Taking the pulse of bioprocesses: at-line and in-line monitoring of mammalian cell cultures

Real-time and near real-time monitoring of cell culture processes are critical to the evolving process analytical technology (PAT) paradigm for upstream bioprocessing. The responses measured from these analytical instruments can enable rapid feedback to perturbations that can otherwise lead to batch failures. Historically, real-time monitoring of bioreactor processes has been relegated to parameters such as pH, dissolved oxygen, and temperature. Other analytical results, such as cell growth and metabolites, are provided through manual daily sampling. In order to reduce sample error and increase throughput, real-time and near real-time instruments have been developed. Here we discuss recent advances in these technologies. This article aims to focus on other developing at-line and in-line technologies that enable monitoring of bioreactor processes, including dielectric spectroscopy, NIR, off-gas spectrometry, integrated at-line HPLC, and nanofluidic devices for monitoring cell growth and health, metabolites, titer, and product quality.