title: Online optimal experimental re-design in robotic parallel fed-batch cultivation facilities.
abstract: We present an integrated framework for the online optimal experimental re-design applied to parallel nonlinear dynamic processes that aims to precisely estimate the parameter set of macro kinetic growth models with minimal experimental effort. This provides a systematic solution for rapid validation of a specific model to new strains, mutants, or products. In biosciences, this is especially important as model identification is a long and laborious process which is continuing to limit the use of mathematical modeling in this field. The strength of this approach is demonstrated by fitting a macro-kinetic differential equation model for Escherichia coli fed-batch processes after 6 h of cultivation. The system includes two fully-automated liquid handling robots; one containing eight mini-bioreactors and another used for automated at-line analyses, which allows for the immediate use of the available data in the modeling environment. As a result, the experiment can be continually re-designed while the cultivations are running using the information generated by periodical parameter estimations. The advantages of an online re-computation of the optimal experiment are proven by a 50-fold lower average coefficient of variation on the parameter estimates compared to the sequential method (4.83% instead of 235.86%). The success obtained in such a complex system is a further step towards a more efficient computer aided bioprocess development. Biotechnol. Bioeng. 2017;114: 610-619. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: M N
authors.initials: MN
authors.lastname: Cruz Bournazou
authors.affiliation: Department of Energy, Austrian Institute of Technology GmbH, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Barz
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: D B
authors.initials: DB
authors.lastname: Nickel
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: D C
authors.initials: DC
authors.lastname: Lopez Cárdenas
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Glauche
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Knepper
authors.affiliation: Chair of Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, Berlin, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Neubauer
mesh_terms: D061249:Batch Cell Culture Techniques / Q000295:instrumentation* / Q000379:methods*; D019149:Bioreactors; D004926:Escherichia coli / Q000378:metabolism; D057166:High-Throughput Screening Assays; D007700:Kinetics; D012107:Research Design; D012371:Robotics / Q000295:instrumentation*
keywords: E. colli; High Throughput Bioprocess Development; Parameter Estimation; fed-batch process; macro-kinetic growth model; online Optimal Experimental re-design; parallel mini bioreactors