Preparative Chromatography for Separation of Proteins

ARNE STABY is a Fellow and Senior Principal Scientist at Novo Nordisk A/S, Denmark, and the author of numerous papers and presentations in the field. ANURAG S. RATHORE is a Professor in the Department of Chemical Engineering at the Indian Institute of Technology, New Delhi, India. He has published several books that include Quality by Design for Biopharmaceuticals: Principles and Case Studies (Wiley, 2009). SATINDER AHUJA is President of Ahuja Consulting, USA, and the author/editor of numerous books including Chiral Separation Methods for Pharmaceutical and Biotechnological Products (Wiley, 2010), Trace and Ultratrace Analysis by HPLC (Wiley, 1992), and Selectivity and Detectability Optimizations in HPLC (Wiley, 1989).

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