Contents XVII. List of Contributors Preface XXIII

Size: px

Start display at page:

Download "Contents XVII. List of Contributors Preface XXIII"

Adela Wilkins
5 years ago
Views:

1 V List of Contributors Preface XXIII XVII 1 Proteins Separation and Purification by Expanded Bed Adsorption and Simulated Moving Bed Technology 1 Ping Li, Pedro Ferreira Gomes, José M. Loureiro, and Alirio E. Rodrigues 1.1 Introduction Protein Capture by Expanded Bed Technology Adsorbent Materials Expanded Bed Adsorption/Desorption of Protein Modeling of the Expanded Bed Proteins Separation and Purification by Salt Gradient Ion Exchange SMB Adsorption Isotherms and Kinetics of BSA and Myoglobin on Ion Exchange Resins Salt Gradient Formation and Process Design for IE-SMB Chromatography Separation Region of Salt Gradient IE-SMB Chromatography Proteins Separation and Purification in Salt Gradient IE-SMB with Open Loop Configuration Conclusion 26 References 27 2 BioSMB Technology as an Enabler for a Fully Continuous Disposable Biomanufacturing Platform 35 Marc Bisschops 2.1 Introduction Integrated Continuous Bioprocessing Multicolumn Chromatography 39

2 VI 2.4 BioSMB Technology Fully Disposable Continuous Processing Case Studies Regulatory Aspects Conclusions 50 References 51 3 Impact of Continuous Processing Techniques on Biologics Supply Chains 53 Aloke Das 3.1 Introduction The Biologics Industry The Biologics Value Chain Downstream Purification Costs Chromatography Techniques Used in Downstream Purification of Biomolecules Need for Continuous Manufacturing in Downstream Purification The Multicolumn Countercurrent Solvent Gradient Purification Chromatography System Next-Generation Biologic Products Bispecific Monoclonal Antibodies Major Biopharma Companies and Their Interest in Bispecific Mabs Challenges in Purification of Bispecific Monoclonal Antibodies Improving the Downstream Processing of Bispecific Mabs by Introduction of MCSGP in the Value Chain Advantages of Utilizing MCSGP Process in Bispecific Mabs Purification as Compared to Batch Chromatography Impact of MCSGP System on Biologic Supply Chains Impact on Patent Approval Structure of Biologic Drugs For a Manufacturer Who Already has a Biologic Drug in the Market For a Manufacturer Who is Developing a Biologic Drug Impact on Big Biopharma Companies Impact on the Chromatography Market Limitations of the MCSGP System Conclusion Further Research 65 Acknowledgments 66 3.A Appendix/Additional Information 66 3.A.1 Regulatory Structure for Bispecific Monoclonal Antibodies 67 3.A.1.1 Regulatory Compliance Comparison between US, EU, and Emerging Economies 67 References 68

3 VII 4 Integrating Continuous and Single-Use Methods to Establish a New Downstream Processing Platform for Monoclonal Antibodies 71 Christopher Gillespie, Mikhail Kozlov, Michael Phillips, Ajish Potty, Romas Skudas, Matthew Stone, Alex Xenopoulos, Alison Dupont, Jad Jaber, and William Cataldo 4.1 Introduction Harvest and Clarification The Challenge and Technology Selection Centrifugation Filtration Impurity Precipitation Summary Capture Background Protein A Chromatography Chromatographic Methods Slurried Bed Methods Continuous Chromatography Capture Case Studies Continuous Protein A Chromatography Capture Case Study Effect of Clarification Method on Protein A Performance Polishing Background Technology Selection Strategy Complete Flow-Through Polishing Case Study Cost of Goods Analysis Methodology Clarification Capture Polishing Overall Summary 92 References 93 5 Modeling of Protein Monomer/Aggregate Purification by Hydrophobic Interaction Chromatography: Application to Column Design and Process Optimization 97 Mark-Henry Kamga, Hae Woo Lee, Namjoon Kim, and Seongkyu Yoon 5.1 Introduction Mathematical Model The Rate-Limiting Step in the HIC Process Dimensional Considerations Adsorption Capacity vs. Concentration of Vacant Sites (q mi vs. C vi ) Concentration of Protein Adsorbed on Resin (q i vs. C ia ) 100

4 VIII Mathematical Model Experimentation Protein Solutions Determination of Adsorption and Desorption Kinetic Constants Column Chromatography Results and Discussion Kinetic Constants Protein Denaturation Model vs. Experimental Results Applications Conclusion 112 Acknowledgments 112 References Continuous Animal Cell Perfusion Processes: The First Step Toward Integrated Continuous Biomanufacturing 115 Leda R. Castilho 6.1 Introduction The Basics of Perfusion Processes Cell Banking and Inoculum Development in the Context of Perfusion Processes Culture Conditions Cell Retention Devices Gravitational Settlers Centrifuges Hydrocyclones Acoustic (Ultrasonic) Separators Tangential Flow-Filtration ATF Systems Floating Membrane Devices Spin-Filters Rotating Cylindrical Filters (Vortex-Flow Filters or External Spin-Filters) Rotating Disc Filters (Controlled-Shear Filters) Integrated Perfusion Purification Processes for Continuous Biomanufacturing Concluding Remarks 144 References Perfusion Process Design in a 2D Rocking Single-Use Bioreactor 155 Nico M.G. Oosterhuis 7.1 Introduction Production Costs Equipment Requirements for a Single-Use Perfusion Process 157

5 IX 7.4 Testing Results Single-Use Perfusion Process Simplified Seeding Process Future Outlook 163 References Advances in the Application of Perfusion Technologies to Drosophila S2 Insects Cell Culture 165 Lars Poulsen and Willem A. de Jongh 8.1 Introduction Case Study 1: Acoustic Separation The Perfusion Setup (BioSep) Results and Discussion Development Cell Count in the Bioreactor Effects of BioSep Settings on Cell Loss and Viability Controlling the Cell Concentration Through Bleed Rate Control Effect of Total Dilution Rate on Culture Viability Development of the Perfusion Rate Profile Initial Testing of Robustness of Upstream Process in 1.5 l Fermentations Scaling Up and Consistency in 4.5 l Fermentations Process Scale-Up Conclusions for Case Study Case Study 2: ATF-Based Cell Retention ATF Technology Methods Results Cell Counts Achieved Using Perfusion Technology Effect of Feed Strategy Yield Improvements Achieved Using Fed-Batch and Concentrated Perfusion Protein Stability Conclusions for Case Study Final Remarks 181 Acknowledgments 181 References Single-Use Systems Support Continuous Bioprocessing by Perfusion Culture 183 William G. Whitford 9.1 Introduction Potential Advantages in Continuous Processing Improved Product Quality Ease in Process Development 188

6 X Improved Scalability Increased Profitability Sustainability Challenges in Adoption of Continuous Processing Continuous Biomanufacturing Single-Use Systems Hybrid Systems Perfusion Culture Single-Use in Continuous Biomanufacturing Roller Bottles Mechanically Agitated Suspension Reactors Hollow Fiber Media Exchange Packed Bed Bioreactors Hollow Fiber Perfusion Bioreactors Continuous Flow Centrifugation Acoustic Wave Separation Conclusion 222 References Multicolumn Countercurrent Gradient Chromatography for the Purification of Biopharmaceuticals 227 Thomas Müller-Späth and Massimo Morbidelli 10.1 Introduction to Multicolumn Countercurrent Chromatography Introduction to Multicolumn Simulated Moving Bed (SMB) Chromatography Capture Applications Introduction Process Principle Application Examples Polishing Applications Introduction Multicolumn Countercurrent Solvent Gradient Purification Principle Multicolumn Countercurrent Solvent Gradient Purification Process Design Multicolumn Countercurrent Solvent Gradient Purification Case Study Discovery and Development Applications Scale-Up of Multicolumn Countercurrent Chromatography Multicolumn Countercurrent Chromatography as Replacement for Batch Chromatography Unit Operations Multicolumn Countercurrent Chromatography in Continuous Manufacturing Process Analytical Tools for Multicolumn Countercurrent Processes 252 References 253

7 XI 11 Monoclonal Antibody Continuous Processing Enabled by Single Use 255 Mark Brower, Ying Hou, and David Pollard 11.1 Introduction Single-Use Revolution to Enable Process Intensification and Continuous Processing Principles of Continuous Multicolumn Chromatography for Biological Production (BioSMB) Continuous Downstream Processing for Monoclonal Antibodies Unit Operation Development Surge Vessels and Balancing Flows Primary Recovery: Centrifugation and Depth Filtration Bulk Purification: Continuous Multicolumn Chromatography BioSMB Protein A Capture and Viral Inactivation Protein A Loading Zone Optimization Protein A Elution Zone Considerations Viral Inactivation Fine Purification: Flow-Through Anion Exchange Chromatography (AEX) Effects of Sample Flow Rate on AEX Membrane Chromatography Effect of Sample Loading Amount on AEX Membrane Chromatography Scaling-Up Membrane Chromatography for Continuous Processing Fine Purification: Continuous Multicolumn Chromatography BioSMB Cation Exchange Chromatography Cation Exchange Loading Zone Optimization Cation Exchange Elution Zone Considerations Formulation: Continuous Ultrafiltration Pilot-Scale Demonstration of the Integrated Continuous Process Summary 293 References Continuous Production of Bacteriophages 297 Ales Podgornik, Nika Janez, Franc Smrekar, and Matjaz Peterka 12.1 Bacteriophages Life Cycle Determination of Bacteriophage Properties Bacteriophage Cultivation Chemostat Cellstat Cellstat Productivity Bacteriophage Selection Technical Challenges 323

8 XII 12.3 Continuous Purification of Bacteriophages Centrifugation Precipitation and Flocculation Filtration Chromatographic and Other Adsorption Methods Conclusions 329 References Very High Cell Density in Perfusion of CHO Cells by ATF, TFF, Wave Bioreactor, and/or CellTank Technologies Impact of Cell Density and Applications 339 Véronique Chotteau, Ye Zhang, and Marie-Francoise Clincke 13.1 Introduction Equipment Results and Discussion Perfusion Using ATF or TFF in Wave-Induced Bioreactor Cell Growth IgG Production Perfusion Using CellTank Cell Growth IgG Production Very High Cell Density Cryopreservation from Very High Cell Density Perfusion Conclusions 353 Acknowledgments 354 References Implementation of CQA (Critical Quality Attribute) Based Approach for Development of Biosimilars 357 Sanjeev K. Gupta 14.1 Background Biosimilar Product Development Attributes/Parameters in Biopharmaceuticals Critical Quality Attributes Critical Process Parameters (CPP) The ICH Q8 Minimal Approach to Pharmaceutical Development Quality-by-Design Quality Attributes and Biosimilars Development Quality, Safety, and Efficacy of Biosimilars Implementing CQA Approach for Biosimilar Development Identification of the CQA CQA-Based Clone Selection and Upstream Process Development Factors Affecting CQAs of the Biologics 366

9 XIII Expression Host and Recombinant Cell Line Process Related Protein Production Host and CQA Cell Line Changes and CQA Host Cell Line and Clone Selection Criteria Sequence Variants Identification by CQA Incomplete Processing of Signal Sequences and CQA Upstream Process Impact on Product Quality Attributes Bioreactor Optimization and Scale Up CQA in Purification and Formulation Downstream Processing of Biosimilars Downstream Processing and CQA CQAs in Formulation and Stability Formulation and Quality Attributes Stability and Quality Attributes Summary 382 References Automated Single-Use Centrifugation Solution for Diverse Biomanufacturing Process 385 Sunil Mehta 15.1 Introduction Separation by Centrifugation Separation by Filtration Downstream Process Challenges of High Cell Density Cultures Single-Use Centrifugation ksep Technology ksep System Configuration Low-Shear Process Perfusion Concentration, Media Replacement, and Harvest of Cells Continuous Harvest Clarification Separation of Cells from Microcarriers Summary 399 References The Review of Flexible Production Platforms for the Future 401 Maik W. Jornitz 16.1 Introduction Today s Processing Technology Advances Single-Use Liquid Hold and Mixing Bags Filtration and Purification Technologies Product and Component Transfer Aseptic Fluid Connections and Disconnections Single-Use Final Filling Systems 417

10 XIV 16.3 Todays Facility Designs Construction and Design Types Process Location and Flow Future Processing and Facility Requirements Upstream Technologies Downstream Technologies Single-Use Engineering and Design Facilities and Process Design 428 References Evaluating the Economic and Operational Feasibility of Continuous Processes for Monoclonal Antibodies 433 Suzanne S. Farid, James Pollock, and Sa V. Ho 17.1 Introduction Background on Continuous Processing Perfusion Culture Semicontinuous Chromatography Tool Description Case Study 1: Fed-batch Versus Perfusion Culture for Commercial mab Production Case Study 2: Semicontinuous Affinity Chromatography for Clinical and Commercial Manufacture Case Study 3: Integrated Continuous Processing Flowsheets Conclusions 452 Acknowledgments 452 References Opportunities and Challenges for the Implementation of Continuous Processing in Biomanufacturing 457 Sadettin S. Ozturk 18.1 Introduction A Brief History of Continuous Processing in Biomanufacturing Opportunities for Continuous Processing in Biomanufacturing Higher Process Yields Higher Process Efficiencies Compact and Flexible Facilities Stable and Consistent Production Better Product Quality Challenges for Implementing Continuous Processing in Biomanufacturing Process Complexity Cell Retention High Cell Density Longer Run Times Process Scalability in a Continuous Perfusion Process 470

11 XV Scale and Capacity Limitations Process Scale-up Process Consistency and Control Process Characterization and Validation Complexity of a Scale-down Model for a Perfusion Process Process Optimization and Characterization for a Perfusion Process Process Validation Conclusions 476 Acknowledgment 476 References The Potential Impact of Continuous Processing on the Practice and Economics of Biopharmaceutical Manufacturing 479 L. Richard Stock, Marc Bisschops, and Thomas C. Ransohoff 19.1 Introduction Background (Review of Status Quo How We Make Biopharmaceutical Products Today) The Rationale for Continuous Processing The Obstacles for Implementation of Continuous Processing for Biopharmaceuticals The Potential Impact of Continuous Manufacturing on Process Economics The Potential Impact of Continuous Processing on Biopharmaceutical Manufacturing Practices Summary 492 References 492 Index 495

Bioprocessing Challenges: High-Titer Mammalian-Based Cell Systems. Elements influencing the way Biologics may be manufactured /supplied in the future

Bioprocessing Challenges: High-Titer Mammalian-Based Cell Systems Jonathan Romero CMC Leadership, Technical Development Pharmaceutical Operations & Technology 2015 ISPE PRODUCT SHOW Business Drivers Elements