TY - JOUR
T1 - Multivariate analysis of cell culture bioprocess data—Lactate consumption as process indicator
AU - Le, Huong
AU - Kabbur, Santosh
AU - Pollastrini, Luciano
AU - Sun, Ziran
AU - Mills, Keri
AU - Johnson, Kevin
AU - Karypis, George
AU - Hu, Wei Shou
PY - 2012/12/31
Y1 - 2012/12/31
N2 - Multivariate analysis of cell culture bioprocess data has the potential of unveiling hidden process characteristics and providing new insights into factors affecting process performance. This study investigated the time-series data of 134 process parameters acquired throughout the inoculum train and the production bioreactors of 243 runs at the Genentech's Vacaville manufacturing facility. Two multivariate methods, kernel-based support vector regression (SVR) and partial least square regression (PLSR), were used to predict the final antibody concentration and the final lactate concentration. Both product titer and the final lactate level were shown to be predicted accurately when data from the early stages of the production scale were employed. Using only process data from the inoculum train, the prediction accuracy of the final process outcome was lower; the results nevertheless suggested that the history of the culture may exert significant influence on the final process outcome. The parameters contributing most significantly to the prediction accuracy were related to lactate metabolism and cell viability in both the production scale and the inoculum train. Lactate consumption, which occurred rather independently of the residual glucose and lactate concentrations, was shown to be a prominent factor in determining the final outcome of production-scale cultures. The results suggest possible opportunities to intervene in metabolism, steering it towards the type with a strong propensity towards high productivity. Such intervention could occur in the inoculum stage or in the early stage of the production-scale reactors. Overall, this study presents pattern recognition as an important process analytical technology (PAT). Furthermore, the high correlation between lactate consumption and high productivity can provide a guide to apply quality by design (QbD) principles to enhance process robustness.
AB - Multivariate analysis of cell culture bioprocess data has the potential of unveiling hidden process characteristics and providing new insights into factors affecting process performance. This study investigated the time-series data of 134 process parameters acquired throughout the inoculum train and the production bioreactors of 243 runs at the Genentech's Vacaville manufacturing facility. Two multivariate methods, kernel-based support vector regression (SVR) and partial least square regression (PLSR), were used to predict the final antibody concentration and the final lactate concentration. Both product titer and the final lactate level were shown to be predicted accurately when data from the early stages of the production scale were employed. Using only process data from the inoculum train, the prediction accuracy of the final process outcome was lower; the results nevertheless suggested that the history of the culture may exert significant influence on the final process outcome. The parameters contributing most significantly to the prediction accuracy were related to lactate metabolism and cell viability in both the production scale and the inoculum train. Lactate consumption, which occurred rather independently of the residual glucose and lactate concentrations, was shown to be a prominent factor in determining the final outcome of production-scale cultures. The results suggest possible opportunities to intervene in metabolism, steering it towards the type with a strong propensity towards high productivity. Such intervention could occur in the inoculum stage or in the early stage of the production-scale reactors. Overall, this study presents pattern recognition as an important process analytical technology (PAT). Furthermore, the high correlation between lactate consumption and high productivity can provide a guide to apply quality by design (QbD) principles to enhance process robustness.
KW - Bioprocess data mining
KW - Cell culture
KW - Chinese hamster ovary (CHO) cells
KW - Lactate consumption
KW - Multivariate data analysis
KW - Partial least square regression
KW - Support vector regression
UR - http://www.scopus.com/inward/record.url?scp=84868481008&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868481008&partnerID=8YFLogxK
U2 - 10.1016/j.jbiotec.2012.08.021
DO - 10.1016/j.jbiotec.2012.08.021
M3 - Article
C2 - 22974585
AN - SCOPUS:84868481008
VL - 162
SP - 210
EP - 223
JO - Journal of Biotechnology
JF - Journal of Biotechnology
SN - 0168-1656
IS - 2-3
ER -