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List of Contributors xv Series Preface xix Preface xxi 1 Model-Based Preparative Chromatography Process Development in the QbD Paradigm 1 Arne Staby, Satinder Ahuja, and Anurag S. Rathore
1.1 Motivation 1
1.2 Regulatory Context of Preparative Chromatography and Process Understanding 1
1.3 Application of Mathematical Modeling to Preparative Chromatography 6 Acknowledgements 8 References 8 2 Adsorption Isotherms: Fundamentals and Modeling Aspects 11 Jørgen M. Mollerup
2.1 Introduction 11
2.2 Definitions 12
2.3 The Solute Velocity Model 14
2.4 Introduction to the Theory of Equilibrium 17
2.5 Association Equilibria 21
2.6 The Classical Adsorption Isotherm 24
2.7 The Classical Ion Exchange Adsorption Isotherm 26
2.8 Hydrophobic Adsorbents, HIC and RPC 38
2.9 Protein-Protein Association and Adsorption Isotherms 47
2.10 The Adsorption Isotherm of a GLP-1 Analogue 51
2.11 Concluding Remarks 59 Appendix
2.A Classical Thermodynamics 60 References 77 3 Simulation of Process Chromatography 81 Bernt Nilsson and Niklas Andersson
3.1 Introduction 81
3.2 Simulation-Based Prediction of Chromatographic Processes 82
3.3 Numerical Methods for Chromatography Simulation 94
3.4 Simulation-Based Model Calibration and Parameter Estimation 96
3.5 Simulation-Based Parametric Analysis of Chromatography 97
3.6 Simulation-Based Optimization of Process Chromatography 101
3.7 Summary 106 Acknowledgement 107 References 108 4 Simplified Methods Based on Mechanistic Models for Understanding and Designing Chromatography Processes for Proteins and Other Biological Products 111 Noriko Yoshimoto and Shuichi Yamamoto
4.1 Introduction 111
4.2 HETP and Related Variables in Isocratic Elution 114
4.3 Linear Gradient Elution (LGE) 120
4.4 Applications of the Model 130
4.5 Summary 145 Appendix
4.A Mechanistic Models for Chromatography 149 Appendix
4.B Distribution Coefficient and Binding Sites [20- 149 References 152 5 Development of Continuous Capture Steps in Bioprocess Applications 159 Frank Riske and Tom Ransohoff
5.1 Introduction 159
5.2 Economic Rationale for Continuous Processing 160
5.3 Developing a Continuous Capture Step 162
5.4 The Operation of MCC Systems 165
5.5 Modeling MCC Operation 167
5.6 Processing Bioreactor Feeds on a Capture MCC 169
5.7 The Future of MCC 171 References 172 6 Computational Modeling in Bioprocess Development 177 Francis Insaidoo, Suvrajit Banerjee, David Roush, and Steven Cramer
6.1 Linkage of Chromatographic Thermodynamics (Affinity, Kinetics, and Capacity) 177
6.2 Binding Maps and Coarse-Grained Modeling 180
6.3 QSPR for Either Classification or Quantification Prediction 188
6.4 All Atoms MD Simulations for Free Solution Studies and Surfaces 192
6.5 Ensemble Average and Comparison of Binding of Different Proteins in Chromatographic Systems 204
6.6 Antibody Homology Modeling and Bioprocess Development 205
6.7 Summary of Gaps and Future State 209 Acknowledgment 212 References 212 7 Chromatographic Scale-Up on a Volume Basis 227 Ernst B. Hansen
7.1 Introduction 227
7.2 Theoretical Background 229
7.3 Proof of Concept Examples 232
7.4 Design Applications: How to Scale up from Development Data 233
7.5 Discussion 240
7.6 Recommendations 242 References 245 8 Scaling Up Industrial Protein Chromatography: Where Modeling Can Help 247 Chris Antoniou, Justin McCue, Venkatesh Natarajan, Jörg Thömmes, and Qing Sarah Yuan
8.1 Introduction 247
8.2 Packing Quality: Why and How to Ensure Column Packing Quality Across Scales 248
8.3 Process Equipment: Using CFD to Describe Effects of Equipment Design on Column Performance 257
8.4 Long-Term Column Operation at Scale: Impact of Resin Lot-to-Lot Variability 264
8.5 Closing Remarks 265 References 265 9 High-Throughput Process Development 269 Silvia M. Pirrung and Marcel Ottens
9.1 Introduction to High-Throughput Process Development in Chromatography 269
9.2 Process Development Approaches 271
9.3 Case Descriptions 279
9.4 Future Directions 286 References 286 10 High-Throughput Column Chromatography Performed on Liquid Handling Stations 293 Patrick Diederich and Jürgen Hubbuch 10.1 Introduction 293
10.2 Chromatographic Methods 299
10.3 Results and Discussion 300
10.4 Summary and Conclusion 328 Acknowledgements 329 References 330 11 Lab-Scale Development of Chromatography Processes 333 Hong Li, Jennifer Pollard, and Nihal Tugcu
11.1 Introduction 333
11.2 Methodology and Proposed Workflow 336
11.3 Conclusions 377 Acknowledgments 377 References 377 12 Problem Solving by Using Modeling 381 Martin P. Breil, Søren S. Frederiksen, Steffen Kidal, and Thomas B. Hansen
12.1 Introduction 381
12.2 Theory 382
12.3 Materials and Methods 385
12.4 Determination of Model Parameters 385
12.5 Optimization In Silico 388
12.6 Extra-Column Effects 390 Abbreviations 397 References 398 13 Modeling Preparative Cation Exchange Chromatography of Monoclonal Antibodies 399 Stephen Hunt, Trent Larsen, and Robert J. Todd
13.1 Introduction 399
13.2 Theory 401
13.3 Model Development 403
13.4 Model Application 413
13.5 Conclusions 424 Nomenclature 425 Greek letters 425 References 426 14 Model-Based Process Development in the Biopharmaceutical Industry 429 Lars Sejergaard, Haleh Ahmadian, Thomas B. Hansen, Arne Staby, and Ernst B. Hansen
14.1 Introduction 429
14.2 Molecule--FVIII 430
14.3 Overall Process Design 431
14.4 Use of Mathematical Models to Ensure Process Robustness 432
14.5 Experimental Design of Verification Experiments 435
14.6 Discussion 438
14.7 Conclusion 439 Acknowledgements 439 Appendix
14.A Practical MATLAB Guideline to SEC 439 Appendix
14.B Derivation of Models Used for Column Simulations 449 References 455 15 Dynamic Simulations as a Predictive Model for a Multicolumn Chromatography Separation 457 Marc Bisschops and Mark Brower
15.1 Introduction 457
15.2 BioSMB Technology 459
15.3 Protein A Model Description 460
15.4 Fitting the Model Parameters 463
15.5 Case Studies 464
15.6 Results for Continuous Chromatography 469
15.7 Conclusions 475 References 476 16 Chemometrics Applications in Process Chromatography 479 Anurag S. Rathore and Sumit K. Singh
16.1 Introduction 479
16.2 Data Types 480
16.3 Data Preprocessing 481
16.4 Modeling Approaches 485
16.5 Case Studies of Use of Chemometrics in Process Chromatography 490
16.6 Guidance on Performing MVDA 495 References 497 17 Mid-UV Protein Absorption Spectra and Partial Least Squares Regression as Screening and PAT Tool 501 Sigrid Hansen, Nina Brestrich, Arne Staby, and Jürgen Hubbuch 17.1 Introduction 501
17.2 Mid-UV Protein Absorption Spectra and Partial Least Squares Regression 503
17.3 Spectral Similarity and Prediction Precision 511
17.4 Application as a Screening Tool: Analytics for High-Throughput Experiments 516
17.5 Application as a PAT Tool: Selective In-line Quantification and Real-Time Pooling 518
17.6 Case Studies 523
17.7 Conclusion and Outlook 532 References 532 18 Recent Progress Toward More Sustainable Biomanufacturing: Practical Considerations for Use in the Downstream Processing of Protein Products 537 Milton T. W. Hearn
18.1 Introduction 537
18.2 The Impact of Individualized Unit Operations versus Integrated Platform Technologies on Sustainable Manufacturing 543
18.3 Implications of Recycling and Reuse in Downstream Processing of Protein Products Generated by Biotechnological Processes: General Considerations 549
18.4 Metrics and Valorization Methods to Assess Process Sustainability 553
18.5 Conclusions and Perspectives 573 Acknowledgment 573 References 574 Index 583