Intelligent process development — An in-line Raman-assisted automatic cell culture process development platform

In the competitive biopharmaceutical industry, rapid cell culture process development is crucial for establishing a high-yield bioprocess. Traditional clone selection and process optimization methods are laborious and time-consuming due to multiple iterative rounds. To enhance efficiency, real-time metabolite monitoring and parameter control are vital. We propose an intelligent process development (IPD) platform utilizing Raman spectroscopy-based process analytical technology (PAT) for real-time monitoring and feedback control. The IPD platform automates optimization, incorporating a cell-specific growth rate (μ)-based temperature downshifting strategy and a dynamic feeding approach. Compared to traditional fed-batch (TFB), the IPD strategy increased the clone's titer by 44% (1490 vs. 1034 mg/L). To meet large-scale manufacturing demands, we adapted the Raman-based IPD process into a TFB process with comparable titer, compatible with facilities lacking PAT or automation. This approach was validated with an alternative clone, demonstrating the IPD's ability to enhance productivity through a single automated round, accelerating development.