Model-Based Design of Process Strategies for Cell Culture Bioprocesses: State of the Art and New Perspectives

Production processes for biopharmaceuticals with mammalian cells have to provide a nearly optimal environment to promote cell growth and product formation. Design and operation of a bioreactor are complex tasks, not only with respect to reactor configuration and size but also with respect to the mode of operation. New concepts for the design and layout of process strategies are required to meet regulatory demands and to guarantee efficient, safe, and reproducible biopharmaceutical production. Key elements are critical process parameters (CPPs), which affect critical quality attributes (CQAs), quality by design (QbD), process analytical tools (PAT), and design of experiment (DoE). In this chapter, some fundamentals including process and control strategies as well as concepts for process development are discussed. Examples for novel model-based concepts for the design of experiments to identify suitable fed-batch-feeding strategies are shown.

[1]  W. Chen,et al.  Automated fed-batch fermentation with feed-back controls based on dissolved oxygen (DO) and pH for production of DNA vaccines , 1997, Journal of Industrial Microbiology and Biotechnology.

[2]  Ralf Pörtner,et al.  Model-based DoE for feed batch cultivation of a CHO cell line , 2015, BMC Proceedings.

[3]  Andrew M Goetze,et al.  Assessing monoclonal antibody product quality attribute criticality through clinical studies , 2010, mAbs.

[4]  Mihai Caramihai,et al.  Bioprocess Modeling and Control , 2013 .

[5]  M. Farcet,et al.  Virus susceptibility of Chinese hamster ovary (CHO) cells and detection of viral contaminations by adventitious agent testing , 2010, Biotechnology and bioengineering.

[6]  J. Reichert,et al.  Development trends for human monoclonal antibody therapeutics , 2010, Nature Reviews Drug Discovery.

[7]  Wei-Shou Hu,et al.  Fedbatch culture and dynamic nutrient feeding. , 2006, Advances in biochemical engineering/biotechnology.

[8]  R. Pörtner,et al.  Improving an on-line feeding strategy for fed-batch cultures of hybridoma cells by dialysis and `Nutrient-Split'-feeding , 1999 .

[9]  J. Fekete,et al.  Establishing column batch repeatability according to Quality by Design (QbD) principles using modeling software. , 2015, Journal of pharmaceutical and biomedical analysis.

[10]  Brandon Berry,et al.  Cross‐scale predictive modeling of CHO cell culture growth and metabolites using Raman spectroscopy and multivariate analysis , 2015, Biotechnology progress.

[11]  Anika Ashok,et al.  ICH Harmonised Tripartite Guideline , 2009 .

[12]  Brian Glennon,et al.  Revisiting Verhulst and Monod models: analysis of batch and fed-batch cultures , 2015, Cytotechnology.

[13]  Margaret J. Robertson,et al.  Design and Analysis of Experiments , 2006, Handbook of statistics.

[14]  M. Matovic.  Biomass Now - Sustainable Growth and Use , 2013 .

[15]  Suzanne S Farid,et al.  Fed‐batch and perfusion culture processes: Economic, environmental, and operational feasibility under uncertainty , 2013, Biotechnology and bioengineering.

[16]  Athanassios Sambanis,et al.  Modeling of cell culture processes , 2004, Cytotechnology.

[17]  Ralf Pörtner,et al.  Cell and Tissue Reaction Engineering , 2008 .

[18]  Leonard A. Smith,et al.  Developement of serum-free media in CHO-DG44 cells using a central composite statistical design , 2007, Cytotechnology.

[19]  J. Box.  R.A. Fisher and the Design of Experiments, 1922–1926 , 1980 .

[20]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[21]  K. Dubey,et al.  Statistical optimization of process variables for the production of an anticancer drug (colchicine derivatives) through fermentation: at scale-up level. , 2011, New biotechnology.

[22]  Bilal M. Ayyub,et al.  Probability, Statistics, and Reliability for Engineers and Scientists , 2003 .

[23]  Barry Lennox,et al.  The development of an industrial-scale fed-batch fermentation simulation. , 2015, Journal of biotechnology.

[24]  M. Rodrigues,et al.  Response surface analysis and simulation as a tool for bioprocess design and optimization , 2000 .

[25]  Volker C. Hass,et al.  Advanced Process and Control Strategies for Bioreactors , 2017 .

[26]  Chun Chen,et al.  Integration of systems biology in cell line and process development for biopharmaceutical manufacturing , 2016 .

[27]  P. Gonzalez-Alegre,et al.  Towards precision medicine , 2017 .

[28]  Udo Reichl,et al.  How can measurement, monitoring, modeling and control advance cell culture in industrial biotechnology? , 2012, Biotechnology journal.

[29]  M. Kendall.  Statistical Methods for Research Workers , 1937, Nature.

[30]  Mitchell Tai,et al.  Efficient high‐throughput biological process characterization: Definitive screening design with the Ambr250 bioreactor system , 2015, Biotechnology progress.

[31]  Ralf Pörtner,et al.  DoE of fed-batch processes – model-based design and experimental evaluation , 2011, BMC proceedings.

[32]  Xinwei Deng,et al.  Experimental design , 2012, WIREs Data Mining Knowl. Discov..

[33]  Weiming Ke,et al.  Probability, Statistics, and Reliability for Engineers and Scientists , 2008, Technometrics.

[34]  Nilay Shah,et al.  Development and design of bio-pharmaceutical processes , 2013 .

[35]  Michael W Laird,et al.  Characterization of a Monoclonal Antibody Cell Culture Production Process Using a Quality by Design Approach , 2010, Molecular biotechnology.

[36]  Cleo Kontoravdi,et al.  Integration of models and experimentation to optimise the production of potential biotherapeutics. , 2013, Drug discovery today.

[37]  Wei-Shou Hu,et al.  Cell culture technology for pharmaceutical and cell-based therapies , 2005 .

[38]  Dana Barrasso,et al.  Population Balance Model Development, Validation, and Prediction of CQAs of a High-Shear Wet Granulation Process: Towards QbD in Drug Product Pharmaceutical Manufacturing , 2014, Journal of Pharmaceutical Innovation.

[39]  Ralf Pörtner,et al.  Evaluation of selected control strategies for fed‐batch cultures of a hybridoma cell line , 2004, Biotechnology and applied biochemistry.

[40]  Martin Gawlitzek,et al.  Identification of cell culture conditions to control N‐glycosylation site‐occupancy of recombinant glycoproteins expressed in CHO cells , 2009, Biotechnology and bioengineering.

[41]  B. Efron.  Forcing a sequential experiment to be balanced , 1971 .

[42]  G. Box,et al.  On the Experimental Attainment of Optimum Conditions , 1951 .

[43]  Katie F Wlaschin,et al.  Recombinant protein therapeutics from CHO cells : 20 years and counting , 2007 .

[44]  Z. Li,et al.  Optimal and consistent protein glycosylation in mammalian cell culture. , 2009, Glycobiology.

[45]  T. Schäfer,et al.  Modelling hybridoma cell growth and metabolism--a comparison of selected models and data. , 1996, Journal of biotechnology.

[46]  Carl-Fredrik Mandenius,et al.  Bioprocess optimization using design‐of‐experiments methodology , 2008, Biotechnology progress.

[47]  Reiner Luttmann,et al.  Designing a fully automated multi‐bioreactor plant for fast DoE optimization of pharmaceutical protein production , 2013, Biotechnology journal.

[48]  Daniel Ibraim Pires Atala,et al.  Factorial design and simulation for the optimization and determination of control structures for an extractive alcoholic fermentation , 2001 .

[49]  Johannes G Khinast,et al.  An integrated Quality by Design (QbD) approach towards design space definition of a blending unit operation by Discrete Element Method (DEM) simulation. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[50]  Gary Walsh,et al.  Biopharmaceutical benchmarks , 2000, Nature Biotechnology.

[51]  R. Fisher,et al.  STUDIES IN CROP VARIATION , 2009 .

[52]  Brian Glennon,et al.  Modelling of Mammalian Cell Cultures , 2015 .

[53]  Brian Glennon,et al.  Process model comparison and transferability across bioreactor scales and modes of operation for a mammalian cell bioprocess , 2013, Biotechnology progress.

[54]  Anurag S Rathore,et al.  Process development in the QbD paradigm: Role of process integration in process optimization for production of biotherapeutics , 2016, Biotechnology progress.

[55]  Mark J. Anderson,et al.  RSM Simplified: Optimizing Processes Using Response Surface Methods for Design of Experiments, Second Edition , 2004 .

[56]  Kelvin H. Lee,et al.  The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line , 2011, Nature Biotechnology.

[57]  Rory A. Fisher,et al.  The Arrangement of Field Experiments , 1992 .

[58]  Gary Walsh,et al.  Biopharmaceutical benchmarks 2014 , 2014, Nature Biotechnology.

[59]  R. W. Hansen,et al.  Journal of Health Economics , 2016 .