Quality by Design for Biopharmaceuticals

Anurag S. Rathore received his PhD in chemical engineering from Yale University and is the Director of Process Development, Amgen Inc. His areas of interest include process development, scale-up, technology transfer, process validation, process analytical technology, and quality by design. He has authored more than 100 publications and presentations in these areas and serves on the editorial advisory boards for Biotechnology Progress, BioPharm International, Pharmaceutical Technology Europe, Journal of Biochemical and Biophysical Methods, and Separation and Purification Reviews. Rohin Mhatre is a Senior Director in the BioProcess Development department at Biogen Idec, Cambridge, Massachusetts, and has been with the company since 1996. His group is responsible for development of analytical methods and product characterization to support the process and formulation development of early and late stage clinical programs. Mhatre is also leading the QbD initiative within Biogen Idec. He has authored several publications and been an invited speaker to numerous scientific meetings.

• Foreword xiii Preface xvPreface to the Wiley Series on Biotechnology and Related Topics xviiContributors xix1 QUALITY BY DESIGN: AN OVERVIEW OF THE BASIC CONCEPTS 1Rohin Mhatre and Anurag S. Rathore1.1 Introduction 11.2 Critical Quality Attributes 21.3 An Overview of Design Space 31.4 Raw Materials and their Impact on QbD 41.5 Process Analytical Technology 41.6 The Utility of Design Space and QbD 51.7 Conclusions 72 CONSIDERATIONS FOR BIOTECHNOLOGY PRODUCT QUALITY BY DESIGN 9Steven Kozlowski and Patrick Swann2.1 Introduction 92.2 Quality by Design 102.3 Relevant Product Attributes 112.4 Manufacturing Process 142.5 Developing a Design Space 182.6 Uncertainty and Complexity 222.7 Future Horizons 232.8 QbD Submission Thoughts 252.9 Implementation Plans 262.10 Summary 273 MOLECULAR DESIGN OF RECOMBINANT MALARIA VACCINES EXPRESSED BY Pichia pastoris 31David L. Narum3.1 Introduction 313.2 The Malaria Genome and Proteome 343.3 Expression of Two Malaria Antigens in P. pastoris 343.4 Summary 464 USING A RISK ASSESSMENT PROCESS TO DETERMINE CRITICALITY OF PRODUCT QUALITY ATTRIBUTES 53Mark A Schenerman, Milton J. Axley, Cynthia N. Oliver, Kripa Ram, and Gail F. Wasserman4.1 Introduction 534.2 Examples of Criticality Determination 604.3 Conclusion 815 CASE STUDY ON DEFINITION OF PROCESS DESIGN SPACE FOR A MICROBIAL FERMENTATION STEP 85Pim van Hoek, Jean Harms, Xiangyang Wang, and Anurag S. Rathore5.1 Introduction 855.2 Approach Toward Process Characterization 875.3 Risk Analysis 885.4 Small-Scale Model Development and Qualification 895.5 Design of Experiment Studies 945.6 Worst Case Studies 965.7 Definition of Design Space 995.8 Definition of Validation Acceptance Limits 1035.9 Regulatory Filing, Process Monitoring, and Postapproval Changes 1066 APPLICATION OF QbD PRINCIPLES TO TANGENTIAL FLOW FILTRATION OPERATIONS 111Peter K. Watler and John Rozembersky6.1 Introduction 1116.2 Applications of TFF in Biotechnology 1136.3 Tangential Flow Filtration Operating Principles 1136.4 TFF Design Objectives 1156.5 Membrane Selection 1156.6 TFF Operating Parameter Design 1186.7 TFF Diafiltration Operating Mode Design 1226.8 Summary 1257 APPLICATIONS OF DESIGN SPACE FOR BIOPHARMACEUTICAL PURIFICATION PROCESSES 127Douglas J. Cecchini7.1 Introduction 1277.2 Establishing Design Space for Purification Processes during Process Development 1287.3 Applications of Design Space 1317.4 Cell Harvest and Product Capture Steps 1317.5 Protein A Capture Column 1367.6 Hydrophobic Interaction Chromatography 1377.7 Anion Exchange Chromatography 1387.8 Summary 1418 VIRAL CLEARANCE: A STRATEGY FOR QUALITY BY DESIGN AND THE DESIGN SPACE 143Gail Sofer and Jeffrey Carter8.1 Introduction 1438.2 Current and Future Approaches to Virus Clearance Characterization 1438.3 Benefits of Applying Design Space Principles to Virus Clearance 1448.4 Technical Limitations Related to Adoption of QdB/Design Space Concepts in Virus Clearance 1458.5 Developing a Virus Clearance Design Space 1488.6 Staying in the Design Space 1568.7 Conclusion 1579 APPLICATION OF QUALITY BY DESIGN AND RISK ASSESSMENT PRINCIPLES FOR THE DEVELOPMENT OF FORMULATION DESIGN SPACE 161Kingman Ng and Natarajan Rajagopalan9.1 Introduction 1619.2 Quality by Design (QbD) Approach 1629.3 Target Product Profile (TPP) 1639.4 Molecular Degradation Characterization 1649.5 Active Pharmaceutical Ingredient (API) Critical Properties 1669.6 Preformulation Characterization 1679.7 Initial Formulation Risk Assessments 1689.8 Formulation Optimization and Design Space 1699.9 Selection of Solution Formulation Composition 1719.10 Summary 17310 APPLICATION OF QbD PRINCIPLES TO BIOLOGICS PRODUCT: FORMULATION AND PROCESS DEVELOPMENT 175Satish K. Singh, Carol F. Kirchhoff, and Amit Banerjee10.1 Introduction: QbD in Biologics Product Development 17510.2 Risk Assessment Process 17710.3 Examples 17810.4 Conclusions 19111 QbD FOR RAW MATERIALS 193Maureen Lanan11.1 Introduction 19311.2 Background 19411.3 Current Practice for Raw Materials 19511.4 QbD in Development 19511.5 QbD in manufacturing 19611.6 QbD for organizations 19711.7 Tests Available 19711.8 Conclusions and Future Prospects 20712 PAT TOOLS FOR BIOLOGICS: CONSIDERATIONS AND CHALLENGES 211Michael Molony and Cenk Undey12.1 Introduction 21112.2 Cell Culture and Fermentation PAT Tools 21412.3 Purification PAT Tools 22312.4 Formulation PAT Tools 22812.5 PAT Tools for Bioprocess Starting Materials, Defined Media, and Complex Raw Materials 23012.6 Chemometrics and Advanced Process Control Tools 23212.7 The power of PLS and PCA 23312.8 "Relevant Time"Column Integrity Monitoring (Moments Analysis versus HETP) 24012.9 Challenges for Implementation of PAT Tools 24412.10 Future PAT Tools 24713 EVOLUTION AND INTEGRATION OF QUALITY BY DESIGN AND PROCESS ANALYTICAL TECHNOLOGY 255Duncan Low and Joseph Phillips13.1 Introduction 25513.2 Evolution of PAT and Quality by Design (QbD): Emerging Guidelines and Standards 25613.3 Process Analytical Technology (PAT) 26113.4 Quality by Design 26313.5 Implementing QbD and PAT 26613.6 Conclusions 282Acknowledgments 283References 283Index 287