The number and use of automated cell culture systems for mammalian cell culture are steadily increasing. Automated cell culture systems require miniaturized analytics with a high throughput to obtain as much information as possible from single experiments. Standard analytics commonly used for conventional bioreactor samples cannot handle the high throughput and the low sample volumes. Spectroscopic methods provide a means of meeting this analytical requirement and afford fast and direct access to process information. In the first part of this review, UV/VIS, fluorescence, Raman, near-infrared, and mid-infrared spectroscopy are presented. In the second part of the review, these spectroscopic methods are evaluated in terms of their applicability in the new field of mammalian cell culture processes in automated cell culture systems. Unlike standard bioreactors, these automated systems have special requirements that apply to the use of spectroscopic methods. Therefore, they are compared with regard to cell culture automation, throughput, and required sample volume.

Recently, we established an automated microtiter plate (MTP)‐based system for suspension cell culture for high‐throughput (HT) applications in biopharmaceutical process development. In the present report, the new system was evaluated regarding its potential to improve clone screening by allowing high‐throughput fed‐batch cultivation at an early stage. For this purpose, a fully automated procedure was compared to a mainly batch mode‐based manual standard process. The new system performed daily measurements of viable cell density and product concentration for a total of 96 clones in biological duplicates that were evaluated for final clone selection. This resulted in a more than fivefold increase in sample throughput and 4 weeks of time saving compared to the reference process. The top clone characterized by the highest cell specific productivity was identified only by the new process. In contrast, this clone was lost in the expansion phase of the reference procedure. Overall, the new system identified more high‐productive clones, offering more alternatives and flexibility for process development. In‐process monitoring of glucose and lactate levels representing crucial secondary selection criteria further enhanced top clone identification. Clone characterization at an early stage was further extended by linking the MTP‐based cell culture system to additional HT‐analytic systems for N‐glycosylation analysis as well as gene expression analysis by reverse transcriptase‐quantitative polymerase chain reaction. These powerful tools connected to the automated MTP‐based cell culture system lead to considerably advanced quality and speed of clone screening, and increase the probability of selecting the most suitable clone. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 35: e2760, 2019.

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