title: Toward intensifying design of experiments in upstream bioprocess development: An industrial Escherichia coli feasibility study.
abstract: In this study, step variations in temperature, pH, and carbon substrate feeding rate were performed within five high cell density Escherichia coli fermentations to assess whether intraexperiment step changes, can principally be used to exploit the process operation space in a design of experiment manner. A dynamic process modeling approach was adopted to determine parameter interactions. A bioreactor model was integrated with an artificial neural network that describes biomass and product formation rates as function of varied fed-batch fermentation conditions for heterologous protein production. A model reliability measure was introduced to assess in which process region the model can be expected to predict process states accurately. It was found that the model could accurately predict process states of multiple fermentations performed at fixed conditions within the determined validity domain. The results suggest that intraexperimental variations of process conditions could be used to reduce the number of experiments by a factor, which in limit would be equivalent to the number of intraexperimental variations per experiment. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1343-1352, 2016.
authors.affiliation: CEAM, Faculty of Science, Agriculture and Engineering, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK. moritz.von-stosch@ncl.ac.uk.|REQUIMTE/DQ, Faculty of Science and Technology, University Nova De Lisboa, Campus De Caparica, Caparica, 2829-516, Portugal. moritz.von-stosch@ncl.ac.uk.
authors.forename: Moritz
authors.initials: M
authors.lastname: von Stosch
authors.affiliation: GSK Vaccines, Laval, Canada.|Lallemand Inc., Montreal, Canada.
authors.forename: Jan-Martijn
authors.initials: JM
authors.lastname: Hamelink
authors.affiliation: REQUIMTE/DQ, Faculty of Science and Technology, University Nova De Lisboa, Campus De Caparica, Caparica, 2829-516, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Oliveira
mesh_terms: D019149:Bioreactors; D004926:Escherichia coli / Q000166:cytology / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000096:biosynthesis*; D005240:Feasibility Studies; D005285:Fermentation; D007221:Industry; D008954:Models, Biological
chemical_list: D029968:Escherichia coli Proteins
keywords: PAT; QbD; dynamic excitations; hybrid modeling; intensified design of experiments; upstream bioprocess development/optimization