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Cell Culture Engineering


Cell Culture Engineering

Recombinant Protein Production
Advanced Biotechnology 1. Aufl.

von: Gyun Min Lee, Helene Faustrup Kildegaard, Sang Yup Lee, Jens Nielsen, Gregory Stephanopoulos

133,99 €

Verlag: Wiley-VCH
Format: PDF
Veröffentl.: 10.09.2019
ISBN/EAN: 9783527811380
Sprache: englisch
Anzahl Seiten: 440

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Beschreibungen

Offers a comprehensive overview of cell culture engineering, providing insight into cell engineering, systems biology approaches and processing technology <br> <br> In Cell Culture Engineering: Recombinant Protein Production, editors Gyun Min Lee and Helene Faustrup Kildegaard assemble top class authors to present expert coverage of topics such as: cell line development for therapeutic protein production; development of a transient gene expression upstream platform; and CHO synthetic biology. They provide readers with everything they need to know about enhancing product and bioprocess attributes using genome-scale models of CHO metabolism; omics data and mammalian systems biotechnology; perfusion culture; and much more. <br> <br> This all-new, up-to-date reference covers all of the important aspects of cell culture engineering, including cell engineering, system biology approaches, and processing technology. It describes the challenges in cell line development and cell engineering, e.g. via gene editing tools like CRISPR/Cas9 and with the aim to engineer glycosylation patterns. Furthermore, it gives an overview about synthetic biology approaches applied to cell culture engineering and elaborates the use of CHO cells as common cell line for protein production. In addition, the book discusses the most important aspects of production processes, including cell culture media, batch, fed-batch, and perfusion processes as well as process analytical technology, quality by design, and scale down models. <br> <br> <br> -Covers key elements of cell culture engineering applied to the production of recombinant proteins for therapeutic use <br> -Focuses on mammalian and animal cells to help highlight synthetic and systems biology approaches to cell culture engineering, exemplified by the widely used CHO cell line <br> -Part of the renowned "Advanced Biotechnology" book series <br> <br> Cell Culture Engineering: Recombinant Protein Production will appeal to biotechnologists, bioengineers, life scientists, chemical engineers, and PhD students in the life sciences. <br>
<p>About the Series Editors xvii</p> <p><b>1 Platform Technology for Therapeutic Protein Production </b><b>1<br /> </b><i>Tae Kwang Ha, Jae Seong Lee, and Gyun Min Lee</i></p> <p>1.1 Introduction 1</p> <p>1.2 Overall Trend Analysis 3</p> <p>1.2.1 Mammalian Cell Lines 3</p> <p>1.2.2 Brief Introduction of Advances and Techniques 5</p> <p>1.3 General Guidelines for Recombinant Cell Line Development 6</p> <p>1.3.1 Host Selection 6</p> <p>1.3.2 Expression Vector 7</p> <p>1.3.3 Transfection/Selection 7</p> <p>1.3.4 Clone Selection 8</p> <p>1.3.4.1 Primary Parameters During Clone Selection 8</p> <p>1.3.4.2 Clone Screening Technologies 9</p> <p>1.4 Process Development 9</p> <p>1.4.1 Media Development 10</p> <p>1.4.2 Culture Environment 10</p> <p>1.4.3 Culture Mode (Operation) 10</p> <p>1.4.4 Scale-up and Single-Use Bioreactor 11</p> <p>1.4.5 Quality Analysis 12</p> <p>1.5 Downstream Process Development 12</p> <p>1.5.1 Purification 12</p> <p>1.5.2 Quality by Design (QbD) 13</p> <p>1.6 Trends in Platform Technology Development 14</p> <p>1.6.1 Rational Strategies for Cell Line and Process Development 14</p> <p>1.6.2 Hybrid Culture Mode and Continuous System 15</p> <p>1.6.3 Recombinant Human Cell Line Development for Therapeutic Protein Production 16</p> <p>1.7 Conclusion 17</p> <p>Acknowledgment 17</p> <p>Conflict of Interest 17</p> <p>References 17</p> <p><b>2 Cell Line Development for Therapeutic Protein Production </b><b>23<br /> </b><i>Soo Min Noh, Seunghyeon Shin, and Gyun Min Lee</i></p> <p>2.1 Introduction 23</p> <p>2.2 Mammalian Host Cell Lines for Therapeutic Protein Production 25</p> <p>2.2.1 CHO Cell Lines 25</p> <p>2.2.2 Human Cell Lines 26</p> <p>2.2.3 Other Mammalian Cell Lines 27</p> <p>2.3 Development of Recombinant CHO Cell Lines 27</p> <p>2.3.1 Expression Systems for CHO Cells 28</p> <p>2.3.2 Cell Line Development Process Using CHO Cells Based on Random Integration 28</p> <p>2.3.2.1 Vector Construction 29</p> <p>2.3.2.2 Transfection and Selection 30</p> <p>2.3.2.3 Gene Amplification 30</p> <p>2.3.2.4 Clone Selection 31</p> <p>2.3.3 Cell Line Development Process Using CHO Cells Based on Site-Specific Integration 32</p> <p>2.4 Development of Recombinant Human Cell Lines 34</p> <p>2.4.1 Necessity for Human Cell Lines 34</p> <p>2.4.2 Stable Cell Line Development Process Using Human Cell Lines 35</p> <p>2.5 Important Consideration for Cell Line Development 36</p> <p>2.5.1 Clonality 36</p> <p>2.5.2 Stability 36</p> <p>2.5.3 Quality of Therapeutic Proteins 37</p> <p>2.6 Conclusion 38</p> <p>References 38</p> <p><b>3 Transient Gene Expression-Based Protein Production in Recombinant Mammalian Cells </b><b>49<br /> </b><i>Joo-Hyoung Lee, Henning G. Hansen, Sun-Hye Park, Jong-Ho Park, and Yeon-Gu Kim</i></p> <p>3.1 Introduction 49</p> <p>3.2 Gene Delivery: Transient Transfection Methods 50</p> <p>3.2.1 Calcium Phosphate-Based Transient Transfection 50</p> <p>3.2.2 Electroporation 51</p> <p>3.2.3 Polyethylenimine-Based Transient Transfection 52</p> <p>3.2.4 Liposome-Based Transient Transfection 52</p> <p>3.3 Expression Vectors 53</p> <p>3.3.1 Expression Vector Composition and Preparation 53</p> <p>3.3.2 Episomal Replication 53</p> <p>3.3.3 Coexpression Strategies 54</p> <p>3.4 Mammalian Cell Lines 54</p> <p>3.4.1 HEK293 Cell-Based TGE Platforms 55</p> <p>3.4.2 CHO Cell-Based TGE Platforms 56</p> <p>3.4.3 TGE Platforms Using Other Cell Lines 58</p> <p>3.5 Cell Culture Strategies 58</p> <p>3.5.1 Culture Media for TGE 58</p> <p>3.5.2 Optimization of Cell Culture Processes for TGE 59</p> <p>3.5.3 <i>q</i><sub>p</sub>-Enhancing Factors in TGE-Based Culture Processes 59</p> <p>3.5.4 Culture Longevity-Enhancing Factors in TGE-Based Culture Processes 59</p> <p>3.6 Large-Scale TGE-Based Protein Production 60</p> <p>3.7 Concluding Remarks 62</p> <p>References 62</p> <p><b>4 Enhancing Product and Bioprocess Attributes Using Genome-Scale Models of CHO Metabolism </b><b>73<br /> </b><i>Shangzhong Li, Anne Richelle, and Nathan E. Lewis</i></p> <p>4.1 Introduction <i>73</i></p> <p>4.1.1 Cell Line Optimization <i>73</i></p> <p>4.1.2 CHO Genome <i>75</i></p> <p>4.1.2.1 Development of Genomic Resources of CHO <i>75</i></p> <p>4.1.2.2 Development of Transcriptomics and Proteomics Resources of CHO <i>75</i></p> <p>4.2 Genome-Scale Metabolic Model 76</p> <p>4.2.1 What Is a Genome-Scale Metabolic Model 76</p> <p>4.2.2 Reconstruction of GEMs 77</p> <p>4.2.2.1 Knowledge-Based Construction 77</p> <p>4.2.2.2 Draft Reconstruction 77</p> <p>4.2.2.3 Curation of the Reconstruction 77</p> <p>4.2.2.4 Conversion to a Computational Format 79</p> <p>4.2.2.5 Model Validation and Evaluation 79</p> <p>4.3 GEM Application 80</p> <p>4.3.1 Common Usage and Prediction Capacities of Genome-Scale Models 82</p> <p>4.3.2 GEMs as a Platform for Omics Data Integration, Linking Genotype to Phenotype 83</p> <p>4.3.3 Predicting Nutrient Consumption and Controlling Phenotype 84</p> <p>4.3.4 Enhancing Protein Production and Bioprocesses 85</p> <p>4.3.5 Case Studies 86</p> <p>4.4 Conclusion 86</p> <p>Acknowledgments 88</p> <p>References 88</p> <p><b>5 Genome Variation, the Epigenome and Cellular Phenotypes </b><b>97<br /> </b><i>Martina Baumann, Gerald Klanert, Sabine Vcelar,Marcus Weinguny, Nicolas Marx, and Nicole Borth</i></p> <p>5.1 Phenotypic Instability in the Context of Mammalian Production Cell Lines 97</p> <p>5.2 Genomic Instability 99</p> <p>5.3 Epigenetics 101</p> <p>5.3.1 DNA Methylation 102</p> <p>5.3.2 Histone Modifications 102</p> <p>5.3.3 Downstream Effectors 104</p> <p>5.3.4 Noncoding RNAs 104</p> <p>5.4 Control of CHO Cell Phenotype by the Epigenome 105</p> <p>5.5 Manipulating the Epigenome 107</p> <p>5.5.1 Global Epigenetic Modification 107</p> <p>5.5.1.1 Manipulating Global DNA Methylation 107</p> <p>5.5.1.2 Manipulating Global Histone Acetylation 108</p> <p>5.5.2 Targeted Epigenetic Modification 109</p> <p>5.5.2.1 Targeted Histone Modification 110</p> <p>5.5.2.2 Targeted DNA Methylation 112</p> <p>5.6 Conclusion and Outlook 113</p> <p>References 114</p> <p><b>6 Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes </b><b>127<br /> </b><i>Calmels Cyrielle, Chintan Joshi, Nathan E. Lewis, Malphettes Laetitia, and Mikael R. Andersen</i></p> <p>6.1 Introduction 127</p> <p>6.1.1 Constraint-Based Models 127</p> <p>6.1.2 Limitations of Flux Balance Analysis 131</p> <p>6.1.2.1 Thermodynamically Infeasible Cycles 131</p> <p>6.1.2.2 Genetic Regulation 131</p> <p>6.1.2.3 Limitation of Intracellular Space 132</p> <p>6.1.2.4 Multiple States in the Solution 132</p> <p>6.1.2.5 Biological Objective Function 133</p> <p>6.1.2.6 Kinetics and Metabolite Concentrations 133</p> <p>6.2 Main Source of Optimization Issues with Large Genome-Scale Models: Thermodynamically Infeasible Cycles 134</p> <p>6.2.1 Definition of Thermodynamically Infeasible Fluxes 134</p> <p>6.2.2 Loops Involving External Exchange Reactions 134</p> <p>6.2.2.1 Reversible Passive Transporters from Major Facilitator Superfamily (MFS) 135</p> <p>6.2.2.2 Reversible Passive Antiporters from Amino Acid-Polyamine-organoCation (APC) Superfamily 136</p> <p>6.2.2.3 Na<sup>+</sup>-linked Transporters 136</p> <p>6.2.2.4 Transport via Proton Symport 137</p> <p>6.2.3 Tools to Identify Thermodynamically Infeasible Cycles 138</p> <p>6.2.3.1 Visualizing Fluxes on a Network Map 138</p> <p>6.2.3.2 Algorithms Developed 138</p> <p>6.2.4 Methods Available to Remove Thermodynamically Infeasible Cycles 139</p> <p>6.2.4.1 Manual Curation 139</p> <p>6.2.4.2 Software and Algorithms Developed for the Removal of Thermodynamically Infeasible Loops from Flux Distributions 140</p> <p>6.3 Consideration of Additional Biological Cellular Constraints 144</p> <p>6.3.1 Genetic Regulation 144</p> <p>6.3.1.1 Advantages of Considering Gene Regulation in Genome-Scale Modeling 144</p> <p>6.3.1.2 Methods Developed to Take into Account a Feedback of FBA on the Regulatory Network 145</p> <p>6.3.2 Context Specificity 146</p> <p>6.3.2.1 What Are Context-Specific Models (CSMs)? 146</p> <p>6.3.2.2 Methods and Algorithms Developed to Reconstruct Context-Specific Models (CSMs) 146</p> <p>6.3.2.3 Performance of CSMs 148</p> <p>6.3.2.4 Cautions About CSMs 149</p> <p>6.3.3 Molecular Crowding 150</p> <p>6.3.3.1 Consequences on the Predictions 150</p> <p>6.3.3.2 Methods Developed to Account for a Total Enzymatic Capacity into the FBA Framework 151</p> <p>6.4 Conclusion 152</p> <p>References 153</p> <p><b>7 Toward Integrated Multi-omics Analysis for Improving CHO Cell Bioprocessing </b><b>163<br /> </b><i>Kok Siong Ang, Jongkwang Hong, Meiyappan Lakshmanan, and Dong-Yup Lee</i></p> <p>7.1 Introduction 163</p> <p>7.2 High-Throughput Omics Technologies 165</p> <p>7.2.1 Sequencing-Based Omics Technologies 165</p> <p>7.2.1.1 Historical Developments of Nucleotide Sequencing Techniques 165</p> <p>7.2.1.2 Genome Sequencing of CHO Cells 166</p> <p>7.2.1.3 Transcriptomics of CHO Cells 167</p> <p>7.2.1.4 Epigenomics of CHO Cells 168</p> <p>7.2.2 Mass Spectrometry-Based Omics Technologies 168</p> <p>7.2.2.1 Mass Spectrometry Techniques 168</p> <p>7.2.2.2 Proteomics of CHO Cells 170</p> <p>7.2.2.3 Metabolomics/Lipidomics of CHO Cells 171</p> <p>7.2.2.4 Glycomics of CHO Cells 172</p> <p>7.3 Current CHO Multi-omics Applications 172</p> <p>7.3.1 Bioprocess Optimization 174</p> <p>7.3.2 Cell Line Characterization 174</p> <p>7.3.3 Engineering Target Identification 176</p> <p>7.4 Future Prospects 177</p> <p>References 178</p> <p><b>8 CRISPR Toolbox for Mammalian Cell Engineering </b><b>185<br /> </b><i>Daria Sergeeva, Karen Julie la Cour Karottki, Jae Seong Lee, and Helene Faustrup Kildegaard</i></p> <p>8.1 Introduction 185</p> <p>8.2 Mechanism of CRISPR/Cas9 Genome Editing 186</p> <p>8.3 Variants of CRISPR-RNA-guided Endonucleases 187</p> <p>8.3.1 Diversity of CRISPR/Cas Systems 187</p> <p>8.3.2 Engineered Cas9 Variants 188</p> <p>8.4 Experimental Design for CRISPR-mediated Genome Editing 188</p> <p>8.4.1 Target Site Selection and Design of gRNAs 189</p> <p>8.4.2 Delivery of CRISPR/Cas9 Components 191</p> <p>8.5 Development of CRISPR/Cas9 Tools 192</p> <p>8.5.1 CRISPR/Cas9-mediated Gene Editing 192</p> <p>8.5.1.1 Gene Knockout 192</p> <p>8.5.1.2 Site-Specific Gene Integration 194</p> <p>8.5.2 CRISPR/Cas9-mediated Genome Modification 195</p> <p>8.5.2.1 Transcriptional Regulation 195</p> <p>8.5.2.2 Epigenetic Modification 196</p> <p>8.5.3 RNA Targeting 196</p> <p>8.6 Genome-Scale CRISPR Screening 197</p> <p>8.7 Applications of CRISPR/Cas9 for CHO Cell Engineering 197</p> <p>8.8 Conclusion 199</p> <p>Acknowledgment 200</p> <p>References 200</p> <p><b>9 CHO Cell Engineering for Improved Process Performance and Product Quality </b><b>207<br /> </b><i>Simon Fischer and Kerstin Otte</i></p> <p>9.1 CHO Cell Engineering 207</p> <p>9.2 Methods in Cell Line Engineering 208</p> <p>9.2.1 Overexpression of Engineering Genes 208</p> <p>9.2.2 Gene Knockout 209</p> <p>9.2.3 Noncoding RNA-mediated Gene Silencing 209</p> <p>9.3 Applications of Cell Line Engineering Approaches in CHO Cells 211</p> <p>9.3.1 Enhancing Recombinant Protein Production 211</p> <p>9.3.2 Repression of Cell Death and Acceleration of Growth 221</p> <p>9.3.3 Modulation of Posttranslational Modifications to Improve Protein Quality 227</p> <p>9.4 Conclusions 233</p> <p>References 234</p> <p><b>10 Metabolite Profiling of Mammalian Cells </b><b>251<br /> </b><i>Claire E. Gaffney, Alan J. Dickson, and Mark Elvin</i></p> <p>10.1 Value of Metabolic Data for the Enhancement of Recombinant Protein Production 251</p> <p>10.2 Technologies Used in the Generation of Metabolic Data Sets 252</p> <p>10.2.1 Targeted and Untargeted Metabolic Analysis 253</p> <p>10.2.2 Analytical Technologies Used in the Generation of Metabolite Profiles 253</p> <p>10.2.2.1 Nuclear Magnetic Resonance 254</p> <p>10.2.2.2 Mass Spectrometry 255</p> <p>10.2.3 Metabolite Sample Preparation 256</p> <p>10.2.3.1 Extracellular Sample Preparation 257</p> <p>10.2.3.2 Quenching of Intracellular Metabolite Samples 257</p> <p>10.2.3.3 Metabolite Extraction from Quenched Cells 257</p> <p>10.2.3.4 Metabolic Flux Analysis 257</p> <p>10.3 Approaches for Metabolic Data Analysis 257</p> <p>10.3.1 Data Processing 258</p> <p>10.3.2 Data Analysis 258</p> <p>10.3.3 Data Interpretation and Integration 260</p> <p>10.4 Implementation of Metabolic Data in Bioprocessing 261</p> <p>10.4.1 Relationship Between Growth Phase and Metabolism 261</p> <p>10.4.2 Identification of Metabolic Indicators Associated with High Cell-Specific Productivity 263</p> <p>10.4.3 Utilizing Metabolic Data to Improve Biomass and Recombinant Protein Yield 263</p> <p>10.4.4 Utilizing Metabolic Understanding to Improve Product Quality 265</p> <p>10.4.5 Cell Line Engineering to Redirect Metabolic Pathways 265</p> <p>10.5 Future Perspectives 266</p> <p>Acknowledgments 267</p> <p>References 267</p> <p><b>11 Current Considerations and Future Advances in Chemically Defined Medium Development for the Production of Protein Therapeutics in CHO Cells </b><b>279<br /> </b><i>Wai Lam W. Ling</i></p> <p>11.1 Introduction 279</p> <p>11.2 Traditional Approach to Medium Development 279</p> <p>11.2.1 Cell Line Selection 279</p> <p>11.2.2 Design and Optimization 280</p> <p>11.2.3 Process Consideration 282</p> <p>11.2.4 Additional Considerations in Medium Development 284</p> <p>11.3 Future Perspectives for Medium Development 284</p> <p>11.3.1 Systems Biology and Synthetic Biology 284</p> <p>Acknowledgment 288</p> <p>Conflict of Interest 288</p> <p>References 288</p> <p><b>12 Host Cell Proteins During Biomanufacturing </b><i>295<br /> Jong Youn Baik, Jing Guo, and Kelvin H. Lee</i></p> <p>12.1 Introduction 295</p> <p>12.2 Removal of HCP Impurities 295</p> <p>12.2.1 Antibody Product 296</p> <p>12.2.2 Non-antibody Protein Product 297</p> <p>12.2.3 Difficult-to-Remove HCPs 298</p> <p>12.3 Impacts of Residual HCPs 298</p> <p>12.3.1 Drug Efficacy, Quality, and Shelf Life 298</p> <p>12.3.2 Immunogenicity 299</p> <p>12.3.3 Biological Activity 299</p> <p>12.4 HCP Detection and Monitoring Methods 300</p> <p>12.4.1 Anti-HCP Antiserum and Enzyme-Linked Immunosorbent Assay (ELISA) 300</p> <p>12.4.2 Proteomics Approaches as Orthogonal Methods 302</p> <p>12.5 Efforts for HCP Control 302</p> <p>12.5.1 Upstream Efforts 303</p> <p>12.5.2 Downstream Efforts 304</p> <p>12.5.3 HCP Risk Assessment in CHO Cells 305</p> <p>12.6 Future Directions 305</p> <p>Acknowledgments 306</p> <p>References 306</p> <p><b>13 Mammalian Fed-batch Cell Culture for Biopharmaceuticals </b><b>313<br /> </b><i>William C. Yang</i></p> <p>13.1 Introduction 313</p> <p>13.2 Objectives of Cell Culture Process Development 314</p> <p>13.2.1 Yield and Product Quality 314</p> <p>13.2.2 Glycosylation 314</p> <p>13.2.3 Charge Heterogeneity 315</p> <p>13.2.4 Aggregation 316</p> <p>13.3 Cells and Cell Culture Formats 316</p> <p>13.3.1 Adherent Cells 316</p> <p>13.3.2 Suspended Cells 316</p> <p>13.3.3 Batch Cultures 317</p> <p>13.4 Fed-batch Cultures 317</p> <p>13.5 Cell Culture Media 319</p> <p>13.5.1 Basal Media 319</p> <p>13.5.2 Feed Media 320</p> <p>13.6 Feeding Strategies 321</p> <p>13.6.1 Metabolite Based 321</p> <p>13.6.2 Respiration Based 323</p> <p>13.7 Feed Media Design 323</p> <p>13.8 Process Variable Design 325</p> <p>13.8.1 Temperature 325</p> <p>13.8.2 pH and <i>p</i>CO<sub>2</sub> 325</p> <p>13.8.3 Dissolved Oxygen 326</p> <p>13.8.4 Culture Duration 327</p> <p>13.9 Cell Culture Supplements 327</p> <p>13.9.1 Yield 328</p> <p>13.9.2 Glycosylation 328</p> <p>13.10 New and Emerging Technologies 329</p> <p>13.10.1 Analytical Technologies 329</p> <p>13.10.2 Bioreactor Technologies 331</p> <p>13.11 Future Directions 332</p> <p>References 333</p> <p><b>14 Continuous Biomanufacturing </b><b>347<br /> </b><i>Sadettin S. Ozturk</i></p> <p>14.1 Introduction 347</p> <p>14.2 Continuous Upstream (Cell Culture) Processes 347</p> <p>14.2.1 Continuous Culture without Cell Retention (Chemostat) 348</p> <p>14.2.2 Continuous Culture with Cell Retention (Perfusion) 348</p> <p>14.2.2.1 Cell Retention by Immobilization or Entrapment 349</p> <p>14.2.2.2 Cell Retention by Cell Retention Device 350</p> <p>14.2.3 Semicontinuous Culture 351</p> <p>14.3 Advantages of Continuous Perfusion 351</p> <p>14.3.1 Higher Volumetric Productivities 351</p> <p>14.3.2 Better Utilization of Biomanufacturing Facilities 352</p> <p>14.3.3 Better Product Quality and Consistency 352</p> <p>14.3.4 Scale-up and Commercial Production 353</p> <p>14.4 Cell Retention Systems for Continuous Perfusion 354</p> <p>14.4.1 Cell Retention Devices 354</p> <p>14.4.1.1 Filtration-Based Devices 354</p> <p>14.4.1.2 Spin Filters 355</p> <p>14.4.1.3 Continuous Centrifugation 356</p> <p>14.4.1.4 Settler 356</p> <p>14.4.1.5 BioSep Device 357</p> <p>14.4.1.6 Hydrocyclones 358</p> <p>14.5 Operation and Control of Continuous Perfusion Bioreactors 358</p> <p>14.5.1 Feed and Harvest Flow and Volume Control 358</p> <p>14.5.2 Circulation or Return Pump 359</p> <p>14.5.3 Control of Perfusion Rate and Cell Density 359</p> <p>14.5.3.1 Cell Build-up Phase 359</p> <p>14.5.3.2 Production Phase 360</p> <p>14.5.3.3 Cell Bleed or Purge 360</p> <p>14.6 Current Status of Continuous Perfusion 360</p> <p>14.7 Conclusions 362</p> <p>Acknowledgment 362</p> <p>References 363</p> <p><b>15 Process Analytical Technology and Quality by Design for Animal Cell Culture </b><b>365<br /> </b><i>Hae-Woo Lee, Hemlata Bhatia, Seo-Young Park, Mark-Henry Kamga, Thomas Reimonn, Sha Sha, Zhuangrong Huang, Shaun Galbraith, Huolong Liu, and Seongkyu Yoon</i></p> <p>15.1 PAT and QbD – US FDA’s Regulatory Initiatives 365</p> <p>15.2 PAT and QbD – Challenges 365</p> <p>15.3 PAT and QbD Implementations 366</p> <p>15.3.1 NIR Spectroscopy 366</p> <p>15.3.2 Mid-Infrared (MIR) Spectroscopy 367</p> <p>15.3.3 Raman Spectroscopy 367</p> <p>15.3.4 Fluorescence Spectroscopy 368</p> <p>15.3.5 Chromatographic Techniques 368</p> <p>15.3.6 Other Useful Techniques 369</p> <p>15.3.7 Data Analysis and Modeling Tools 369</p> <p>15.4 Case Studies 370</p> <p>15.4.1 Estimation of Raw Material Performance in Mammalian Cell Culture Using Near-Infrared Spectra Combined with Chemometrics Approaches 370</p> <p>15.4.2 Design Space Exploration for Control of Critical Quality Attributes of mAb 372</p> <p>15.4.3 Quantification of Protein Mixture in Chromatographic Separation Using Multiwavelength UV Spectra 372</p> <p>15.4.4 Characterization of Mammalian Cell Culture Raw Materials by Combining Spectroscopy and Chemometrics 374</p> <p>15.4.5 Effect of Amino Acid Supplementation on Titer and Glycosylation Distribution in Hybridoma Cell Cultures 375</p> <p>15.4.6 Metabolic Responses and Pathway Changes of Mammalian Cells Under Different Culture Conditions with Media Supplementations 377</p> <p>15.4.7 Estimation and Control of N-Linked Glycoform Profiles of Monoclonal Antibody with Extracellular Metabolites and Two-Step Intracellular Models 378</p> <p>15.4.8 Quantitative Intracellular Flux Modeling and Applications in Biotherapeutic Development and Production Using CHO Cell Cultures 381</p> <p>15.5 Conclusion 383</p> <p>References 383</p> <p><b>16 Development and Qualification of a Cell Culture Scale-Down Model </b><b>391<br /> </b><i>Sarwat Khattak and Valerie Pferdeort</i></p> <p>16.1 Purpose of the Scale-Down Model 391</p> <p>16.1.1 Development Challenges 391</p> <p>16.2 Types of Scale-Down Models 392</p> <p>16.2.1 Power/Volume (<i>P</i>/<i>V</i>) and Air velocity 392</p> <p>16.2.2 Oxygen Transfer Coefficient (<i>k</i><sub>L</sub><i>a</i>) 392</p> <p>16.2.3 Gas Entrance Velocity (GEV) 393</p> <p>16.2.4 Oxygen Transfer Rate (OTR) 393</p> <p>16.2.5 Model Refinement Workflow 395</p> <p>16.3 Evaluation of a Scale-Down Model 395</p> <p>16.3.1 Univariate Analysis 395</p> <p>16.3.2 Multivariate Analysis 396</p> <p>16.3.2.1 Statistical Background 396</p> <p>16.3.2.2 Qualification Data Set 396</p> <p>16.3.2.3 Observation Level Analysis 397</p> <p>16.3.2.4 Batch-Level Analysis 397</p> <p>16.3.2.5 Scores Contribution Plots 398</p> <p>16.3.3 Equivalence Testing 399</p> <p>16.3.3.1 Statistical Background 399</p> <p>16.3.3.2 Considerations for Evaluation and Test Data Sets 399</p> <p>16.3.3.3 Types of Analysis Outcomes 400</p> <p>16.4 Conclusions and Perspectives 401</p> <p>References 402</p> <p>Index 407 </p>
Gyun Min Lee, PhD, is Professor at the Department of Biological Sciences at KAIST, South Korea, and heads the Animal Cell Engineering Laboratory. He is also Scientific Director at the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark. <br> <br> Helene Faustrup Kildegaard, PhD, is a senior researcher and Co-PI for the CHO Cell Line Engineering and Design section at the Novo Nordisk Foundation Center for Biosustainability at the Technical University of Denmark (DTU). <br>

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von: Wilhelm Keim
PDF ebook
99,99 €