Process analytical technology (PAT) tools for the cultivation step in biopharmaceutical production

The process analytical technology (PAT) initiative is now 10 years old. This has resulted in the development of many tools and software packages dedicated to PAT application on pharmaceutical processes. However, most applications are restricted to small molecule drugs, mainly for the relatively simple process steps like drying or tableting where only a limited number of parameters need to be controlled. A big challenge for PAT still lies in applications for biopharmaceuticals and then especially in the cultivation process step, where the quality of a biopharmaceutical product is largely determined. This review gives an overview of the currently available tools for monitoring and controlling the biopharmaceutical cultivation step and of the main challenges for the most common cell platforms (i.e. Escherichia coli, yeast, and mammalian cells) used in biopharmaceutical manufacturing. The real challenge is to understand how intracellular mechanisms (from synthesis to excretion) influence the quality of biopharmaceuticals and how these mechanisms can be monitored and controlled to yield the desired end product quality. Modern “omics” tools and advanced process analyzers have opened up the way for PAT applications for the biopharmaceutical cultivation process step.

[1]  Thomas A Kost,et al.  Baculovirus as versatile vectors for protein expression in insect and mammalian cells , 2005, Nature Biotechnology.

[2]  C. Clarke,et al.  Large scale microarray profiling and coexpression network analysis of CHO cells identifies transcriptional modules associated with growth and productivity. , 2011, Journal of biotechnology.

[3]  Thomas Ryll,et al.  Maximizing productivity of CHO cell‐based fed‐batch culture using chemically defined media conditions and typical manufacturing equipment , 2010, Biotechnology progress.

[4]  Thomas F. Edgar,et al.  Bio-reactor monitoring with multiway-PCA and Model Based-PCA , 2006 .

[5]  Urs von Stockar,et al.  On‐line biomass monitoring of CHO perfusion culture with scanning dielectric spectroscopy , 2003, Biotechnology and bioengineering.

[6]  H. Fukuhara.  The Kluyver effect revisited. , 2003, FEMS yeast research.

[7]  Gary Walsh.  Biopharmaceuticals : Approval Trends in 2007 , 2006 .

[8]  A. Bradbury,et al.  Antibodies in proteomics II: screening, high-throughput characterization and downstream applications. , 2003, Trends in biotechnology.

[9]  Roland Ulber,et al.  Optical sensor systems for bioprocess monitoring , 2003, Analytical and bioanalytical chemistry.

[10]  Anurag S Rathore,et al.  Large scale demonstration of a process analytical technology application in bioprocessing: Use of on‐line high performance liquid chromatography for making real time pooling decisions for process chromatography , 2009, Biotechnology progress.

[11]  C. Perry Chou,et al.  Engineering cell physiology to enhance recombinant protein production in Escherichia coli , 2007, Applied Microbiology and Biotechnology.

[12]  Kunal Aggarwal,et al.  Bioprocess optimization for cell culture based influenza vaccine production. , 2011, Vaccine.

[13]  H. Blanch,et al.  Recombinant Protein Expression in High Cell Density Fed-Batch Cultures of Escherichia Coli , 1992, Bio/Technology.

[14]  A. Demain,et al.  Production of recombinant proteins by microbes and higher organisms. , 2009, Biotechnology advances.

[15]  Leo A. van der Pol,et al.  Online automatic tuning and control for fed-batch cultivation , 2007, Bioprocess and biosystems engineering.

[16]  Donhee Ham,et al.  Chip–NMR biosensor for detection and molecular analysis of cells , 2008, Nature Medicine.

[17]  Florian M. Wurm,et al.  Recombinant protein production by large-scale transient gene expression in mammalian cells: state of the art and future perspectives , 2007, Biotechnology Letters.

[18]  A. Dickson,et al.  Phenotypic variation during cloning procedures: Analysis of the growth behavior of clonal cell lines , 2006, Biotechnology and bioengineering.

[19]  Zizhuo Xing,et al.  Scale‐up analysis for a CHO cell culture process in large‐scale bioreactors , 2009, Biotechnology and bioengineering.

[20]  S. Enfors,et al.  Modeling of Overflow Metabolism in Batch and Fed‐Batch Cultures of Escherichiacoli , 1999, Biotechnology progress.

[21]  Olivier van Noortlaan.  Physiological and technological aspects of large-scale heterologous-protein production with yeasts , 1995 .

[22]  G. Walsh.  Biopharmaceuticals : Approvals and addroval trends in 2004 , 2005 .

[23]  T. Jakobi,et al.  Unraveling the Chinese hamster ovary cell line transcriptome by next-generation sequencing. , 2011, Journal of biotechnology.

[24]  J Baranyi,et al.  The effect of inoculum size on the lag phase of Listeria monocytogenes. , 2001, International journal of food microbiology.

[25]  Nigel Jenkins,et al.  Post-translational Modifications of Recombinant Proteins: Significance for Biopharmaceuticals , 2008, Molecular biotechnology.

[26]  A. Heck,et al.  Unbiased Selective Isolation of Protein N-terminal Peptides from Complex Proteome Samples Using Phospho Tagging (PTAG) and TiO2-based Depletion* , 2012, Molecular & Cellular Proteomics.

[27]  Jarka Glassey,et al.  An assessment of seed quality and its influence on productivity estimation in an industrial antibiotic fermentation. , 2002, Biotechnology and bioengineering.

[28]  Reiner Luttmann,et al.  Applications of PAT‐Process Analytical Technology in Recombinant Protein Processes with Escherichia coli , 2008 .

[29]  Anurag S Rathore,et al.  Roadmap for implementation of quality by design (QbD) for biotechnology products. , 2009, Trends in biotechnology.

[30]  Johannes Tramper,et al.  Modeling Neisseria meningitidis metabolism: from genome to metabolic fluxes , 2007, Genome Biology.

[31]  R. Werner,et al.  Glycosylation of therapeutic proteins in different production systems , 2007, Acta paediatrica.

[32]  Jack T. Pronk,et al.  Kinetics of growth and sugar consumption in yeasts , 2004, Antonie van Leeuwenhoek.

[33]  J. Goergen,et al.  Intracellular nucleotide and nucleotide sugar contents of cultured CHO cells determined by a fast, sensitive, and high-resolution ion-pair RP-HPLC. , 2006, Analytical biochemistry.

[34]  Anurag S Rathore,et al.  Chemometrics applications in biotech processes: A review , 2011, Biotechnology progress.

[35]  C. Hewitt,et al.  Use of multi-staining flow cytometry to characterise the physiological state of Escherichia coli W3110 in high cell density fed-batch cultures. , 1999, Biotechnology and bioengineering.

[36]  Klaus Graumann,et al.  Manufacturing of recombinant therapeutic proteins in microbial systems , 2006, Biotechnology journal.

[37]  B M Mackey,et al.  The effect of the growth environment on the lag phase of Listeria monocytogenes. , 1998, International journal of food microbiology.

[38]  Mohamed Al-Rubeai,et al.  Selection methods for high-producing mammalian cell lines. , 2007, Trends in biotechnology.

[39]  Guangxing Li,et al.  Select what you need: a comparative evaluation of the advantages and limitations of frequently used expression systems for foreign genes. , 2007, Journal of biotechnology.

[40]  S. Wildt,et al.  The humanization of N-glycosylation pathways in yeast , 2005, Nature Reviews Microbiology.

[41]  S. Makrides.  Strategies for achieving high-level expression of genes in Escherichia coli , 1996 .

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

[43]  A. Nienow.  Reactor Engineering in Large Scale Animal Cell Culture , 2006, Cytotechnology.

[44]  Anurag S Rathore,et al.  Case study and application of process analytical technology (PAT) towards bioprocessing: Use of tryptophan fluorescence as at‐line tool for making pooling decisions for process chromatography , 2009, Biotechnology progress.

[45]  Timothy J Griffin,et al.  Advancing mammalian cell culture engineering using genome-scale technologies. , 2007, Trends in biotechnology.

[46]  Gary Walsh,et al.  Biopharmaceutical benchmarks 2006 , 2006, Nature Biotechnology.

[47]  J. Pronk,et al.  Physiological and technological aspects of large-scale heterologous-protein production with yeasts , 2004, Antonie van Leeuwenhoek.

[48]  Alisa Rudnitskaya,et al.  Sensor systems, electronic tongues and electronic noses, for the monitoring of biotechnological processes , 2008, Journal of Industrial Microbiology & Biotechnology.

[49]  Rui Oliveira,et al.  Hybrid elementary flux analysis/nonparametric modeling: application for bioprocess control , 2007, BMC Bioinformatics.

[50]  Johannes Tramper,et al.  Gene‐expression‐based quality scores indicate optimal harvest point in Bordetella pertussis cultivation for vaccine production , 2009, Biotechnology and bioengineering.

[51]  Ana Patricia Ferreira,et al.  PAT within the QbD Framework: Real-Time End Point Detection for Powder Blends in a Compliant Environment , 2012, Journal of Pharmaceutical Innovation.

[52]  M. Toft,et al.  A practical approach for exploration and modeling of the design space of a bacterial vaccine cultivation process , 2009, Biotechnology and bioengineering.

[53]  T. Jakobi,et al.  Next-generation sequencing of the CHO cell transcriptome , 2011, BMC proceedings.

[54]  M. Butler,et al.  Optimisation of the Cellular Metabolism of Glycosylation for Recombinant Proteins Produced by Mammalian Cell Systems , 2006, Cytotechnology.

[55]  Mangesh D. Kapadi,et al.  Optimal control of fed-batch fermentation involving multiple feeds using Differential Evolution , 2004 .

[56]  A. Pugsley.  The complete general secretory pathway in gram-negative bacteria. , 1993, Microbiological reviews.

[57]  R. Steel,et al.  Dissolved oxygen measurements in pilot‐ and production‐scale novobiocin fermentations , 1966 .

[58]  Gary Walsh,et al.  Biopharmaceutical benchmarks 2010 , 2010, Nature Biotechnology.

[59]  Johannes Tramper,et al.  PAT for vaccines: the first stage of PAT implementation for development of a well-defined whole-cell vaccine against whooping cough disease. , 2007, Vaccine.

[60]  Mihaela Sbarciog,et al.  Accelerating animal cell growth in perfusion mode by multivariable control: simulation studies , 2013, Bioprocess and Biosystems Engineering.

[61]  D. Kirwan,et al.  Correlation of Fermentation Yield with Yeast Extract Composition as Characterized by Near‐Infrared Spectroscopy , 1998, Biotechnology progress.

[62]  Mathieu Streefland,et al.  Manufacturing Vaccines: An Illustration of Using PAT Tools for Controlling the Cultivation of Bordetella pertussis , 2007 .

[63]  Anurag S Rathore,et al.  Case study and application of process analytical technology (PAT) towards bioprocessing: II. Use of ultra-performance liquid chromatography (UPLC) for making real-time pooling decisions for process chromatography. , 2008, Biotechnology and bioengineering.

[64]  M. Radmacher,et al.  pH Regulates Genes for Flagellar Motility, Catabolism, and Oxidative Stress in Escherichia coli K-12 , 2005, Journal of bacteriology.

[65]  Patrick Hossler,et al.  Protein glycosylation control in mammalian cell culture: past precedents and contemporary prospects. , 2012, Advances in biochemical engineering/biotechnology.

[66]  Gerrit van Straten,et al.  Assessment of near infrared and “software sensor” for biomass monitoring and control , 2008 .

[67]  Wei-Shou Hu,et al.  Transcriptional Response of Escherichia coli to Temperature Shift , 2008, Biotechnology progress.

[68]  Z. Soons,et al.  Constant specific growth rate in fed-batch cultivation of Bordetella pertussis using adaptive control. , 2006, Journal of biotechnology.

[69]  A. Rathore,et al.  Quality by design for biopharmaceuticals , 2009, Nature Biotechnology.

[70]  L. Quek,et al.  Flux balance analysis of CHO cells before and after a metabolic switch from lactate production to consumption. , 2013, Biotechnology and bioengineering.

[71]  Ian W. Marison,et al.  Biocalorimetry as a process analytical technology process analyser; robust in-line monitoring and control of aerobic fed-batch cultures of crabtree-negative yeast cells , 2011 .

[72]  S Gnoth,et al.  Process Analytical Technology (PAT): batch-to-batch reproducibility of fermentation processes by robust process operational design and control. , 2007, Journal of biotechnology.

[73]  Johannes Tramper,et al.  Evaluation of a critical process parameter: Oxygen limitation during cultivation has a fully reversible effect on gene expression of Bordetella pertussis , 2009, Biotechnology and bioengineering.

[74]  Effects of high passage cultivation on CHO cells: a global analysis , 2012, Applied Microbiology and Biotechnology.

[75]  Gary Walsh,et al.  Biopharmaceutical benchmarks—2003 , 2003, Nature Biotechnology.

[76]  C. Hewitt,et al.  The use of multi-parameter flow cytometry to compare the physiological response of Escherichia coli W3110 to glucose limitation during batch, fed-batch and continuous culture cultivations. , 1999, Journal of Biotechnology.

[77]  Beatrix Fahnert,et al.  Inclusion bodies: formation and utilisation. , 2004, Advances in biochemical engineering/biotechnology.

[78]  M H Zwietering,et al.  Comparison of definitions of the lag phase and the exponential phase in bacterial growth. , 1992, The Journal of applied bacteriology.

[79]  A S Rathore,et al.  Use of computational fluid dynamics as a tool for establishing process design space for mixing in a bioreactor , 2012, Biotechnology progress.

[80]  Anurag S Rathore,et al.  Case study and application of process analytical technology (PAT) towards bioprocessing: Use of on‐line high‐performance liquid chromatography (HPLC) for making real‐time pooling decisions for process chromatography , 2008, Biotechnology and bioengineering.

[81]  R. Greasham,et al.  Chemically defined media for commercial fermentations , 1999, Applied Microbiology and Biotechnology.

[82]  M. Thalen,et al.  Improving the cellular pertussis vaccine: increased potency and consistency. , 2008, Vaccine.

[83]  Friedrich Srienc,et al.  Mammalian cell culture scale-up and fed-batch control using automated flow cytometry. , 2008, Journal of biotechnology.

[84]  Gary Walsh,et al.  Post-translational modifications in the context of therapeutic proteins , 2006, Nature Biotechnology.