (e.g. electrophoresis, electrochromatography), hyphenated and other multi-dimensional techniques, sample preparation, and detection methods such as mass spectrometry. Contributions consist mainly of research papers dealing with the theory of separation methods, instrumental developments and analytical and preparative applications of general interest.
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