Quality by Design for Biopharmaceuticals

Wiley Series in Biotechnology and bioengineering Anurag S. Rathore, Series Editor Quality by Design for Biopharmaceuticals Principles and Case Studies Edited by Anurag S. Rathore Rohin Mhatre

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.>/p>

Foreword	p. xiii
Preface	p. xv
Preface to the Wiley Series on Biotechnology and Related Topics	p. xvii
Contributors	p. xix
Quality by Design: An Overview of the Basic Concepts	p. 1
Introduction	p. 1
Critical Quality Attributes	p. 2
An Overview of Design Space	p. 3
Raw Materials and their Impact on QbD	p. 4
Process Analytical Technology	p. 4
The Utility of Design Space and QbD	p. 5
Conclusions	p. 7
References	p. 7
Considerations for Biotechnology Product Quality By Design	p. 9
Introduction	p. 9
Quality by Design	p. 10
Relevant Product Attributes	p. 11
Manufacturing Process	p. 14
Developing a Design Space	p. 18
Uncertainty and Complexity	p. 22
Future Horizons	p. 23
QbD Submission Thoughts	p. 25
Implementation Plans	p. 26
Summary	p. 27
Acknowledgments	p. 27
References	p. 27
Molecular Design of Recombinant Malaria Vaccines Expressed By Pichia pastoris	p. 31
Introduction	p. 31
The Malaria Genome and Proteome	p. 34
Expression of Two Malaria Antigens in P. pastoris	p. 34
Summary	p. 46
Acknowledgments	p. 48
References	p. 48
Using A Risk Assessment Process to Determine Criticality of Product Quality Attributes	p. 53
Introduction	p. 53
Examples of Criticality Determination	p. 60
Conclusion	p. 81
Acknowledgments	p. 82
References	p. 82
Case Study on Definition of Process Design Space for A Microbial Fermentation Step	p. 85
Introduction	p. 85
Approach Toward Process Characterization	p. 87
Risk Analysis	p. 88
Small-Scale Model Development and Qualification	p. 89
Design of Experiment Studies	p. 94
Worst Case Studies	p. 96
Definition of Design Space	p. 99
Definition of Validation Acceptance Limits	p. 103
Regulatory Filing, Process Monitoring, and Postapproval Changes	p. 106
Acknowledgment	p. 108
References	p. 108
Application of QbD Principles to Tangential Flow Filtration Operations	p. 111
Introduction	p. 111
Applications of TFF in Biotechnology	p. 113
Tangential Flow Filtration Operating Principles	p. 113
TFF Design Objectives	p. 115
Membrane Selection	p. 115
TFF Operating Parameter Design	p. 118
TFF Diafiltration Operating Mode Design	p. 122
Summary	p. 125
References	p. 125
Applications of Design Space for Biopharmaceutical Purification Processes	p. 127
Introduction	p. 127
Establishing Design Space for Purification Processes during Process Development	p. 128
Applications of Design Space	p. 131
Cell Harvest and Product Capture Steps	p. 131
Protein A Capture Column	p. 136
Hydrophobic Interaction Chromatography	p. 137
Anion Exchange Chromatography	p. 138
Summary	p. 141
Acknowledgments	p. 141
References	p. 141
Viral Clearance: A Strategy for Quality by Design and the Design Space	p. 143
Introduction	p. 143
Current and Future Approaches to Virus Clearance Characterization	p. 143
Benefits of Applying Design Space Principles to Virus Clearance	p. 144
Technical Limitations Related to Adoption of QdB/Design Space Concepts in Virus Clearance	p. 145
Developing a Virus Clearance Design Space	p. 148
Staying in the Design Space	p. 156
Conclusion	p. 157
Acknowledgments	p. 157
References	p. 158
Application of Quality by Design and Risk Assessment Principles for the Development of Formulation Design Space	p. 161
Introduction	p. 161
Quality by Design (QbD) Approach	p. 162
Target Product Profile (TPP)	p. 163
Molecular Degradation Characterization	p. 164
Active Pharmaceutical Ingredient (API) Critical Properties	p. 166
Preformulation Characterization	p. 167
Initial Formulation Risk Assessments	p. 168
Formulation Optimization and Design Space	p. 169
Selection of Solution Formulation Composition	p. 171
Summary	p. 173
Acknowledgments	p. 174
References	p. 174
Application of QbD Principles to Biologics Product: Formulation and Process Development	p. 175
Introduction: QbD in Biologics Product Development	p. 175
Risk Assessment Process	p. 177
Examples	p. 178
Conclusions	p. 191
References	p. 191
QbD For Raw Materials	p. 193
Introduction	p. 193
Background	p. 194
Current Practice for Raw Materials	p. 195
QbD in Development	p. 195
QbD in manufacturing	p. 196
QbD for organizations	p. 197
Tests Available	p. 197
Conclusions and Future Prospects	p. 207
Acknowledgments	p. 208
References	p. 208
Pat Tools for Biologics: Considerations and Challenges	p. 211
Introduction	p. 211
Cell Culture and Fermentation PAT Tools	p. 214
Purification PAT Tools	p. 223
Formulation PAT Tools	p. 228
PAT Tools for Bioprocess Starting Materials, Defined Media, and Complex Raw Materials	p. 230
Chemometrics and Advanced Process Control Tools	p. 232
The power of PLS and PCA	p. 233
"Relevant Time" Column Integrity Monitoring (Moments Analysis versus HETP)	p. 240
Challenges for Implementation of PAT Tools	p. 244
Future PAT Tools	p. 247
Acknowledgments	p. 248
References	p. 249
Evolution and Integration of Quality by Design and Process Analytical Technology	p. 255
Introduction	p. 255
Evolution of PAT and Quality by Design (QbD): Emerging Guidelines and Standards	p. 256
Process Analytical Technology (PAT)	p. 261
Quality by Design	p. 263
Implementing QbD and PAT	p. 266
Conclusions	p. 282
Acknowledgments	p. 283
References	p. 283
Index	p. 287
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Quality by Design for Biopharmaceuticals Principles and Case Studies

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