Advanced Development Strategies for Biopharmaceutical Cell Culture Processes

Abstract

The shift from empirical to science-based process development is considered to be a key factor to increase bioprocess performance and to reduce time to market for biopharmaceutical products in the near future. In the last decade, expanding knowledge in systems biology and bioprocess technology has delivered the foundation of the scientific understanding of relationships between process input parameters and process output features. Based on this knowledge, advanced process development approaches can be applied to maximize process performance and to generate process understanding. This review focuses on tools which enable the integration of physiological knowledge into cell culture process development. As a structured approach, the availability and the proposed benefit of the application of these tools are discussed for the subsequent stages of process development. The ultimate aim is to deliver a comprehensive overview of the current role of physiological understanding during cell culture process development from clone selection to the scale-up of advanced control strategies for ensuring process robustness.

Workflow for Target‐Oriented Parametrization of an Enhanced Mechanistic Cell Culture Model

“…Glutamine uptake or its influence on cell growth are generally modeled Monod-like in the literature, [7,8,43] which was also assumed for this model (Eq. [5]). Frequently, a glutamine maintenance term is Table 1.…”

“…The complexity of mechanistic bioprocess models ranges from very detailed models (structured models) describing intracellular mechanisms to rather coarse descriptions of the underlying mechanisms (unstructured or macroscopic models) . For mammalian cell culture macroscopic mechanistic models are becoming increasingly popular, e.g., for model based optimal bioprocess development, evaluation of scale up effects, or optimal bioprocess control . These cells (especially Chinese Hamster Ovary (CHO) cells) are frequently cultivated for the production of valuable therapeutic products like monoclonal antibodies .…”

Closed loop control of lactate concentration in mammalian cell culture by Raman spectroscopy leads to improved cell density, viability, and biopharmaceutical protein production

“…Mammalian cell culture is a key technique for the manufacturing of therapeutic proteins which depend on post‐translational modifications for efficacy (Ivarsson et al, ; Ozturk and Hu, ). Culture productivity remains a bottleneck in the production of many therapeutic proteins, and increasing productivity has been the subject of numerous efforts (Dietmair et al, ; Farrell et al, ; Huang et al, ; Lu et al, ; Zalai et al, ). A key limitation of many mammalian cell culture processes is the accumulation of secreted lactate (Lao and Toth, ; Omasa et al, ).…”

Combining mechanistic and data‐driven approaches to gain process knowledge on the control of the metabolic shift to lactate uptake in a fed‐batch CHO process

“…In the last decades, significant efforts have been made to increase the productivity and robustness of cell culture processes, enabling the accumulation of an extensive knowledge on interactions between process control features, cell physiology and product formation. 1 Thereby, the investigation of cell metabolism has become a key method in bioprocess characterization and optimization. 2 Metabolomic analysis is essential to identify shifts in cell physiology typically occurring during industrial fed-batch cultivations and to adapt pro-cess control to the metabolic phenotype.…”