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E-raamat: Cell Culture Engineering - Recombinant Protein Production: Recombinant Protein Production [Wiley Online]

Series edited by (Massachusetts Institute of Technologie, USA), Edited by , Series edited by (KAIST,Daejon,Republik Korea), Series edited by (Center for Microbial Biotechnology), Edited by
  • Formaat: 440 pages
  • Sari: Advanced Biotechnology
  • Ilmumisaeg: 13-Nov-2019
  • Kirjastus: Blackwell Verlag GmbH
  • ISBN-10: 3527811419
  • ISBN-13: 9783527811410
Teised raamatud teemal:
  • Wiley Online
  • Hind: 185,03 €*
  • * hind, mis tagab piiramatu üheaegsete kasutajate arvuga ligipääsu piiramatuks ajaks
Cell Culture Engineering - Recombinant Protein Production: Recombinant Protein ProductionSuurem pilt
  • Formaat: 440 pages
  • Sari: Advanced Biotechnology
  • Ilmumisaeg: 13-Nov-2019
  • Kirjastus: Blackwell Verlag GmbH
  • ISBN-10: 3527811419
  • ISBN-13: 9783527811410
Teised raamatud teemal:
Wiley Online e-raamatudRohkem infot Wiley Online kohta
Raamatu kodulehekülg: https://onlinelibrary.wiley.com/doi/book/10.1002/9783527811410
Offers a comprehensive overview of cell culture engineering, providing insight into cell engineering, systems biology approaches and processing technology

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.

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.



-Covers key elements of cell culture engineering applied to the production of recombinant proteins for therapeutic use -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 -Part of the renowned "Advanced Biotechnology" book series

Cell Culture Engineering: Recombinant Protein Production will appeal to biotechnologists, bioengineers, life scientists, chemical engineers, and PhD students in the life sciences.
About the Series Editors xvii
1 Platform Technology for Therapeutic Protein Production
1(22)
Tae Kwang Ha
Jae Seong Lee
Gyun Min Lee
1.1 Introduction
1(2)
1.2 Overall Trend Analysis
3(3)
1.2.1 Mammalian Cell Lines
3(2)
1.2.2 Brief Introduction of Advances and Techniques
5(1)
1.3 General Guidelines for Recombinant Cell Line Development
6(3)
1.3.1 Host Selection
6(1)
1.3.2 Expression Vector
7(1)
1.3.3 Transfection/Selection
7(1)
1.3.4 Clone Selection
8(1)
1.3.4.1 Primary Parameters During Clone Selection
8(1)
1.3.4.2 Clone Screening Technologies
9(1)
1.4 Process Development
9(3)
1.4.1 Media Development
10(1)
1.4.2 Culture Environment
10(1)
1.4.3 Culture Mode (Operation)
10(1)
1.4.4 Scale-up and Single-Use Bioreactor
11(1)
1.4.5 Quality Analysis
12(1)
1.5 Downstream Process Development
12(2)
1.5.1 Purification
12(1)
1.5.2 Quality by Design (QbD)
13(1)
1.6 Trends in Platform Technology Development
14(3)
1.6.1 Rational Strategies for Cell Line and Process Development
14(1)
1.6.2 Hybrid Culture Mode and Continuous System
15(1)
1.6.3 Recombinant Human Cell Line Development for Therapeutic Protein Production
16(1)
1.7 Conclusion
17(6)
Acknowledgment 17(1)
Conflict of Interest 17(1)
References 17(390)
2 Cell Line Development for Therapeutic Protein Production
23(26)
Soo Min Noh
Seunghyeon Shin
Gyun Min Lee
2.1 Introduction
23(2)
2.2 Mammalian Host Cell Lines for Therapeutic Protein Production
25(2)
2.2.1 CHO Cell Lines
25(1)
2.2.2 Human Cell Lines
26(1)
2.2.3 Other Mammalian Cell Lines
27(1)
2.3 Development of Recombinant CHO Cell Lines
27(7)
2.3.1 Expression Systems for CHO Cells
28(1)
2.3.2 Cell Line Development Process Using CHO Cells Based on Random Integration
28(1)
2.3.2.1 Vector Construction
29(1)
2.3.2.2 Transfection and Selection
30(1)
2.3.2.3 Gene Amplification
30(1)
2.3.2.4 Clone Selection
31(1)
2.3.3 Cell Line Development Process Using CHO Cells Based On Site-Specific Integration
32(2)
2.4 Development of Recombinant Human Cell Lines
34(2)
2.4.1 Necessity for Human Cell Lines
34(1)
2.4.2 Stable Cell Line Development Process Using Human Cell Lines
35(1)
2.5 Important Consideration for Cell Line Development
36(2)
2.5.1 Clonality
36(1)
2.5.2 Stability
36(1)
2.5.3 Quality of Therapeutic Proteins
37(1)
2.6 Conclusion
38(1)
References
38(11)
3 Transient Gene Expression-Based Protein Production in Recombinant Mammalian Cells
49(24)
Joo-Hyoung Lee
Henning G. Hansen
Sun-Hye Park
Jong-Ho Park
Yeon-Gu Kim
3.1 Introduction
49(1)
3.2 Gene Delivery: Transient Transfection Methods
50(3)
3.2.1 Calcium Phosphate-Based Transient Transfection
50(1)
3.2.2 Electroporation
51(1)
3.2.3 Polyethylenimine-Based Transient Transfection
52(1)
3.2.4 Liposome-Based Transient Transfection
52(1)
3.3 Expression Vectors
53(1)
3.3.1 Expression Vector Composition and Preparation
53(1)
3.3.2 Episomal Replication
53(1)
3.3.3 Coexpression Strategies
54(1)
3.4 Mammalian Cell Lines
54(4)
3.4.1 HEK293 Cell-Based TGE Platforms
55(1)
3.4.2 CHO Cell-Based TGE Platforms
56(2)
3.4.3 TGE Platforms Using Other Cell Lines
58(1)
3.5 Cell Culture Strategies
58(2)
3.5.1 Culture Media for TGE
58(1)
3.5.2 Optimization of Cell Culture Processes for TGE
59(1)
3.5.3 (L-Enhancing Factors in TGE-Based Culture Processes
59(1)
3.5.4 Culture Longevity-Enhancing Factors in TGE-Based Culture Processes
59(1)
3.6 Large-Scale TGE-Based Protein Production
60(2)
3.7 Concluding Remarks
62(1)
References
62(11)
4 Enhancing Product and Bioprocess Attributes Using Genome-Scale Models of CHO Metabolism
73(24)
Shangzhong Li
Anne Richelle
Nathan E. Lewis
4.1 Introduction
73(3)
4.1.1 Cell Line Optimization
73(2)
4.1.2 CHO Genome
75(1)
4.1.2.1 Development of Genomic Resources of CHO
75(1)
4.1.2.2 Development of Transcriptomics and Proteomics Resources of CHO
75(1)
4.2 Genome-Scale Metabolic Model
76(4)
4.2.1 What Is a Genome-Scale Metabolic Model
76(1)
4.2.2 Reconstruction of GEMs
77(1)
4.2.2.1 Knowledge-Based Construction
77(1)
4.2.2.2 Draft Reconstruction
77(1)
4.2.2.3 Curation of the Reconstruction
77(2)
4.2.2.4 Conversion to a Computational Format
79(1)
4.2.2.5 Model Validation and Evaluation
79(1)
4.3 GEM Application
80(6)
4.3.1 Common Usage and Prediction Capacities of Genome-Scale Models
82(1)
4.3.2 GEMs as a Platform for Omics Data Integration, Linking Genotype to Phenotype
83(1)
4.3.3 Predicting Nutrient Consumption and Controlling Phenotype
84(1)
4.3.4 Enhancing Protein Production and Bioprocesses
85(1)
4.3.5 Case Studies
86(1)
4.4 Conclusion
86(2)
Acknowledgments
88(1)
References
88(9)
5 Genome Variation, the Epigenome and Cellular Phenotypes
97(30)
Martina Baumann
Gerald Klanert
Sabine Vcelar
Marcus Weinguny
Nicolas Marx
Nicole Borth
5.1 Phenotypic Instability in the Context of Mammalian Production Cell Lines
97(2)
5.2 Genomic Instability
99(2)
5.3 Epigenetics
101(4)
5.3.1 DNA Methylation
102(1)
5.3.2 Histone Modifications
102(2)
5.3.3 Downstream Effectors
104(1)
5.3.4 Noncoding RNAs
104(1)
5.4 Control of CHO Cell Phenotype by the Epigenome
105(2)
5.5 Manipulating the Epigenome
107(6)
5.5.1 Global Epigenetic Modification
107(1)
5.5.1.1 Manipulating Global DNA Methylation
107(1)
5.5.1.2 Manipulating Global Histone Acetylation
108(1)
5.5.2 Targeted Epigenetic Modification
109(1)
5.5.2.1 Targeted Histone Modification
110(2)
5.5.2.2 Targeted DNA Methylation
112(1)
5.6 Conclusion and Outlook
113(1)
References
114(13)
6 Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes
127(36)
Calmels Cyrielle
Chintan Joshi
Nathan E. Lewis
Malphettes Laetitia
Mikael R. Andersen
6.1 Introduction
127(7)
6.1.1 Constraint-Based Models
127(4)
6.1.2 Limitations of Flux Balance Analysis
131(1)
6.1.2.1 Thermodynamically Infeasible Cycles
131(1)
6.1.2.2 Genetic Regulation
131(1)
6.1.2.3 Limitation of Intracellular Space
132(1)
6.1.2.4 Multiple States in the Solution
132(1)
6.1.2.5 Biological Objective Function
133(1)
6.1.2.6 Kinetics and Metabolite Concentrations
133(1)
6.2 Main Source of Optimization Issues with Large Genome-Scale Models: Thermodynamically Infeasible Cycles
134(10)
6.2.1 Definition of Thermodynamically Infeasible Fluxes
134(1)
6.2.2 Loops Involving External Exchange Reactions
134(1)
6.2.2.1 Reversible Passive Transporters from Major Facilitator Superfamily (MFS)
135(1)
6.2.2.2 Reversible Passive Antiporters from Amino Acid-Polyamine-organoCation (APC) Superfamily
136(1)
6.2.2.3 Na+-linked Transporters
136(1)
6.2.2.4 Transport via Proton Symport
137(1)
6.2.3 Tools to Identify Thermodynamically Infeasible Cycles
138(1)
6.2.3.1 Visualizing Fluxes on a Network Map
138(1)
6.2.3.2 Algorithms Developed
138(1)
6.2.4 Methods Available to Remove Thermodynamically Infeasible Cycles
139(1)
6.2.4.1 Manual Curation
139(1)
6.2.4.2 Software and Algorithms Developed for the Removal of Thermodynamically Infeasible Loops from Flux Distributions
140(4)
6.3 Consideration of Additional Biological Cellular Constraints
144(8)
6.3.1 Genetic Regulation
144(1)
6.3.1.1 Advantages of Considering Gene Regulation in Genome-Scale Modeling
144(1)
6.3.1.2 Methods Developed to Take into Account a Feedback of FBA on the Regulatory Network
145(1)
6.3.2 Context Specificity
146(1)
6.3.2.1 What Are Context-Specific Models (CSMs)?
146(1)
6.3.2.2 Methods and Algorithms Developed to Reconstruct Context-Specific Models (CSMs)
146(2)
6.3.2.3 Performance of CSMs
148(1)
6.3.2.4 Cautions About CSMs
149(1)
6.3.3 Molecular Crowding
150(1)
6.3.3.1 Consequences on the Predictions
150(1)
6.3.3.2 Methods Developed to Account for a Total Enzymatic Capacity into the FBA Framework
151(1)
6.4 Conclusion
152(1)
References
153(10)
7 Toward Integrated Multi-omics Analysis for Improving CHO Cell Bioprocessing
163(1)
Kok Siong Ang
Jongkwang Hong
Meiyappan Lakshmanan
Dong-Yup Lee
7.1 Introduction
163(2)
7.2 High-Throughput Omics Technologies
165(1)
7.2.1 Sequencing-Based Omics Technologies
165(1)
7.2.1.1 Historical Developments of Nucleotide Sequencing Techniques
165(1)
7.2.1.2 Genome Sequencing of CHO Cells
166(1)
7.2.1.3 Transcriptomics of CHO Cells
167(1)
7.2.1.4 Epigenomics of CHO Cells
168(1)
7.2.2 Mass Spectrometry-Based Omics Technologies
168(1)
7.2.2.1 Mass Spectrometry Techniques
168(2)
7.2.2.2 Proteomics of CHO Cells
170(1)
7.2.2.3 Metabolomics/Lipidomics of CHO Cells
171(1)
7.2.2.4 Glycomics of CHO Cells
172(1)
7.3 Current CHO Multi-omics Applications
172(5)
7.3.1 Bioprocess Optimization
174(1)
7.3.2 Cell Line Characterization
174(2)
7.3.3 Engineering Target Identification
176(1)
7.4 Future Prospects
177(1)
References
178(7)
8 CRISPR Toolbox for Mammalian Cell Engineering
185(1)
Dana Sergeeva
Karen Julie la Cour Karottki
Jae Seong Lee
Helene Faustrup Kildegaard
8.1 Introduction
185(1)
8.2 Mechanism of CRISPR/Cas9 Genome Editing
186(1)
8.3 Variants of CRISPR-RNA-guided Endonucleases
187(1)
8.3.1 Diversity of CRISPR/Cas Systems
187(1)
8.3.2 Engineered Cas9 Variants
188(1)
8.4 Experimental Design for CRISPR-mediated Genome Editing
188(4)
8.4.1 Target Site Selection and Design of gRNAs
189(2)
8.4.2 Delivery of CRISPR/Cas9 Components
191(1)
8.5 Development of CRISPR/Cas9 Tools
192(5)
8.5.1 CRISPR/Cas9-mediated Gene Editing
192(1)
8.5.1.1 Gene Knockout
192(2)
8.5.1.2 Site-Specific Gene Integration
194(1)
8.5.2 CRISPR/Cas9-mediated Genome Modification
195(1)
8.5.2.1 Transcriptional Regulation
195(1)
8.5.2.2 Epigenetic Modification
196(1)
8.5.3 RNA Targeting
196(1)
8.6 Genome-Scale CRISPR Screening
197(1)
8.7 Applications of CRISPR/Cas9 for CHO Cell Engineering
197(2)
8.8 Conclusion
199(1)
Acknowledgment
200(1)
References
200(7)
9 CHO Cell Engineering for Improved Process Performance and Product Quality
207(44)
Simon Fischer
Kerstin Otte
9.1 CHO Cell Engineering
207(1)
9.2 Methods in Cell Line Engineering
208(3)
9.2.1 Overexpression of Engineering Genes
208(1)
9.2.2 Gene Knockout
209(1)
9.2.3 Noncoding RNA-mediated Gene Silencing
209(2)
9.3 Applications of Cell Line Engineering Approaches in CHO Cells
211(22)
9.3.1 Enhancing Recombinant Protein Production
211(10)
9.3.2 Repression of Cell Death and Acceleration of Growth
221(6)
9.3.3 Modulation of Posttranslational Modifications to Improve Protein Quality
227(6)
9.4 Conclusions
233(1)
References
234(17)
10 Metabolite Profiling of Mammalian Cells
251(28)
Claire E. Gaffney
Alan J. Dickson
Mark Elvin
10.1 Value of Metabolic Data for the Enhancement of Recombinant Protein Production
251(1)
10.2 Technologies Used in the Generation of Metabolic Data Sets
252(5)
10.2.1 Targeted and Untargeted Metabolic Analysis
253(1)
10.2.2 Analytical Technologies Used in the Generation of Metabolite Profiles
253(1)
10.2.2.1 Nuclear Magnetic Resonance
254(1)
10.2.2.2 Mass Spectrometry
255(1)
10.2.3 Metabolite Sample Preparation
256(1)
10.2.3.1 Extracellular Sample Preparation
257(1)
10.2.3.2 Quenching of Intracellular Metabolite Samples
257(1)
10.2.3.3 Metabolite Extraction from Quenched Cells
257(1)
10.2.3.4 Metabolic Flux Analysis
257(1)
10.3 Approaches for Metabolic Data Analysis
257(4)
10.3.1 Data Processing
258(1)
10.3.2 Data Analysis
258(2)
10.3.3 Data Interpretation and Integration
260(1)
10.4 Implementation of Metabolic Data in Bioprocessing
261(5)
10.4.1 Relationship Between Growth Phase and Metabolism
261(2)
10.4.2 Identification of Metabolic Indicators Associated with High Cell-Specific Productivity
263(1)
10.4.3 Utilizing Metabolic Data to Improve Biomass and Recombinant Protein Yield
263(2)
10.4.4 Utilizing Metabolic Understanding to Improve Product Quality
265(1)
10.4.5 Cell Line Engineering to Redirect Metabolic Pathways
265(1)
10.5 Future Perspectives
266(1)
Acknowledgments
267(1)
References
267(12)
11 Current Considerations and Future Advances in Chemically Defined Medium Development for the Production of Protein Therapeutics in CHO Cells
279(16)
Wai Lam W. Ling
11.1 Introduction
279(1)
11.2 Traditional Approach to Medium Development
279(5)
11.2.1 Cell Line Selection
279(1)
11.2.2 Design and Optimization
280(2)
11.2.3 Process Consideration
282(2)
11.2.4 Additional Considerations in Medium Development
284(1)
11.3 Future Perspectives for Medium Development
284(4)
11.3.1 Systems Biology and Synthetic Biology
284(4)
Acknowledgment
288(1)
Conflict of Interest
288(1)
References
288(7)
12 Host Cell Proteins During Biomanufacturing
295(18)
Jong Youn Baik
Jing Guo
Kelvin H. Lee
12.1 Introduction
295(1)
12.2 Removal of HCP Impurities
295(3)
12.2.1 Antibody Product
296(1)
12.2.2 Non-antibody Protein Product
297(1)
12.2.3 Difficult-to-Remove HCPs
298(1)
12.3 Impacts of Residual HCPs
298(2)
12.3.1 Drug Efficacy, Quality, and Shelf Life
298(1)
12.3.2 Immunogenicity
299(1)
12.3.3 Biological Activity
299(1)
12.4 HCP Detection and Monitoring Methods
300(2)
12.4.1 Anti-HCP Antiserum and Enzyme-Linked Immunosorbent Assay (ELISA)
300(2)
12.4.2 Proteomics Approaches as Orthogonal Methods
302(1)
12.5 Efforts for HCP Control
302(3)
12.5.1 Upstream Efforts
303(1)
12.5.2 Downstream Efforts
304(1)
12.5.3 HCP Risk Assessment in CHO Cells
305(1)
12.6 Future Directions
305(1)
Acknowledgments
306(1)
References
306(7)
13 Mammalian Fed-batch Cell Culture for Biopharmaceuticals
313(34)
William C. Yang
13.1 Introduction
313(1)
13.2 Objectives of Cell Culture Process Development
314(2)
13.2.1 Yield and Product Quality
314(1)
13.2.2 Glycosylation
314(1)
13.2.3 Charge Heterogeneity
315(1)
13.2.4 Aggregation
316(1)
13.3 Cells and Cell Culture Formats
316(1)
13.3.1 Adherent Cells
316(1)
13.3.2 Suspended Cells
316(1)
13.3.3 Batch Cultures
317(1)
13.4 Fed-batch Cultures
317(2)
13.5 Cell Culture Media
319(2)
13.5.1 Basal Media
319(1)
13.5.2 Feed Media
320(1)
13.6 Feeding Strategies
321(2)
13.6.1 Metabolite Based
321(2)
13.6.2 Respiration Based
323(1)
13.7 Feed Media Design
323(2)
13.8 Process Variable Design
325(2)
13.8.1 Temperature
325(1)
13.8.2 pH and pC02
325(1)
13.8.3 Dissolved Oxygen
326(1)
13.8.4 Culture Duration
327(1)
13.9 Cell Culture Supplements
327(2)
13.9.1 Yield
328(1)
13.9.2 Glycosylation
328(1)
13.10 New and Emerging Technologies
329(3)
13.10.1 Analytical Technologies
329(2)
13.10.2 Bioreactor Technologies
331(1)
13.11 Future Directions
332(1)
References
333(14)
14 Continuous Biomanufacturing
347(18)
Sadettin S. Ozturk
14.1 Introduction
347(1)
14.2 Continuous Upstream (Cell Culture) Processes
347(4)
14.2.1 Continuous Culture without Cell Retention (Chemostat)
348(1)
14.2.2 Continuous Culture with Cell Retention (Perfusion)
348(1)
14.2.2.1 Cell Retention by Immobilization or Entrapment
349(1)
14.2.2.2 Cell Retention by Cell Retention Device
350(1)
14.2.3 Semicontinuous Culture
351(1)
14.3 Advantages of Continuous Perfusion
351(3)
14.3.1 Higher Volumetric Productivities
351(1)
14.3.2 Better Utilization of Biomanufacturing Facilities
352(1)
14.3.3 Better Product Quality and Consistency
352(1)
14.3.4 Scale-up and Commercial Production
353(1)
14.4 Cell Retention Systems for Continuous Perfusion
354(4)
14.4.1 Cell Retention Devices
354(1)
14.4.1.1 Filtration-Based Devices
354(1)
14.4.1.2 Spin Filters
355(1)
14.4.1.3 Continuous Centrifugation
356(1)
14.4.1.4 Settler
356(1)
14.4.1.5 BioSep Device
357(1)
14.4.1.6 Hydrocyclones
358(1)
14.5 Operation and Control of Continuous Perfusion Bioreactors
358(2)
14.5.1 Feed and Harvest Flow and Volume Control
358(1)
14.5.2 Circulation or Return Pump
359(1)
14.5.3 Control of Perfusion Rate and Cell Density
359(1)
14.5.3.1 Cell Build-up Phase
359(1)
14.5.3.2 Production Phase
360(1)
14.5.3.3 Cell Bleed or Purge
360(1)
14.6 Current Status of Continuous Perfusion
360(2)
14.7 Conclusions
362(1)
Acknowledgment
362(1)
References
363(2)
15 Process Analytical Technology and Quality by Design for Animal Cell Culture
365(26)
Hae-Woo Lee
Hemlata Bhatia
Seo-Young Park
Mark-Henry Kamga
Thomas Reimonn
Sha Sha
Zhuangrong Huang
Shaun Galbraith
Huolong Liu
Seongkyu Yoon
15.1 PAT and QbD - US FDA's Regulatory Initiatives
365(1)
15.2 PAT and QbD - Challenges
365(1)
15.3 PAT and QbD Implementations
366(4)
15.3.1 NIR Spectroscopy
366(1)
15.3.2 Mid-Infrared (MIR) Spectroscopy
367(1)
15.3.3 Raman Spectroscopy
367(1)
15.3.4 Fluorescence Spectroscopy
368(1)
15.3.5 Chromatographic Techniques
368(1)
15.3.6 Other Useful Techniques
369(1)
15.3.7 Data Analysis and Modeling Tools
369(1)
15.4 Case Studies
370(13)
15.4.1 Estimation of Raw Material Performance in Mammalian Cell Culture Using Near-Infrared Spectra Combined with Chemometrics Approaches
370(2)
15.4.2 Design Space Exploration for Control of Critical Quality Attributes of mAb
372(1)
15.4.3 Quantification of Protein Mixture in Chromatographic Separation Using Multiwavelength UV Spectra
372(2)
15.4.4 Characterization of Mammalian Cell Culture Raw Materials by Combining Spectroscopy and Chemometrics
374(1)
15.4.5 Effect of Amino Acid Supplementation on Titer and Glycosylation Distribution in Hybridoma Cell Cultures
375(2)
15.4.6 Metabolic Responses and Pathway Changes of Mammalian Cells Under Different Culture Conditions with Media Supplementations
377(1)
15.4.7 Estimation and Control of N-Linked Glycoform Profiles of Monoclonal Antibody with Extracellular Metabolites and Two-Step Intracellular Models
378(3)
15.4.8 Quantitative Intracellular Flux Modeling and Applications in Biotherapeutic Development and Production Using CHO Cell Cultures
381(2)
15.5 Conclusion
383(1)
References
383(8)
16 Development and Qualification of a Cell Culture Scale-Down Model
391(16)
Sarwat Khattak
Valerie Pferdeort
16.1 Purpose of the Scale-Down Model
391(1)
16.1.1 Development Challenges
391(1)
16.2 Types of Scale-Down Models
392(3)
16.2.1 Power/Volume (P/V) and Air velocity
392(1)
16.2.2 Oxygen Transfer Coefficient (kla)
392(1)
16.2.3 Gas Entrance Velocity (GEV)
393(1)
16.2.4 Oxygen Transfer Rate (OTR)
393(2)
16.2.5 Model Refinement Workflow
395(1)
16.3 Evaluation of a Scale-Down Model
395(6)
16.3.1 Univariate Analysis
395(1)
16.3.2 Multivariate Analysis
396(1)
16.3.2.1 Statistical Background
396(1)
16.3.2.2 Qualification Data Set
396(1)
16.3.2.3 Observation Level Analysis
397(1)
16.3.2.4 Batch-Level Analysis
397(1)
16.3.2.5 Scores Contribution Plots
398(1)
16.3.3 Equivalence Testing
399(1)
16.3.3.1 Statistical Background
399(1)
16.3.3.2 Considerations for Evaluation and Test Data Sets
399(1)
16.3.3.3 Types of Analysis Outcomes
400(1)
16.4 Conclusions and Perspectives
401(1)
References
402(5)
Index 407
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.

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).
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