This is the first book that explains the underlying concepts of Quality by Design (QbD) and the practical aspects of implementing QbD in biopharmaceutical manufacturing. A systematic approach leads the reader through a process, outlining the understanding of the critical quality attributes of the molecule, the development of the design space to meet the quality attributes, filing of the QbD information in regulatory documents, risk management, and the application of QbD. Complete with real-world case studies, this is a core reference for scientists in the biopharmaceutical industry, regulatory agencies, and students.

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.
Preface.
Preface to the Wiley Series on Biotechnology and Related Topics.
Contributors.
1 QUALITY BY DESIGN: AN OVERVIEW OF THE BASIC CONCEPTS (Rohin Mhatre and Anurag S. Rathore).
1.1 Introduction.
1.2 Critical Quality Attributes.
1.3 An Overview of Design Space.
1.4 Raw Materials and their Impact on QbD.
1.5 Process Analytical Technology.
1.6 The Utility of Design Space and QbD.
1.7 Conclusions.
References.
2 CONSIDERATIONS FOR BIOTECHNOLOGY PRODUCT QUALITY BY DESIGN (Steven Kozlowski and Patrick Swann).
2.1 Introduction.
2.2 Quality by Design.
2.3 Relevant Product Attributes.
2.4 Manufacturing Process.
2.5 Developing a Design Space.
2.6 Uncertainty and Complexity.
2.7 Future Horizons.
2.8 QbD Submission Thoughts.
2.9 Implementation Plans.
2.10 Summary.
Acknowledgments.
References.
3 MOLECULAR DESIGN OF RECOMBINANT MALARIA VACCINES EXPRESSED BY Pichia pastoris (David L. Narum).
3.1 Introduction.
3.2 The Malaria Genome and Proteome.
3.3 Expression of Two Malaria Antigens in P. pastoris.
3.4 Summary.
Acknowledgments.
References.
4 USING A RISK ASSESSMENT PROCESS TO DETERMINE CRITICALITY OF PRODUCT QUALITY ATTRIBUTES (Mark A Schenerman, Milton J. Axley, Cynthia N. Oliver, Kripa Ram, and Gail F. Wasserman).
4.1 Introduction.
4.2 Examples of Criticality Determination.
4.3 Conclusion.
Acknowledgments.
References.
5 CASE STUDY ON DEFINITION OF PROCESS DESIGN SPACE FOR A MICROBIAL FERMENTATION STEP (Pim van Hoek, Jean Harms, Xiangyang Wang, and Anurag S. Rathore).
5.1 Introduction.
5.2 Approach Toward Process Characterization.
5.3 Risk Analysis.
5.4 Small-Scale Model Development and Qualification.
5.5 Design of Experiment Studies.
5.6 Worst Case Studies.
5.7 Definition of Design Space.
5.8 Definition of Validation Acceptance Limits.
5.9 Regulatory Filing, Process Monitoring, and Postapproval Changes.
Acknowledgment.
References.
6 APPLICATION OF QbD PRINCIPLES TO TANGENTIAL FLOW FILTRATION OPERATIONS (Peter K. Watler and John Rozembersky).
6.1 Introduction.
6.2 Applications of TFF in Biotechnology.
6.3 Tangential Flow Filtration Operating Principles.
6.4 TFF Design Objectives.
6.5 Membrane Selection.
6.6 TFF Operating Parameter Design.
6.7 TFF Diafiltration Operating Mode Design.
6.8 Summary.
References.
7 APPLICATIONS OF DESIGN SPACE FOR BIOPHARMACEUTICAL PURIFICATION PROCESSES (Douglas J. Cecchini).
7.1 Introduction.
7.2 Establishing Design Space for Purification Processes during Process Development.
7.3 Applications of Design Space.
7.4 Cell Harvest and Product Capture Steps.
7.5 Protein A Capture Column.
7.6 Hydrophobic Interaction Chromatography.
7.7 Anion Exchange Chromatography.
7.8 Summary.
Acknowledgments.
References.
8 VIRAL CLEARANCE: A STRATEGY FOR QUALITY BY DESIGN AND THE DESIGN SPACE (Gail Sofer and Jeffrey Carter).
8.1 Introduction.
8.2 Current and Future Approaches to Virus Clearance Characterization.
8.3 Benefits of Applying Design Space Principles to Virus Clearance.
8.4 Technical Limitations Related to Adoption of QdB/Design Space Concepts in Virus Clearance.
8.5 Developing a Virus Clearance Design Space.
8.6 Staying in the Design Space.
8.7 Conclusion.
Acknowledgments.
References.
9 APPLICATION OF QUALITY BY DESIGN AND RISK ASSESSMENT PRINCIPLES FOR THE DEVELOPMENT OF FORMULATION DESIGN SPACE (Kingman Ng and Natarajan Rajagopalan).
9.1 Introduction.
9.2 Quality by Design (QbD) Approach.
9.3 Target Product Profile (TPP).
9.4 Molecular Degradation Characterization.
9.5 Active Pharmaceutical Ingredient (API) Critical Properties.
9.6 Preformulation Characterization.
9.7 Initial Formulation Risk Assessments.
9.8 Formulation Optimization and Design Space.
9.9 Selection of Solution Formulation Composition.
9.10 Summary.
Acknowledgments.
References.
10 APPLICATION OF QbD PRINCIPLES TO BIOLOGICS PRODUCT: FORMULATION AND PROCESS DEVELOPMENT (Satish K. Singh, Carol F. Kirchhoff, and Amit Banerjee).
10.1 Introduction: QbD in Biologics Product Development.
10.2 Risk Assessment Process.
10.3 Examples.
10.4 Conclusions.
References.
11 QbD FOR RAW MATERIALS (Maureen Lanan).
11.1 Introduction.
11.2 Background.
11.3 Current Practice for Raw Materials.
11.4 QbD in Development.
11.5 QbD in manufacturing.
11.6 QbD for organizations.
11.7 Tests Available.
11.8 Conclusions and Future Prospects.
Acknowledgments.
References.
12 PAT TOOLS FOR BIOLOGICS: CONSIDERATIONS AND CHALLENGES (Michael Molony and Cenk Undey).
12.1 Introduction.
12.2 Cell Culture and Fermentation PAT Tools.
12.3 Purification PAT Tools.
12.4 Formulation PAT Tools.
12.5 PAT Tools for Bioprocess Starting Materials, Defined Media, and Complex Raw Materials.
12.6 Chemometrics and Advanced Process Control Tools.
12.7 The power of PLS and PCA.
12.8 ''Relevant Time'' Column Integrity Monitoring (Moments Analysis versus HETP).
12.9 Challenges for Implementation of PAT Tools.
12.10 Future PAT Tools.
Acknowledgments.
References.
13 EVOLUTION AND INTEGRATION OF QUALITY BY DESIGN AND PROCESS ANALYTICAL TECHNOLOGY (Duncan Low and Joseph Phillips).
13.1 Introduction.
13.2 Evolution of PAT and Quality by Design (QbD): Emerging Guidelines and Standards.
13.3 Process Analytical Technology (PAT).
13.4 Quality by Design.
13.5 Implementing QbD and PAT.
13.6 Conclusions.
Acknowledgments.
References.
Index.