title: Advanced process monitoring and feedback control to enhance cell culture process production and robustness.
abstract: It is a common practice in biotherapeutic manufacturing to define a fixed-volume feed strategy for nutrient feeds, based on historical cell demand. However, once the feed volumes are defined, they are inflexible to batch-to-batch variations in cell growth and physiology and can lead to inconsistent productivity and product quality. In an effort to control critical quality attributes and to apply process analytical technology (PAT), a fully automated cell culture feedback control system has been explored in three different applications. The first study illustrates that frequent monitoring and automatically controlling the complex feed based on a surrogate (glutamate) level improved protein production. More importantly, the resulting feed strategy was translated into a manufacturing-friendly manual feed strategy without impact on product quality. The second study demonstrates the improved process robustness of an automated feed strategy based on online bio-capacitance measurements for cell growth. In the third study, glucose and lactate concentrations were measured online and were used to automatically control the glucose feed, which in turn changed lactate metabolism. These studies suggest that the auto-feedback control system has the potential to significantly increase productivity and improve robustness in manufacturing, with the goal of ensuring process performance and product quality consistency.
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Research Triangle Park, 5000 Davis Drive, North Carolina, 27709. an.zhang@biogenidec.com.
authors.forename: An
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Research Triangle Park, 5000 Davis Drive, North Carolina, 27709.
authors.forename: Valerie Liu
authors.initials: VL
authors.lastname: Tsang
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Research Triangle Park, 5000 Davis Drive, North Carolina, 27709.
authors.forename: Brandon
authors.initials: B
authors.lastname: Moore
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Research Triangle Park, 5000 Davis Drive, North Carolina, 27709.
authors.forename: Vivian
authors.initials: V
authors.lastname: Shen
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Research Triangle Park, 5000 Davis Drive, North Carolina, 27709.
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Huang
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kshirsagar
authors.affiliation: Cell Culture Development, Biogen Idec, Inc., Cambridge, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ryll
mesh_terms: D000818:Animals; D019149:Bioreactors; D016466:CHO Cells / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation; D003412:Cricetulus; D003470:Culture Media / Q000737:chemistry; D005947:Glucose / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism
chemical_list: D003470:Culture Media; D019344:Lactic Acid; D005947:Glucose
keywords: Chinese hamster ovary (CHO) cell culture; auto-feedback control; capacitance; fed-batch; glucose/lactate control; human embryonic kidney (HEK) cell culture