title: Advancing biopharmaceutical process development by system-level data analysis and integration of omics data.
abstract: Development of efficient bioprocesses is essential for cost-effective manufacturing of recombinant therapeutic proteins. To achieve further process improvement and process rationalization comprehensive data analysis of both process data and phenotypic cell-level data is essential. Here, we present a framework for advanced bioprocess data analysis consisting of multivariate data analysis (MVDA), metabolic flux analysis (MFA), and pathway analysis for mapping of large-scale gene expression data sets. This data analysis platform was applied in a process development project with an IgG-producing Chinese hamster ovary (CHO) cell line in which the maximal product titer could be increased from about 5 to 8 g/L.Principal component analysis (PCA), k-means clustering, and partial least-squares (PLS) models were applied to analyze the macroscopic bioprocess data. MFA and gene expression analysis revealed intracellular information on the characteristics of high-performance cell cultivations. By MVDA, for example, correlations between several essential amino acids and the product concentration were observed. Also, a grouping into rather cell specific productivity-driven and process control-driven processes could be unraveled. By MFA, phenotypic characteristics in glycolysis, glutaminolysis, pentose phosphate pathway, citrate cycle, coupling of amino acid metabolism to citrate cycle, and in the energy yield could be identified. By gene expression analysis 247 deregulated metabolic genes were identified which are involved, inter alia, in amino acid metabolism, transport, and protein synthesis.
authors.affiliation: Department of Biopharmaceutical Process Science, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany, jochen.schaub@boehringer-ingelheim.com.
authors.forename: Jochen
authors.initials: J
authors.lastname: Schaub
authors.forename: Christoph
authors.initials: C
authors.lastname: Clemens
authors.forename: Hitto
authors.initials: H
authors.lastname: Kaufmann
authors.forename: Torsten W
authors.initials: TW
authors.lastname: Schulz
mesh_terms: D000818:Animals; D015870:Gene Expression; D023281:Genomics / Q000379:methods*; D064688:Metabolic Flux Analysis / Q000379:methods*; D015999:Multivariate Analysis; D025341:Principal Component Analysis / Q000379:methods; D040901:Proteomics / Q000379:methods*; D013223:Statistics as Topic / Q000379:methods*