title: Progress toward forecasting product quality and quantity of mammalian cell culture processes by performance-based modeling.
abstract: The production of biopharmaceuticals requires highly sophisticated, complex cell based processes. Once a process has been developed, acceptable ranges for various control parameters are typically defined based on process characterization studies often comprising several dozens of small scale bioreactor cultivations. A lot of data is generated during these studies and usually only the information needed to define acceptable ranges is processed in more detail. Making use of the wealth of information contained in such data sets, we present here a methodology that uses performance data (such as metabolite profiles) to forecast the product quality and quantity of mammalian cell culture processes based on a toolbox of advanced statistical methods. With this performance based modeling (PBM) the final product concentration and 12 quality attributes (QAs) for two different biopharmaceutical products were predicted in daily intervals throughout the main stage process. The best forecast was achieved for product concentration in a very early phase of the process. Furthermore, some glycan isoforms were predicted with good accuracy several days before the bioreactor was harvested. Overall, PBM clearly demonstrated its capability of early process endpoint prediction by only using commonly available data, even though it was not possible to predict all QAs with the desired accuracy. Knowing the product quality prior to the harvest allows the manufacturer to take counter measures in case the forecasted quality or quantity deviates from what is expected. This would be a big step towards real-time release, an important element of the FDA's PAT initiative.
authors.affiliation: Sandoz GmbH, Biochemiestrasse 10, Langkampfen, 6336, Austria.
authors.forename: Timo
authors.initials: T
authors.lastname: Schmidberger
authors.affiliation: Sandoz GmbH, Biochemiestrasse 10, Langkampfen, 6336, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Posch
authors.affiliation: Sandoz GmbH, Biochemiestrasse 10, Langkampfen, 6336, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sasse
authors.affiliation: Sandoz GmbH, Biochemiestrasse 10, Langkampfen, 6336, Austria.
authors.forename: Carina
authors.initials: C
authors.lastname: Gülch
authors.affiliation: Dept. of Engineering and Management, University of Applied Sciences Munich, Lothstrasse 64, Munich, 80335, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
mesh_terms: D000818:Animals; D019149:Bioreactors; D016466:CHO Cells; D018929:Cell Culture Techniques / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D008239:Lysine / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D008962:Models, Theoretical; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D008239:Lysine; D008358:Mannose
keywords: CHO cell culture; bioprocess modeling; multivariate statistics; product quality forecast