GINTARAS.V. REKLAITIS, PhD, is Professor of Chemical Engineering and Industrial & Physical Pharmacy at Purdue University, member of the U.S. National Academy of Engineering, and the Deputy Director of the NSF Engineering Research Center on Structured Organic Particulate Systems.

CHRISTINE SEYMOUR, PhD, is Director in Global Regulatory Chemistry, Manufacturing & Controls at Pfizer Inc, the 2018 President of AIChE, and a Director in AIChE's Society for Biological Engineering.

SALVADOR GARCÍA-MUNOZ, PhD, is a Senior Engineering Advisor in Process Modeling and Optimization in Small Molecule Development at Eli Lilly and Company.

Covers a widespread view of Quality by Design (QbD) encompassing the many stages involved in the development of a new drug product.
The book provides a broad view of Quality by Design (QbD) and shows how QbD concepts and analysis facilitate the development and manufacture of high quality products. QbD is seen as a framework for building process understanding, for implementing robust and effective manufacturing processes and provides the underpinnings for a science-based regulation of the pharmaceutical industry.
Edited by the three renowned researchers in the field, Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture guides pharmaceutical engineers and scientists involved in product and process development, as well as teachers, on how to utilize QbD practices and applications effectively while complying with government regulations. The material is divided into three main sections: the first six chapters address the role of key technologies, including process modeling, process analytical technology, automated process control and statistical methodology in supporting QbD and establishing the associated design space. The second section consisting of seven chapters present a range of thoroughly developed case studies in which the tools and methodologies discussed in the first section are used to support specific drug substance and drug-product QbD related developments. The last section discussed the needs for integrated tools and reviews the status of information technology tools available for systematic data and knowledge management to support QbD and related activities.
Highlights
* Demonstrates Quality by Design (QbD) concepts through concrete detailed industrial case studies involving of the use of best practices and assessment of regulatory implications
* Chapters are devoted to applications of QbD methodology in three main processing sectors--drug substance process development, oral drug product manufacture, parenteral product processing, and solid-liquid processing
* Reviews the spectrum of process model types and their relevance, the range of state-of-the-art real-time monitoring tools and chemometrics, and alternative automatic process control strategies and methods for both batch and continuous processes
* The role of the design space is demonstrated through specific examples and the importance of understanding the risk management aspects of design space definition is highlighted
Comprehensive Quality by Design for Pharmaceutical Product Development and Manufacture is an ideal book for practitioners, researchers, and graduate students involved in the development, research, or studying of a new drug and its associated manufacturing process.

List of Contributors xiii
Preface xix
1 Introduction 1
Christine Seymour and Gintaras V. Reklaitis
1.1 Quality by Design Overview 1
1.2 Pharmaceutical Industry 2
1.3 Quality by Design Details 3
1.4 Chapter Summaries 4
References 7
2 An Overview of the Role of Mathematical Models in Implementation of Quality by Design Paradigm for Drug Development and Manufacture 9
Sharmista Chatterjee, Christine M. V. Moore, and Moheb M. Nasr
2.1 Introduction 9
2.2 Overview of Models 9
2.3 Role of Models in QbD 12
2.4 General Scientific Considerations for Model Development 20
2.5 Scientific Considerations for Maintenance of Models 22
2.6 Conclusion 23
References 23
3 Role of Automatic Process Control in Quality by Design 25
Mo Jiang, Nicholas C. S. Kee, Xing Yi Woo, Li May Goh, Joshua D. Tice, Lifang Zhou, Reginald B. H. Tan, Charles F. Zukoski, Mitsuko Fujiwara, Zoltan K. Nagy, Paul J. A. Kenis, and Richard D. Braatz
3.1 Introduction 25
3.2 Design of Robust Control Strategies 31
3.3 Some Example Applications of Automatic Feedback Control 35
3.4 The Role of Kinetics Modeling 40
3.5 Ideas for a Deeper QbD Approach 42
3.6 Summary 44
Acknowledgments 46
References 47
4 Predictive Distributions for Constructing the ICH Q8 Design Space 55
John J. Peterson, Mohammad Yahyah, Kevin Lief, and Neil Hodnett
4.1 Introduction 55
4.2 Overlapping Means Approach 56
4.3 Predictive Distribution Approach 59
4.4 Examples 61
4.5 Summary and Discussion 68
Acknowledgments 69
References 69
5 Design of Novel Integrated Pharmaceutical Processes: A Model?]Based Approach 71
Alicia Román?]Martínez, John M. Woodley, and Rafiqul Gani
5.1 Introduction 71
5.2 Problem Description 73
5.3 Methodology 76
5.4 Application: Case Study 80
5.5 Conclusions 91
References 91
6 Methods and Tools for Design Space Identification in Pharmaceutical Development 95
Fani Boukouvala, Fernando J. Muzzio, and Marianthi G. Ierapetritou
6.1 Introduction 95
6.2 Design Space: A Multidisciplinary Concept 98
6.3 Integration of Design Space and Control Strategy 102
6.4 Case Studies 102
6.5 Conclusions 119
Acknowledgment 120
References 120
7 Using Quality by Design Principles as a Guide for Designing a Process Control Strategy 125
Christopher L. Burcham, Mark LaPack, Joseph R. Martinelli, and Neil McCracken
7.1 Introduction 125
7.2 Chemical Sequence, Impurity Formation, and Control Strategy 130
7.3 Mass Transfer and Reaction Kinetics 140
7.4 Optimal Processing Conditions 165
7.5 Predicted Product Quality under Varied Processing Conditions 174
7.6 Conclusions 186
Acknowledgments 187
Notation 187
Acronyms 187
Symbols 187
Notes 189
References 189
8 A Strategy for Tablet Active Film Coating Formulation Development Using a Content Uniformity Model and Quality by Design Principles 193
Wei Chen, Jennifer Wang, Divyakant Desai, Shih?]Ying Chang, San Kiang, and Olav Lyngberg
8.1 Introduction 193
8.2 Content Uniformity Model Development 197
8.3 RSD Model Validation and Sensitivity Analysis for Model Parameters 212
8.4 Model?]Based Design Space Establishment for Tablet Active Film Coating 219
8.5 Summary 229
Notations 230
References 230
9 Quality by Design: Process Trajectory Development for a Dynamic Pharmaceutical Coprecipitation Process Based on an Integrated Real?]Time Process Monitoring Strategy 235
Huiquan Wu and Mansoor A. Khan
9.1 Introduction 235
9.2 Experimental 237
9.3 Data Analysis Methods 239
9.4 Results and Discussion 240
9.5 Challenges and Opportunities for PCA?]Based Data Analysis and Modeling in Pharmaceutical PAT and QbD
Development 250
9.6 Conclusions 252
Acknowledgments 252
References 253
10 Application of Advanced Simulation Tools for Establishing Process Design Spaces Within the Quality by Design Framework 257
Siegfried Adam, Daniele Suzzi, Gregor Toschkoff, and Johannes G. Khinast
10.1 Introduction 257
10.2 Computer Simulation?]Based Process Characterization of a Pharmaceutical Blending Process 261
10.3 Characterization of a Tablet Coating Process via CFD Simulations 276
10.4 Overall Conclusions 294
References 295
11 Design Space Definition: A Case Study--Small Molecule Lyophilized Parenteral 301
Linas Mockus, David LeBlond, Gintaras V. Reklaitis, Prabir K. Basu, Tim Paul, Nathan Pease, Steven L. Nail, and Mansoor A. Khan
11.1 Introduction 301
11.2 Case Study: Bayesian Treatment of Design Space for a Lyophilized Small Molecule Parenteral 302
11.3 Results 307
11.4 Conclusions 311
Appendix 11.A Implementation Using WinBUGS and R 311
Shelf Life 315
Notation 316
Acknowledgments 317
References 317
12 Enhanced Process Design and Control of a Multiple?]Input Multiple?]Output Granulation Process 319
Rohit Ramachandran
12.1 Introduction and Objectives 319
12.2 Population Balance Model 320
12.3 Simulation and Controllability Studies 323
12.4 Identification of Existing "Optimal" Control?]Loop Pairings 327
12.5 Novel Process Design 330
12.6 Conclusions 335
References 336
13 A Perspective on the Implementation of QbD on Manufacturing through Control System: The Fluidized Bed Dryer Control with MPC and NIR Spectroscopy Case 339
Leonel Quiñones, Luis Obregón, and Carlos Velázquez
13.1 Introduction 339
13.2 Theory 340
13.3 Materials and Methods 344
13.4 Results and Discussion 348
13.5 Continuous Fluidized Bed Drying 355
13.6 Control Limitations 356
13.7 Conclusions 357
Acknowledgment 357
References 357
14 Knowledge Management in Support of QbD 361
G. Joglekar, Gintaras V. Reklaitis, A. Giridhar, and Linas Mockus
14.1 Introduction 361
14.2 Knowledge Hierarchy 363
14.3 Review of Existing Software 364
14.4 Workflow?]Based Framework 365
14.5 Drug Substance Case Study 368
14.6 Design Space 374
14.7 Technical Challenges 382
14.8 Conclusions 384
References 385
Index 387