Industrial chemistry and chemical engineering Books

Book SynopsisComprehensively introduces readers to the production, modifications, and applications of nanocellulose This book gives a thorough introduction to the structure, properties, surface modification, theory, mechanism of composites, and functional materials derived from nanocellulose. It also provides in-depth descriptions of plastics, composites, and functional nanomaterials specifically derived from cellulose nanocrystals, cellulose nanofibrils, and bacterial cellulose. It includes the most recent progress in developing a conceptual framework of nanocellulose, as well as its numerous applications in the design and manufacture of nanocomposites and functional nanomaterials. The book also looks at the relationship between structure and properties. Featuring contributions from many noted experts in the field, Nanocellulose: From Fundamentals to Advanced Materials examines the current status of nanocomposites based on nanocelluloses. It covers surface modification of nanocellulose in the nanocomposites development; reinforcing mechanism of cellulose nanocrystals in nanocomposites; and advanced materials based on self-organization of cellulose nanocrystals. The book studies the role of cellulose nanofibrils in nanocomposites, as well as a potential application based on colloidal properties of cellulose nanocrystals. It also offers strategies to explore biomedical applications of nanocellulose. Provides comprehensive knowledge on the topic of nanocellulose, including the preparation, structure, properties, surface modification and strategy Covers new reports on the application of nanocellulose Summarizes three kinds of nanocellulose (cellulose nanocrystals, cellulose nanofibrils, and bacterial cellulose) and their production, modification, and applications Nanocellulose: From Fundamentals to Advanced Materials is a useful resource for specialist researchers of chemistry, materials, and nanotechnology science, as well as for researchers and students of the subject.Table of ContentsPreface xiii Acknowledgments xv 1 Introduction to Nanocellulose 1Jin Huang, Xiaozhou Ma, Guang Yang, and Dufresne Alain 1.1 Introduction 1 1.2 Preparation of Nanocellulose 2 1.2.1 Cellulose Nanocrystals 2 1.2.2 Cellulose Nanofibers 3 1.2.3 Bacterial Nanocellulose 4 1.3 Surface Modification of Nanocellulose 4 1.3.1 Esterification 7 1.3.2 Oxidation 7 1.3.3 Etherification 8 1.3.4 Amidation 8 1.3.5 Other Chemical Methods 8 1.3.6 Physical Interaction 9 1.4 Nanocellulose-Based Materials and Applications 9 1.5 Conclusions and Prospects 13 References 15 2 Structure and Properties of Cellulose Nanocrystals 21Chunyu Chang, Junjun Hou, Peter R. Chang, and Jin Huang 2.1 Introduction 21 2.2 Extraction of Cellulose Nanocrystals 21 2.2.1 Extraction of Cellulose Nanocrystals by Acid Hydrolysis 21 2.2.2 Pretreatments of Cellulose Before Acid Hydrolysis 27 2.2.3 Other Methods of Preparing Cellulose Nanocrystals 31 2.3 Structures and Properties of Cellulose Nanocrystals 32 2.3.1 Physical Properties of Cellulose Nanocrystals 32 2.3.2 Properties of Cellulose Nanocrystal Suspension 39 References 45 3 Structure and Properties of Cellulose Nanofibrils 53Pei Huang, Chao Wang, Yong Huang, and Min Wu 3.1 Production of CNF 53 3.1.1 Chemical Bleaching 54 3.1.2 Mechanical Disintegration 54 3.1.2.1 Homogenization 54 3.1.2.2 Grinding 58 3.1.2.3 Ball-milling 59 3.1.2.4 Ultrasonication 59 3.1.2.5 Steam Explosion 61 3.1.2.6 Aqueous Counter Collision 61 3.1.2.7 Refining 62 3.1.2.8 Cryocrushing 62 3.1.2.9 Twin-Screw Extrusion 62 3.1.2.10 Other Methods 63 3.1.3 Pretreatment 63 3.2 Features and Properties 64 3.2.1 Morphology of CNF 64 3.2.2 Rheology 64 3.2.3 CNF in Different Forms 65 3.2.3.1 Suspensions 65 3.2.3.2 Powders 66 3.2.3.3 Films 67 3.2.3.4 Hydrogels 70 3.2.3.5 Aerogels CNF 72 3.3 Conclusion 72 References 74 4 Synthesis, Structure, and Properties of Bacterial Cellulose 81Muhammad Wajid Ullah, Sehrish Manan, Sabella J. Kiprono, Mazhar Ul-Islam, and Guang Yang 4.1 Introduction 81 4.2 Biogenesis of Bacterial Cellulose 83 4.2.1 Biochemistry of BC Synthesis 83 4.2.2 Biochemical Pathway of BC Production 85 4.2.3 Molecular Regulation of BC Synthesis 87 4.3 Structure and Exciting Features of Bacterial Cellulose 88 4.3.1 Chemical Structure and Properties 89 4.3.2 Physiological Features 89 4.3.3 Self-assembly and Crystallization 90 4.3.4 Ultrafine Thin Fibrous Structure 90 4.3.5 Macrostructure Control and Orientation 91 4.3.6 Porosity and Materials Absorption Potential of BC for Composite Synthesis 91 4.3.7 Biocompatibility 92 4.3.8 Biodegradability 92 4.4 Production of Bacterial Cellulose: Synthesis Approaches 93 4.4.1 Static Fermentative Cultivation: Production of BC Membrane, Film, or Sheet 93 4.4.2 Shaking Fermentative Cultivation: Production of BC Pellets 94 4.4.3 Agitation Fermentative Cultivation: Production of BC Granules 94 4.4.3.1 Rotating Disk Reactor 95 4.4.3.2 Trickling Bed Reactor 95 4.5 Additives to Enhance BC Production 95 4.5.1 Carboxymethylcellulose 97 4.5.2 Organic Acids 97 4.5.3 Vitamin C 97 4.5.4 Sodium Alginate 99 4.5.5 Alcohols 99 4.5.6 SSGO 99 4.5.7 Lignosulfate 100 4.5.8 Agar and Xanthan 100 4.5.9 Thin Stillage 100 4.6 Strategies Toward Low-Cost BC Production 101 4.6.1 Fruit Juices 101 4.6.2 Sugarcane Molasses 101 4.6.3 Agricultural and Industrial Wastes 103 4.6.4 Food Wastes 104 4.7 Conclusions and Future Prospects 105 Acknowledgment 105 References 106 5 Surface Chemistry of Nanocellulose 115Ge Zhu and Ning Lin 5.1 Brief Introduction to Nanocellulose Family 115 5.1.1 Cellulose Nanocrystals (CNCs) 115 5.1.2 Cellulose Nanofibrils (CNFs) 117 5.1.3 Bacterial Cellulose (BC) 117 5.2 Surface Modification of Nanocellulose 119 5.2.1 Physical Adsorption of Surfactants 119 5.2.2 Sulfonation 121 5.2.3 TEMPO-oxidation 122 5.2.4 Esterification 123 5.2.5 Silylation 125 5.2.6 Grafting Onto 126 5.2.7 Grafting From 131 5.2.7.1 Ring-Opening Polymerization (ROP) 132 5.2.7.2 Living Radical Polymerization (LRP) 134 5.2.8 Chemical Modification from End Hemiacetal 137 5.3 Advanced Functional Modifications 139 5.3.1 Fluorescent and Dye Molecules 139 5.3.2 Amino Acid and DNA 142 5.3.3 Self-cross-linking of Nanocrystals 144 References 145 6 Current Status of Nanocellulose-Based Nanocomposites 155Xiaozhou Ma, Yuhuan Wang, Yang Shen, Jin Huang, and Alain Dufresne 6.1 Introduction 155 6.2 Cellulose Nanocrystal-Filled Nanocomposites 156 6.2.1 Polyolefin-Based Nanocomposites 156 6.2.2 Rubber-Based Nanocomposites 161 6.2.3 Polyester-Based Nanocomposites 164 6.2.4 Polyurethane- and Waterborne Polyurethane-Based Nanocomposites 167 6.2.5 Epoxy- and Waterborne Epoxy-Based Nanocomposites 169 6.2.6 Natural Polymer-Based Nanocomposites 171 6.3 Fibrillated Cellulose-Filled Nanocomposites 172 6.3.1 Polyolefin-Based Nanocomposites 172 6.3.2 Rubber-Based Nanocomposites 176 6.3.3 Polyester-Based Nanocomposites 178 6.3.4 Polyurethane- andWaterborne Polyurethane-Based Nanocomposites 180 6.3.5 Natural Polymer-Based Nanocomposites 182 6.3.6 Other Polymer Nanocomposites Filled with Fibrillated Cellulose 184 6.4 Conclusion and Prospect 186 References 186 7 Reinforcing Mechanism of Cellulose Nanocrystals in Nanocomposites 201Yaoyao Chen, Lin Gan, Jin Huang, and Alain Dufresne 7.1 Percolation Approach 201 7.1.1 Mean-Field Theory 202 7.1.2 Percolation Model 204 7.1.3 Factors Influencing the Percolation Network Formation 208 7.2 Interfacial Behaviors Between Cellulose Nanocrystals and Matrix 211 7.2.1 Effect of Functional Groups on CNC Surface on Interfacial Interaction 211 7.2.2 Effect of Segmental Entanglement Mediated with Grafted Chains on CNC Surface 225 7.2.3 Role of Co-continuous Structure Derived from Chemical Coupling of Filler/Matrix 229 7.2.3.1 Thiol−ene Coupling Process Between Modified Cellulose Nanocrystals (CNCs) and Matrix 230 7.2.3.2 Huisgen Cycloaddition Click Chemistry Between Modified CNCs and Matrices 232 7.2.3.3 Schiff’s Base Reaction Between Cellulose Nanocrystals (CNCs) and Matrix 233 7.2.3.4 Esterification Reaction Between CNCs and The Matrix 237 7.2.3.5 Chemical Coupling Between Hydroxyl Groups of Matrix and Aldehyded CNCs or Modified CNCs 237 7.3 Conclusions 242 References 243 8 Role of Cellulose Nanofibrils in Polymer Nanocomposites 251Thiago H. S. Maia, Marília Calazans, Vitor Lima, Francys K. V.Moreira, and Alessandra de Almeida Lucas 8.1 Introduction 251 8.2 Characteristics of Cellulose Nanofibrils 252 8.3 Mechanical Properties of CNF Polymer Nanocomposites 253 8.3.1 Thermoset Resins 254 8.3.2 Thermoplastics 255 8.3.3 Waterborne Polymer Systems 257 8.4 Effects of Extrusion on Mechanical Properties of PE/CNF Nanocomposites 258 8.5 Effect of Fiber Size and Lignin Presence 264 8.6 Multifunctionality: Optical and Barrier Properties of CNF Nanocomposites 267 8.7 Outlooks in CNF Nanocomposites 269 References 269 9 Advanced Materials Based on Self-assembly of Cellulose Nanocrystals 277Lin Gan, Siyuan Liu, Dong Li, and Jin Huang 9.1 Self-assembly Structure of CNCs 277 9.1.1 Structure of CNC Liquid Crystals 278 9.1.2 Components of CNC Self-assembly 279 9.1.3 Form of CNC Self-assembly Products 279 9.2 Self-assembly Methods and Materials 281 9.2.1 Casting Method and Spin Coating Method 281 9.2.2 Vacuum-Assisted Self-assembly 283 9.2.3 Evaporation-Induced Self-assembly 284 9.3 Structural Adjustment of CNC Self-assembly 284 9.3.1 Cholesteric Structure of Neat CNC Films 284 9.3.2 Cholesteric Structure and Cross-linking Structure in Gel 286 9.3.3 Cholesteric Structure in Bulk Materials of CNC Composite Self-assembly 288 9.3.4 Nematic Structure 290 9.4 Modifying Surface Chemical Structure of CNC 291 9.5 Properties of CNC Self-assembly 295 9.5.1 Mechanical Properties 295 9.5.1.1 Mechanical Properties of CNC Films 295 9.5.1.2 Mechanical Properties of CNC Composite Films 295 9.5.2 Iridescent Color 298 9.5.2.1 Iridescent Color Control of CNC Films 298 9.5.2.2 Iridescent Color Control of CNC Composite Materials 300 9.5.2.3 Optical Control of CNC Self-assembly Gels 302 9.5.3 Plasmonic Properties of CNC 304 9.6 Potential Applications 305 9.6.1 Oil/Water Separation 305 9.6.2 Application of Optical Materials 306 9.6.2.1 Optical Application of CNC Films 306 9.6.2.2 Optical Application of CNC Composite Films 306 9.6.3 Sensors 307 References 309 10 Potential Application Based on Colloidal Properties of Cellulose Nanocrystals 315Shiyu Fu and Linxin Zhong 10.1 Colloidal Properties of CNC and Applications in Functional Materials 315 10.2 Nanocellulose for Paper and Packaging 324 10.2.1 Nanocellulose for Paper Coating 326 10.2.2 Microfibrillated Cellulose Coated Paper for Delivery System 328 10.2.3 Water-Resistant Nanopaper Based on Modified Nanocellulose 329 10.2.4 Effect of Chemical Composition on Microfibrillar Cellulose Film 334 10.2.5 Antimicrobial Diffusion Films Based on Microfibrillated Cellulose 336 10.3 Nanocellulose for Wood Coatings 339 References 341 11 Strategies to Explore Biomedical Application of Nanocellulose 349Yanjie Zhang, Peter R. Chang, Xiaozhou Ma, Ning Lin, and Jin Huang 11.1 Introduction 349 11.2 Research on Biological Toxicity of Nanocellulose 349 11.3 Application of Nanocellulose for Immobilization and Recognition of Biological Macromolecules 355 11.4 Application of Nanocellulose for Cell Imaging 360 11.5 Application of Nanocellulose for Cell Scaffolds 361 11.6 Application of Nanocellulose in Tissue Engineering 366 11.6.1 Tissue Repairing, Regeneration, and Healing 366 11.6.1.1 Skin Tissue Repairing 368 11.6.1.2 Bone Tissue Regeneration 370 11.6.2 Tissue Replacement 371 11.6.2.1 Artificial Blood Vessels 371 11.6.2.2 Soft Tissues, Meniscus, and Cartilage 373 11.6.2.3 Nucleus Pulposus Replacement 375 11.7 Application of Nanocellulose in Drug Carrier and Delivery 375 11.8 Application of Nanocellulose as Biomedical Materials 382 11.8.1 Antimicrobial Nanomaterials 382 11.8.1.1 Nanocellulose Incorporated with Inorganic Antimicrobial Agents 385 11.8.1.2 Nanocellulose Incorporated with Organic Antimicrobial Agents 386 11.8.2 Medical Composite Material 388 11.9 Summary 389 References 389 12 Application of Nanocellulose in Energy Materials and Devices 397Gang Chen and Zhiqiang Fang 12.1 Introduction 397 12.2 Nanocellulose for Lithium Ion Batteries (LIBs) 398 12.2.1 Nanocellulose-Based Electrodes 398 12.2.2 Nanocellulose-Based Separators 401 12.2.3 Nanocellulose-Based Electrolytes 403 12.2.4 Nanocellulose-Based Binders 403 12.3 Nanocellulose for Supercapacitors 404 12.3.1 Nanocellulose As a Substrate 405 12.3.2 Nanocellulose As a Nano-template 406 12.3.3 Nanocellulose As a Mesoporous Membrane 410 12.4 Nanocellulose for Other Energy Devices 411 12.4.1 Fuel Cells 411 12.4.2 Solar Cells 412 12.4.3 Nanogenerators 414 12.5 Conclusion and Outlook 415 References 416 13 Exploration of Other High-Value Applications of Nanocellulose 423Ruitao Cha, Xiaonan Hao, Kaiwen Mou, Keying Long, Juanjuan Li, and Xingyu Jiang 13.1 Fire Resistant Materials 423 13.1.1 Introduction 423 13.1.2 Flame Retardant Additives 424 13.1.2.1 Halogenated Flame Retardants 424 13.1.2.2 Phosphorus-Based Flame Retardants 424 13.1.2.3 Nitrogen-Based Flame Retardants 424 13.1.2.4 Silicon-Based Flame Retardants 424 13.1.2.5 Mineral Flame Retardants 425 13.1.2.6 Nanoparticles 425 13.1.3 Fire Resistance of Clay Nanopaper Based on Nanocellulose 425 13.1.4 Conclusion 432 13.2 Thermal Insulation Materials 432 13.2.1 Introduction 432 13.2.2 Thermal Building Insulation Materials 432 13.2.2.1 Mineral Wool 433 13.2.2.2 Expanded Polystyrene (EPS) 433 13.2.2.3 Polyurethane (PUR) 433 13.2.2.4 Aerogel 433 13.2.3 Thermal Insulation Performance of Nanocellulose-Based Materials 434 13.2.4 Conclusion 437 13.3 The Templated Materials 438 13.3.1 Introduction 438 13.3.2 Synthesis of Magnetic Composite Aerogels 442 13.3.3 Synthesis of Inorganic Hollow Nanotube Aerogels 454 13.3.4 The Self-assembled CNC Templates 458 13.3.5 Conclusion 464 References 464 Index 475

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Book SynopsisOffers a comprehensive overview of cell culture engineering, providing insight into cell engineering, systems biology approaches and processing technology In Cell Culture Engineering: Recombinant Protein Production, editors Gyun Min Lee and Helene Faustrup Kildegaard assemble top class authors to present expert coverage of topics such as: cell line development for therapeutic protein production; development of a transient gene expression upstream platform; and CHO synthetic biology. They provide readers with everything they need to know about enhancing product and bioprocess attributes using genome-scale models of CHO metabolism; omics data and mammalian systems biotechnology; perfusion culture; and much more. This all-new, up-to-date reference covers all of the important aspects of cell culture engineering, including cell engineering, system biology approaches, and processing technology. It describes the challenges in cell line development and cell engineering, e.g. via gene editing tools like CRISPR/Cas9 and with the aim to engineer glycosylation patterns. Furthermore, it gives an overview about synthetic biology approaches applied to cell culture engineering and elaborates the use of CHO cells as common cell line for protein production. In addition, the book discusses the most important aspects of production processes, including cell culture media, batch, fed-batch, and perfusion processes as well as process analytical technology, quality by design, and scale down models. -Covers key elements of cell culture engineering applied to the production of recombinant proteins for therapeutic use -Focuses on mammalian and animal cells to help highlight synthetic and systems biology approaches to cell culture engineering, exemplified by the widely used CHO cell line -Part of the renowned "Advanced Biotechnology" book series Cell Culture Engineering: Recombinant Protein Production will appeal to biotechnologists, bioengineers, life scientists, chemical engineers, and PhD students in the life sciences. Table of ContentsAbout the Series Editors xvii 1 Platform Technology for Therapeutic Protein Production 1 Tae Kwang Ha, Jae Seong Lee, and Gyun Min Lee 1.1 Introduction 1 1.2 Overall Trend Analysis 3 1.2.1 Mammalian Cell Lines 3 1.2.2 Brief Introduction of Advances and Techniques 5 1.3 General Guidelines for Recombinant Cell Line Development 6 1.3.1 Host Selection 6 1.3.2 Expression Vector 7 1.3.3 Transfection/Selection 7 1.3.4 Clone Selection 8 1.3.4.1 Primary Parameters During Clone Selection 8 1.3.4.2 Clone Screening Technologies 9 1.4 Process Development 9 1.4.1 Media Development 10 1.4.2 Culture Environment 10 1.4.3 Culture Mode (Operation) 10 1.4.4 Scale-up and Single-Use Bioreactor 11 1.4.5 Quality Analysis 12 1.5 Downstream Process Development 12 1.5.1 Purification 12 1.5.2 Quality by Design (QbD) 13 1.6 Trends in Platform Technology Development 14 1.6.1 Rational Strategies for Cell Line and Process Development 14 1.6.2 Hybrid Culture Mode and Continuous System 15 1.6.3 Recombinant Human Cell Line Development for Therapeutic Protein Production 16 1.7 Conclusion 17 Acknowledgment 17 Conflict of Interest 17 References 17 2 Cell Line Development for Therapeutic Protein Production 23 Soo Min Noh, Seunghyeon Shin, and Gyun Min Lee 2.1 Introduction 23 2.2 Mammalian Host Cell Lines for Therapeutic Protein Production 25 2.2.1 CHO Cell Lines 25 2.2.2 Human Cell Lines 26 2.2.3 Other Mammalian Cell Lines 27 2.3 Development of Recombinant CHO Cell Lines 27 2.3.1 Expression Systems for CHO Cells 28 2.3.2 Cell Line Development Process Using CHO Cells Based on Random Integration 28 2.3.2.1 Vector Construction 29 2.3.2.2 Transfection and Selection 30 2.3.2.3 Gene Amplification 30 2.3.2.4 Clone Selection 31 2.3.3 Cell Line Development Process Using CHO Cells Based on Site-Specific Integration 32 2.4 Development of Recombinant Human Cell Lines 34 2.4.1 Necessity for Human Cell Lines 34 2.4.2 Stable Cell Line Development Process Using Human Cell Lines 35 2.5 Important Consideration for Cell Line Development 36 2.5.1 Clonality 36 2.5.2 Stability 36 2.5.3 Quality of Therapeutic Proteins 37 2.6 Conclusion 38 References 38 3 Transient Gene Expression-Based Protein Production in Recombinant Mammalian Cells 49 Joo-Hyoung Lee, Henning G. Hansen, Sun-Hye Park, Jong-Ho Park, and Yeon-Gu Kim 3.1 Introduction 49 3.2 Gene Delivery: Transient Transfection Methods 50 3.2.1 Calcium Phosphate-Based Transient Transfection 50 3.2.2 Electroporation 51 3.2.3 Polyethylenimine-Based Transient Transfection 52 3.2.4 Liposome-Based Transient Transfection 52 3.3 Expression Vectors 53 3.3.1 Expression Vector Composition and Preparation 53 3.3.2 Episomal Replication 53 3.3.3 Coexpression Strategies 54 3.4 Mammalian Cell Lines 54 3.4.1 HEK293 Cell-Based TGE Platforms 55 3.4.2 CHO Cell-Based TGE Platforms 56 3.4.3 TGE Platforms Using Other Cell Lines 58 3.5 Cell Culture Strategies 58 3.5.1 Culture Media for TGE 58 3.5.2 Optimization of Cell Culture Processes for TGE 59 3.5.3 qp-Enhancing Factors in TGE-Based Culture Processes 59 3.5.4 Culture Longevity-Enhancing Factors in TGE-Based Culture Processes 59 3.6 Large-Scale TGE-Based Protein Production 60 3.7 Concluding Remarks 62 References 62 4 Enhancing Product and Bioprocess Attributes Using Genome-Scale Models of CHO Metabolism 73 Shangzhong Li, Anne Richelle, and Nathan E. Lewis 4.1 Introduction 73 4.1.1 Cell Line Optimization 73 4.1.2 CHO Genome 75 4.1.2.1 Development of Genomic Resources of CHO 75 4.1.2.2 Development of Transcriptomics and Proteomics Resources of CHO 75 4.2 Genome-Scale Metabolic Model 76 4.2.1 What Is a Genome-Scale Metabolic Model 76 4.2.2 Reconstruction of GEMs 77 4.2.2.1 Knowledge-Based Construction 77 4.2.2.2 Draft Reconstruction 77 4.2.2.3 Curation of the Reconstruction 77 4.2.2.4 Conversion to a Computational Format 79 4.2.2.5 Model Validation and Evaluation 79 4.3 GEM Application 80 4.3.1 Common Usage and Prediction Capacities of Genome-Scale Models 82 4.3.2 GEMs as a Platform for Omics Data Integration, Linking Genotype to Phenotype 83 4.3.3 Predicting Nutrient Consumption and Controlling Phenotype 84 4.3.4 Enhancing Protein Production and Bioprocesses 85 4.3.5 Case Studies 86 4.4 Conclusion 86 Acknowledgments 88 References 88 5 Genome Variation, the Epigenome and Cellular Phenotypes 97 Martina Baumann, Gerald Klanert, Sabine Vcelar,Marcus Weinguny, Nicolas Marx, and Nicole Borth 5.1 Phenotypic Instability in the Context of Mammalian Production Cell Lines 97 5.2 Genomic Instability 99 5.3 Epigenetics 101 5.3.1 DNA Methylation 102 5.3.2 Histone Modifications 102 5.3.3 Downstream Effectors 104 5.3.4 Noncoding RNAs 104 5.4 Control of CHO Cell Phenotype by the Epigenome 105 5.5 Manipulating the Epigenome 107 5.5.1 Global Epigenetic Modification 107 5.5.1.1 Manipulating Global DNA Methylation 107 5.5.1.2 Manipulating Global Histone Acetylation 108 5.5.2 Targeted Epigenetic Modification 109 5.5.2.1 Targeted Histone Modification 110 5.5.2.2 Targeted DNA Methylation 112 5.6 Conclusion and Outlook 113 References 114 6 Adaption of Generic Metabolic Models to Specific Cell Lines for Improved Modeling of Biopharmaceutical Production and Prediction of Processes 127 Calmels Cyrielle, Chintan Joshi, Nathan E. Lewis, Malphettes Laetitia, and Mikael R. Andersen 6.1 Introduction 127 6.1.1 Constraint-Based Models 127 6.1.2 Limitations of Flux Balance Analysis 131 6.1.2.1 Thermodynamically Infeasible Cycles 131 6.1.2.2 Genetic Regulation 131 6.1.2.3 Limitation of Intracellular Space 132 6.1.2.4 Multiple States in the Solution 132 6.1.2.5 Biological Objective Function 133 6.1.2.6 Kinetics and Metabolite Concentrations 133 6.2 Main Source of Optimization Issues with Large Genome-Scale Models: Thermodynamically Infeasible Cycles 134 6.2.1 Definition of Thermodynamically Infeasible Fluxes 134 6.2.2 Loops Involving External Exchange Reactions 134 6.2.2.1 Reversible Passive Transporters from Major Facilitator Superfamily (MFS) 135 6.2.2.2 Reversible Passive Antiporters from Amino Acid-Polyamine-organoCation (APC) Superfamily 136 6.2.2.3 Na+-linked Transporters 136 6.2.2.4 Transport via Proton Symport 137 6.2.3 Tools to Identify Thermodynamically Infeasible Cycles 138 6.2.3.1 Visualizing Fluxes on a Network Map 138 6.2.3.2 Algorithms Developed 138 6.2.4 Methods Available to Remove Thermodynamically Infeasible Cycles 139 6.2.4.1 Manual Curation 139 6.2.4.2 Software and Algorithms Developed for the Removal of Thermodynamically Infeasible Loops from Flux Distributions 140 6.3 Consideration of Additional Biological Cellular Constraints 144 6.3.1 Genetic Regulation 144 6.3.1.1 Advantages of Considering Gene Regulation in Genome-Scale Modeling 144 6.3.1.2 Methods Developed to Take into Account a Feedback of FBA on the Regulatory Network 145 6.3.2 Context Specificity 146 6.3.2.1 What Are Context-Specific Models (CSMs)? 146 6.3.2.2 Methods and Algorithms Developed to Reconstruct Context-Specific Models (CSMs) 146 6.3.2.3 Performance of CSMs 148 6.3.2.4 Cautions About CSMs 149 6.3.3 Molecular Crowding 150 6.3.3.1 Consequences on the Predictions 150 6.3.3.2 Methods Developed to Account for a Total Enzymatic Capacity into the FBA Framework 151 6.4 Conclusion 152 References 153 7 Toward Integrated Multi-omics Analysis for Improving CHO Cell Bioprocessing 163 Kok Siong Ang, Jongkwang Hong, Meiyappan Lakshmanan, and Dong-Yup Lee 7.1 Introduction 163 7.2 High-Throughput Omics Technologies 165 7.2.1 Sequencing-Based Omics Technologies 165 7.2.1.1 Historical Developments of Nucleotide Sequencing Techniques 165 7.2.1.2 Genome Sequencing of CHO Cells 166 7.2.1.3 Transcriptomics of CHO Cells 167 7.2.1.4 Epigenomics of CHO Cells 168 7.2.2 Mass Spectrometry-Based Omics Technologies 168 7.2.2.1 Mass Spectrometry Techniques 168 7.2.2.2 Proteomics of CHO Cells 170 7.2.2.3 Metabolomics/Lipidomics of CHO Cells 171 7.2.2.4 Glycomics of CHO Cells 172 7.3 Current CHO Multi-omics Applications 172 7.3.1 Bioprocess Optimization 174 7.3.2 Cell Line Characterization 174 7.3.3 Engineering Target Identification 176 7.4 Future Prospects 177 References 178 8 CRISPR Toolbox for Mammalian Cell Engineering 185 Daria Sergeeva, Karen Julie la Cour Karottki, Jae Seong Lee, and Helene Faustrup Kildegaard 8.1 Introduction 185 8.2 Mechanism of CRISPR/Cas9 Genome Editing 186 8.3 Variants of CRISPR-RNA-guided Endonucleases 187 8.3.1 Diversity of CRISPR/Cas Systems 187 8.3.2 Engineered Cas9 Variants 188 8.4 Experimental Design for CRISPR-mediated Genome Editing 188 8.4.1 Target Site Selection and Design of gRNAs 189 8.4.2 Delivery of CRISPR/Cas9 Components 191 8.5 Development of CRISPR/Cas9 Tools 192 8.5.1 CRISPR/Cas9-mediated Gene Editing 192 8.5.1.1 Gene Knockout 192 8.5.1.2 Site-Specific Gene Integration 194 8.5.2 CRISPR/Cas9-mediated Genome Modification 195 8.5.2.1 Transcriptional Regulation 195 8.5.2.2 Epigenetic Modification 196 8.5.3 RNA Targeting 196 8.6 Genome-Scale CRISPR Screening 197 8.7 Applications of CRISPR/Cas9 for CHO Cell Engineering 197 8.8 Conclusion 199 Acknowledgment 200 References 200 9 CHO Cell Engineering for Improved Process Performance and Product Quality 207 Simon Fischer and Kerstin Otte 9.1 CHO Cell Engineering 207 9.2 Methods in Cell Line Engineering 208 9.2.1 Overexpression of Engineering Genes 208 9.2.2 Gene Knockout 209 9.2.3 Noncoding RNA-mediated Gene Silencing 209 9.3 Applications of Cell Line Engineering Approaches in CHO Cells 211 9.3.1 Enhancing Recombinant Protein Production 211 9.3.2 Repression of Cell Death and Acceleration of Growth 221 9.3.3 Modulation of Posttranslational Modifications to Improve Protein Quality 227 9.4 Conclusions 233 References 234 10 Metabolite Profiling of Mammalian Cells 251 Claire E. Gaffney, Alan J. Dickson, and Mark Elvin 10.1 Value of Metabolic Data for the Enhancement of Recombinant Protein Production 251 10.2 Technologies Used in the Generation of Metabolic Data Sets 252 10.2.1 Targeted and Untargeted Metabolic Analysis 253 10.2.2 Analytical Technologies Used in the Generation of Metabolite Profiles 253 10.2.2.1 Nuclear Magnetic Resonance 254 10.2.2.2 Mass Spectrometry 255 10.2.3 Metabolite Sample Preparation 256 10.2.3.1 Extracellular Sample Preparation 257 10.2.3.2 Quenching of Intracellular Metabolite Samples 257 10.2.3.3 Metabolite Extraction from Quenched Cells 257 10.2.3.4 Metabolic Flux Analysis 257 10.3 Approaches for Metabolic Data Analysis 257 10.3.1 Data Processing 258 10.3.2 Data Analysis 258 10.3.3 Data Interpretation and Integration 260 10.4 Implementation of Metabolic Data in Bioprocessing 261 10.4.1 Relationship Between Growth Phase and Metabolism 261 10.4.2 Identification of Metabolic Indicators Associated with High Cell-Specific Productivity 263 10.4.3 Utilizing Metabolic Data to Improve Biomass and Recombinant Protein Yield 263 10.4.4 Utilizing Metabolic Understanding to Improve Product Quality 265 10.4.5 Cell Line Engineering to Redirect Metabolic Pathways 265 10.5 Future Perspectives 266 Acknowledgments 267 References 267 11 Current Considerations and Future Advances in Chemically Defined Medium Development for the Production of Protein Therapeutics in CHO Cells 279 Wai Lam W. Ling 11.1 Introduction 279 11.2 Traditional Approach to Medium Development 279 11.2.1 Cell Line Selection 279 11.2.2 Design and Optimization 280 11.2.3 Process Consideration 282 11.2.4 Additional Considerations in Medium Development 284 11.3 Future Perspectives for Medium Development 284 11.3.1 Systems Biology and Synthetic Biology 284 Acknowledgment 288 Conflict of Interest 288 References 288 12 Host Cell Proteins During Biomanufacturing 295 Jong Youn Baik, Jing Guo, and Kelvin H. Lee 12.1 Introduction 295 12.2 Removal of HCP Impurities 295 12.2.1 Antibody Product 296 12.2.2 Non-antibody Protein Product 297 12.2.3 Difficult-to-Remove HCPs 298 12.3 Impacts of Residual HCPs 298 12.3.1 Drug Efficacy, Quality, and Shelf Life 298 12.3.2 Immunogenicity 299 12.3.3 Biological Activity 299 12.4 HCP Detection and Monitoring Methods 300 12.4.1 Anti-HCP Antiserum and Enzyme-Linked Immunosorbent Assay (ELISA) 300 12.4.2 Proteomics Approaches as Orthogonal Methods 302 12.5 Efforts for HCP Control 302 12.5.1 Upstream Efforts 303 12.5.2 Downstream Efforts 304 12.5.3 HCP Risk Assessment in CHO Cells 305 12.6 Future Directions 305 Acknowledgments 306 References 306 13 Mammalian Fed-batch Cell Culture for Biopharmaceuticals 313 William C. Yang 13.1 Introduction 313 13.2 Objectives of Cell Culture Process Development 314 13.2.1 Yield and Product Quality 314 13.2.2 Glycosylation 314 13.2.3 Charge Heterogeneity 315 13.2.4 Aggregation 316 13.3 Cells and Cell Culture Formats 316 13.3.1 Adherent Cells 316 13.3.2 Suspended Cells 316 13.3.3 Batch Cultures 317 13.4 Fed-batch Cultures 317 13.5 Cell Culture Media 319 13.5.1 Basal Media 319 13.5.2 Feed Media 320 13.6 Feeding Strategies 321 13.6.1 Metabolite Based 321 13.6.2 Respiration Based 323 13.7 Feed Media Design 323 13.8 Process Variable Design 325 13.8.1 Temperature 325 13.8.2 pH and pCO2 325 13.8.3 Dissolved Oxygen 326 13.8.4 Culture Duration 327 13.9 Cell Culture Supplements 327 13.9.1 Yield 328 13.9.2 Glycosylation 328 13.10 New and Emerging Technologies 329 13.10.1 Analytical Technologies 329 13.10.2 Bioreactor Technologies 331 13.11 Future Directions 332 References 333 14 Continuous Biomanufacturing 347 Sadettin S. Ozturk 14.1 Introduction 347 14.2 Continuous Upstream (Cell Culture) Processes 347 14.2.1 Continuous Culture without Cell Retention (Chemostat) 348 14.2.2 Continuous Culture with Cell Retention (Perfusion) 348 14.2.2.1 Cell Retention by Immobilization or Entrapment 349 14.2.2.2 Cell Retention by Cell Retention Device 350 14.2.3 Semicontinuous Culture 351 14.3 Advantages of Continuous Perfusion 351 14.3.1 Higher Volumetric Productivities 351 14.3.2 Better Utilization of Biomanufacturing Facilities 352 14.3.3 Better Product Quality and Consistency 352 14.3.4 Scale-up and Commercial Production 353 14.4 Cell Retention Systems for Continuous Perfusion 354 14.4.1 Cell Retention Devices 354 14.4.1.1 Filtration-Based Devices 354 14.4.1.2 Spin Filters 355 14.4.1.3 Continuous Centrifugation 356 14.4.1.4 Settler 356 14.4.1.5 BioSep Device 357 14.4.1.6 Hydrocyclones 358 14.5 Operation and Control of Continuous Perfusion Bioreactors 358 14.5.1 Feed and Harvest Flow and Volume Control 358 14.5.2 Circulation or Return Pump 359 14.5.3 Control of Perfusion Rate and Cell Density 359 14.5.3.1 Cell Build-up Phase 359 14.5.3.2 Production Phase 360 14.5.3.3 Cell Bleed or Purge 360 14.6 Current Status of Continuous Perfusion 360 14.7 Conclusions 362 Acknowledgment 362 References 363 15 Process Analytical Technology and Quality by Design for Animal Cell Culture 365 Hae-Woo Lee, Hemlata Bhatia, Seo-Young Park, Mark-Henry Kamga, Thomas Reimonn, Sha Sha, Zhuangrong Huang, Shaun Galbraith, Huolong Liu, and Seongkyu Yoon 15.1 PAT and QbD – US FDA’s Regulatory Initiatives 365 15.2 PAT and QbD – Challenges 365 15.3 PAT and QbD Implementations 366 15.3.1 NIR Spectroscopy 366 15.3.2 Mid-Infrared (MIR) Spectroscopy 367 15.3.3 Raman Spectroscopy 367 15.3.4 Fluorescence Spectroscopy 368 15.3.5 Chromatographic Techniques 368 15.3.6 Other Useful Techniques 369 15.3.7 Data Analysis and Modeling Tools 369 15.4 Case Studies 370 15.4.1 Estimation of Raw Material Performance in Mammalian Cell Culture Using Near-Infrared Spectra Combined with Chemometrics Approaches 370 15.4.2 Design Space Exploration for Control of Critical Quality Attributes of mAb 372 15.4.3 Quantification of Protein Mixture in Chromatographic Separation Using Multiwavelength UV Spectra 372 15.4.4 Characterization of Mammalian Cell Culture Raw Materials by Combining Spectroscopy and Chemometrics 374 15.4.5 Effect of Amino Acid Supplementation on Titer and Glycosylation Distribution in Hybridoma Cell Cultures 375 15.4.6 Metabolic Responses and Pathway Changes of Mammalian Cells Under Different Culture Conditions with Media Supplementations 377 15.4.7 Estimation and Control of N-Linked Glycoform Profiles of Monoclonal Antibody with Extracellular Metabolites and Two-Step Intracellular Models 378 15.4.8 Quantitative Intracellular Flux Modeling and Applications in Biotherapeutic Development and Production Using CHO Cell Cultures 381 15.5 Conclusion 383 References 383 16 Development and Qualification of a Cell Culture Scale-Down Model 391 Sarwat Khattak and Valerie Pferdeort 16.1 Purpose of the Scale-Down Model 391 16.1.1 Development Challenges 391 16.2 Types of Scale-Down Models 392 16.2.1 Power/Volume (P/V) and Air velocity 392 16.2.2 Oxygen Transfer Coefficient (kLa) 392 16.2.3 Gas Entrance Velocity (GEV) 393 16.2.4 Oxygen Transfer Rate (OTR) 393 16.2.5 Model Refinement Workflow 395 16.3 Evaluation of a Scale-Down Model 395 16.3.1 Univariate Analysis 395 16.3.2 Multivariate Analysis 396 16.3.2.1 Statistical Background 396 16.3.2.2 Qualification Data Set 396 16.3.2.3 Observation Level Analysis 397 16.3.2.4 Batch-Level Analysis 397 16.3.2.5 Scores Contribution Plots 398 16.3.3 Equivalence Testing 399 16.3.3.1 Statistical Background 399 16.3.3.2 Considerations for Evaluation and Test Data Sets 399 16.3.3.3 Types of Analysis Outcomes 400 16.4 Conclusions and Perspectives 401 References 402 Index 407

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Book SynopsisSolid State Development and Processing of Pharmaceutical Molecules A guide to the lastest industry principles for optimizing the production of solid state active pharmaceutical ingredients Solid State Development and Processing of Pharmaceutical Molecules is an authoritative guide that covers the entire pharmaceutical value chain. The authors—noted experts on the topic—examine the importance of the solid state form of chemical and biological drugs and review the development, production, quality control, formulation, and stability of medicines. The book explores the most recent trends in the digitization and automation of the pharmaceutical production processes that reflect the need for consistent high quality. It also includes information on relevant regulatory and intellectual property considerations. This resource is aimed at professionals in the pharmaceutical industry and offers an in-depth examination of the commercially relevant issues facing developers, producers and distributors of drug substances. This important book: Provides a guide for the effective development of solid drug forms Compares different characterization methods for solid state APIs Offers a resource for understanding efficient production methods for solid state forms of chemical and biological drugs Includes information on automation, process control, and machine learning as an integral part of the development and production workflows Covers in detail the regulatory and quality control aspects of drug development Written for medicinal chemists, pharmaceutical industry professionals, pharma engineers, solid state chemists, chemical engineers, Solid State Development and Processing of Pharmaceutical Molecules reviews information on the solid state of active pharmaceutical ingredients for their efficient development and production.Table of ContentsSeries Editors Preface xxi Preface xxiii 1 Aspects for Developing and Processing Solid Forms 1Michael Gruss 1.1 Aspects for Developing and Processing Solid Forms 1 1.1.1 Introduction 1 1.1.2 Education and Personal Background 1 1.1.3 Societal Impact – Fishing in ForeignWaters 4 1.1.3.1 Motivation 4 1.1.3.2 The Personal Dimension 5 1.1.3.3 Beyond the Impact on Individuals 6 1.1.3.4 Understanding the Market – Not an Easy Task 7 1.1.3.5 Benefits of an Interdisciplinary Mindset 9 1.1.4 The Basis for Mutual Understanding 9 1.1.5 Crystallization is a Separation, Not a Separated Process 11 1.1.6 Some Early Information About Solid-state Properties 13 1.1.7 Digitalization (Not Only) in the Laboratory 13 1.1.7.1 Prerequisites – Technology and People 13 1.1.7.2 Connect Data and the Right Information from Synthesis and Analysis 15 1.1.7.3 Contributions and Choices 17 1.1.7.4 Application of Digitalization 18 1.1.7.5 Fully Digitalized Infrastructure 20 1.1.8 Basic Terms and Concepts in theWorld of Solid State 21 1.1.8.1 Crystalline and Amorphous 21 1.1.8.2 Crystallization and Precipitation 23 1.1.8.3 Understanding the Phase Diagram – Analytical Characterization of the Solid–Liquid and Solid–Solid Systems 23 1.1.8.4 Polymorphism 24 1.1.8.5 Multi-component Compounds – Salt, Cocrystal, Solvate, and Hydrate 25 1.1.8.6 Solvates, Hydrates, Non-solvated Forms, or Ansolvates 26 1.1.8.7 Dispersed Primary Particles, Aggregates, and Agglomerates 29 1.1.8.8 Particle Size and Particle Size Distribution (PSD) 29 1.1.9 Investigating and Understanding the Polymorphic Landscape 29 1.1.10 Performing the Crystallization 31 1.1.11 Objectives for the Optimization of Crystallization Processes and Solid-State Properties 32 1.1.12 Implementation of In Silico and Simulation Techniques 32 1.1.13 Saving the Investment – Addressing Intellectual Property Rights 35 1.1.14 Concluding Remarks 36 List of Abbreviations 37 References 38 2 Determination of Current Knowledge 45Andriy Kuzmov and Ronak Savla 2.1 Why is it Important to Search for Relevant Information Before Starting a Solid-State Project? 45 2.2 Where to Begin a Literature Search for a Solid-State Project? 47 2.2.1 Literature Search 48 2.2.1.1 Focusing Your Literature Search 49 2.2.2 Staying on Top of the Latest Publications 51 2.3 Patent Search 51 2.3.1 Types of Patent Reports 52 2.3.2 Understanding the Elements of Patents 53 2.3.3 Patent Classification 54 2.3.4 Patent Databases 56 2.3.4.1 Free Patent Databases 57 2.4 Other Useful Resources for Solid-State Projects 61 2.4.1 Cambridge Structural Database 61 2.4.2 Crystallography Open Database 62 List of Abbreviations 62 References 63 3 Systematic Screening and Investigation of Solid-State Landscapes 67Ulrike Werthmann 3.1 Introduction 67 3.2 General Aspects of Solid-State Investigations in Early Drug Discovery Phase 68 3.3 Transition Phase from Late Stage Research to Early Stage Development 69 3.4 Solid-State Characteristics in Preclinical Formulations 70 3.5 API-crystallization Strategy in Candidate Profiling Phase 73 3.6 Selection Criteria of a Suitable Solid Form 77 3.7 Knowledge Management 79 3.8 Control of Solid Form Properties in Development 79 3.9 Exploratory Crystallization Experiments 80 List of Abbreviations 87 References 88 4.1 Solid-State Characterization Techniques: Microscopy 91Luis Almeida e Sousa and Constança Cacela 4.1.1 Microscopy 91 4.1.1.1 Optical Microscopy 91 4.1.1.1.1 Bright-Field Microscopy 92 4.1.1.1.2 Dark-Field Microscopy 93 4.1.1.1.3 Polarized Light Microscopy 93 4.1.1.1.4 Other Optical Microscopy Variants 95 4.1.1.2 Electron Microscopy 96 4.1.1.2.1 Scanning Electron Microscopy 96 4.1.1.2.2 Transmission Electron Microscopy 100 4.1.1.3 Atomic Force Microscopy 101 4.1.1.4 Microscopy in Regulatory Documents 103 List of Abbreviations 103 References 104 4.2 Standards and Trends in Analytical Characterization – X-ray Diffraction (XRD) 107Clemens Kühn 4.2.1 X-ray Diffraction 107 4.2.1.1 Introduction 107 4.2.1.2 Measurement Principles 108 4.2.1.2.1 The Crystal Lattice 108 4.2.1.2.2 The Space Group Symmetry 108 4.2.1.2.3 What Determines a Diffraction Peak 109 4.2.1.2.4 X-ray Scattering Technics 110 4.2.2 Technics 110 4.2.2.1 Single Crystal X-ray Diffraction 110 4.2.2.2 Powder X-ray Diffraction 111 4.2.2.2.1 Alternative Methods for Structure Determination 111 4.2.3 Instrumentation 112 4.2.3.1 X-ray Sources 112 4.2.3.2 Diffractometer Geometries 113 4.2.3.2.1 Reflection Geometry 113 4.2.3.2.2 Transmission Geometry 114 4.2.3.2.3 Benchtop Diffractometers 115 4.2.3.3 Detectors 115 4.2.3.4 Peak Asymmetry 115 4.2.3.5 Reproducibility of Diffraction Patterns: The Texture Effect (Preferred Orientation) 116 4.2.3.6 Databases of Known Diffraction Patterns 118 4.2.4 Measurement 118 4.2.4.1 Instrument Calibration 118 4.2.4.2 Sample Preparation 119 4.2.5 Data Evaluation 119 4.2.5.1 Qualitative Phase Analysis 119 4.2.5.1.1 Phase Identification or Identity Check 120 4.2.5.1.2 Amorphous Content 121 4.2.5.2 Quantification 122 4.2.5.2.1 Based on Calibration Curve 123 4.2.5.2.2 Based on Internal Standard Addition 123 4.2.5.2.3 Based on Rietveld Refinement 123 4.2.5.3 Advanced Phase Analysis 124 List of Abbreviations 125 References 125 Further Reading 127 4.3 Standards and Trends in Solid-State Characterization Techniques – Thermal Analysis 129Juergen Thun and Nikolaus Martin 4.3.1 Introduction 129 4.3.2 Thermal Analysis in Drug Development 130 4.3.2.1 Solid form Landscape 130 4.3.2.2 Compatibility Studies 130 4.3.2.3 Other Applications 130 4.3.3 Methods 131 4.3.3.1 Differential Scanning Calorimetry 131 4.3.3.1.1 Techniques 131 4.3.3.1.2 Sample Preparation and Measuring Parameters 131 4.3.3.1.3 Evaluation 132 4.3.3.1.4 Special Applications 134 4.3.3.1.5 Detection Limits 134 4.3.3.2 Thermogravimetric Analysis 134 4.3.3.2.1 Technique 134 4.3.3.2.2 Sample Preparation and Measuring Parameters 135 4.3.3.2.3 Evaluation 135 4.3.3.2.4 Special Applications 136 4.3.4 Case Studies 136 4.3.4.1 Understanding Polymorphic Transitions 136 4.3.4.2 The Power of Ultra-fast Heating Rates 139 4.3.4.3 Understanding Amorphous Phases 141 4.3.4.4 Identification of Solvate Structures 142 4.3.5 Quality and Regulatory Aspects 144 4.3.6 Outlook 145 Acknowledgments 146 List of Abbreviations 146 Notes 146 References 146 4.4 Standards and Trends in Solid-State Characterization Techniques: Infrared (IR) Spectroscopy 151Dagmar Lischke 4.4.1 Infrared (IR) Spectroscopy 151 4.4.1.1 Introduction 151 4.4.1.2 IR Spectroscopy as Identity Method for Drug Substances 152 4.4.1.2.1 Transmission Mode 152 4.4.1.2.2 Attenuated Total Reflectance (ATR) 152 4.4.1.2.3 Sample preparation 153 4.4.1.2.4 Analysis and Reporting 153 4.4.1.2.5 Examples and Limitations 154 4.4.1.2.6 Method Validation of IR Spectroscopy Identification and Quantification Methods 155 4.4.1.3 Application of IR Microscopy-Imaging Methods in Drug Development 156 4.4.1.3.1 Spatial Resolution 156 4.4.1.3.2 Measurement Setups 157 4.4.1.3.3 Case Studies 158 4.4.1.4 Conclusion 162 List of Abbreviations 162 References 163 4.5 Transmission Raman Spectroscopy – Implementation in Pharmaceutical Quality Control 165Meike Römer 4.5.1 Raman Spectroscopy – From Research to Broad Applications in Industry 165 4.5.1.1 Objective 165 4.5.1.1.1 History 165 4.5.1.1.2 Introduction 165 4.5.1.1.3 The Raman Effect 166 4.5.2 Analytical use of Raman Spectroscopy for Pharmaceutical Purposes 167 4.5.2.1 Transmission Raman Spectroscopy (TRS) 167 4.5.2.1.1 Principles of Transmission Raman Spectroscopy 168 4.5.2.1.2 A Practical Guide to a Successful Business Case 171 4.5.3 Transmission Raman Spectroscopy – Another Practical Guide 173 4.5.3.1 Evaluation Phase 174 4.5.3.1.1 Prefeasibility Evaluation 174 4.5.3.1.2 Feasibility of a Product 176 4.5.3.2 Transmission Raman Method Development 177 4.5.3.2.1 Transmission Raman Spectroscopic Method Development 177 4.5.3.2.2 Risk Analysis 179 4.5.3.2.3 Transmission Raman Model Development, Calibration, and Validation 180 4.5.4 Regulatory Assessment and Guidelines 180 List of Abbreviations 181 References 182 4.6 Solid-state Characterization Techniques: Particle Size 185Maria Paisana and Constança Cacela 4.6.1 Introduction 185 4.6.2 Analytical Methodologies Used to Measure Particle Size 187 4.6.2.1 Sedimentation 187 4.6.2.2 Electrozone Sensing 187 4.6.2.3 Sieving 188 4.6.2.4 Microscopy 188 4.6.2.5 Dynamic Light Scattering 188 4.6.2.6 Laser Diffraction 189 4.6.3 Method Development for Precise Particle-size Measurements by Laser Diffraction 189 4.6.3.1 Instrumentation and Measurement 189 4.6.3.2 Selection of an Appropriate Optical Model 190 4.6.3.3 Sample Dispersion 191 4.6.3.3.1 Wet Dispersion 192 4.6.3.3.2 Dry Dispersion 194 4.6.3.4 Sample Representativeness and Obscuration 195 4.6.3.5 Readiness for Method Validation 196 4.6.4 Unexpected Results and Troubleshooting in Laser Diffraction Measurement 197 4.6.4.1 Inconsistent Disconnected Peaks 197 4.6.4.2 Repeatable Artifact Peaks 199 List of Abbreviations 199 References 200 4.7 Micro Computational Tomography 203Susana Campos and Constança Cacela 4.7.1 Tomography Imaging Techniques 203 4.7.2 Micro X-ray Computed Tomography Scan 203 4.7.2.1 The Use of CT in the Pharmaceutical Industry 204 4.7.2.1.1 μCT Applied to Density Distribution and Porous Characterization 205 4.7.2.1.2 μCT Applied for Characterization of Structural Features: Size, Shape, and Dimensions and Interfaces 207 4.7.2.1.3 μCT Applied to Coating Characterization 207 4.7.2.1.4 μCT Applied to Performance Evaluation 209 4.7.2.1.5 Foreign Matter Detection by μCT 210 List of Abbreviations 211 Notes 211 References 211 4.8 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 215Adam A. L. Michalchuk, Anke Kabelitz, and Franziska Emmerling 4.8.1 In Situ Methods for Monitoring Solid-State Processes in Molecular Materials 215 4.8.1.1 The Complexity of Solid Materials 215 4.8.1.2 Methods to Consider 216 4.8.1.3 Methods to Monitor Crystallization Kinetics from Solution 218 4.8.1.3.1 UV–Vis Spectroscopy 218 4.8.1.3.2 Infrared Spectroscopy 219 4.8.1.4 Monitoring Crystallization from Solution: Following Solid Product Formation 221 4.8.1.4.1 Light Scattering 221 4.8.1.5 Methods to Monitor Extrinsic Solid Properties 224 4.8.1.5.1 Acoustic Emission 224 4.8.1.5.2 Thermography 226 4.8.1.6 Methods to Monitor Intrinsic Solid Properties 228 4.8.1.6.1 X-ray Diffraction 228 4.8.1.6.2 Raman Spectroscopy 232 4.8.1.7 Benefits of Combining Methods for In Situ Monitoring 236 4.8.1.8 Summary 240 List of Abbreviations 242 References 243 4.9 Application of Process Monitoring and Modeling 249Jochen Schoell and Roberto Irizarry 4.9.1 In-process Solid Form Monitoring Techniques 249 4.9.1.1 Direct Characterization Techniques 250 4.9.1.1.1 Raman Spectroscopy 250 4.9.1.1.2 Near Infrared Spectroscopy 252 4.9.1.2 Indirect Monitoring Tools 254 4.9.1.2.1 Focused Beam Reflectance Measurement (FBRM) 254 4.9.1.2.2 Monitoring Particle Shape Using In-process Microscopy 256 4.9.1.2.3 Monitoring Solute Concentration 256 4.9.1.3 Advantages and Challenges of In Situ Solid Form Monitoring Techniques 257 4.9.2 Quantification Methods and Application to Solid Form Transformation Modeling 258 4.9.2.1 Multivariate Data Analysis 259 4.9.2.2 Data-driven Model for CLD–PSD Prediction 260 4.9.2.3 Process Modeling of Polymorph Transformation Processes 262 List of Abbreviations 265 References 266 4.10 Photon Density Wave (PDW) Spectroscopy for Nano- and Microparticle Sizing 271Lena Bressel and Roland Hass 4.10.1 Classification of Particle Sizing Technologies 271 4.10.2 Particle Size and Solid Fraction Ranges 272 4.10.3 Photon DensityWave (PDW) Spectroscopy – Theory, Instrumentation, and Application Examples 275 4.10.4 Particle Sizing by PDWSpectroscopy 277 4.10.5 Sample Versus Process Measurements 280 4.10.6 Technical Implementation and Data Access 281 4.10.7 Examples for Process Analysis with PDWSpectroscopy 282 4.10.7.1 Crystallization of Lactose 283 4.10.7.2 Precipitation of Barium Sulfate 284 4.10.8 Summary 285 List of Abbreviations 286 References 287 5 Impact of Solid Forms on API Scale-Up 289Sophie Janbon, Clare Mayes, and Amy L. Robertson 5.1 Introduction 289 5.2 Background 290 5.3 Small-Scale Crystallization Development 291 5.3.1 Form Selection 291 5.3.2 Solvent Selection 293 5.3.2.1 Solvent Screening 293 5.3.2.2 Solubility Diagram 294 5.3.2.3 Solubility Measurement 295 5.3.3 Crystallization Process Selection 298 5.3.3.1 Process Outline Selection 298 5.3.3.2 Process Outline Evaluation 299 5.3.3.3 Process Exploration 300 5.3.4 Process Development Conclusions 302 5.4 Crystallization Scale-Up 302 5.4.1 Crystallization Process Accommodation 303 5.4.1.1 Vessel Size and MoC 304 5.4.1.2 Agitation 304 5.4.1.3 Heat Transfer 305 5.4.1.4 Solution Addition 305 5.4.1.5 Solid Addition 305 5.4.1.6 Alternative Technologies 306 5.4.2 Risks and Common Problems 307 5.4.2.1 Metastable Forms 307 5.4.2.2 Amorphous 307 5.4.2.3 Salt Stoichiometry 308 5.4.2.4 Oiling and Phase Separations 308 5.4.3 Isolation and Drying 308 5.4.3.1 Isolation 309 5.4.3.2 Drying 311 5.4.4 Agglomeration 314 5.4.5 Particle Size Reduction 314 5.4.5.1 Delumping 314 5.4.5.2 Milling and Micronization 314 5.4.5.3 Storage and Packing 315 5.4.6 Scale-up Conclusions 315 5.5 People and Skill Requirements 315 5.6 Regulatory Requirements 315 5.6.1 Process Documentation 316 5.6.2 Safety 316 5.6.3 Quality and Manufacturability 316 5.7 Closing Remarks 317 List of Abbreviations 318 References 318 6 Impact on Drug Development and Drug Product Processing 325Susanne Page and Anikó Szepes 6.1 Introduction 325 6.2 Pharmaceutical Profiling 327 6.3 Formulation Development 330 6.3.1 Liquid Formulations: Solutions and Suspensions 332 6.3.2 Solid Dosage Forms 335 6.3.3 Solubility Enhanced Formulations 339 6.3.3.1 Lipid-Based Formulations and Drug Delivery Systems 339 6.3.3.2 Solid Solutions and Amorphous Solid Dispersions 343 6.4 Process Development and Transfer to Commercial Manufacturing 344 6.4.1 Particle Size Reduction 345 6.4.2 Blending 345 6.4.3 Granulation 345 6.4.3.1 Wet Granulation and Drying 346 6.4.3.2 Dry Granulation/Roller Compaction 347 6.4.4 Tablet Compression 347 6.4.5 Film Coating 348 6.5 Control Strategy 348 6.6 Regulatory Submissions 349 List of Abbreviations 352 References 353 7 Workflow Management 365Christian Große 7.1 Motivation 365 7.2 Workflow Management 365 7.3 Organization of Solid-State Development by Project Management 366 7.3.1 Stakeholders 366 7.3.2 CMC Project Management 367 7.3.3 Substance Requirement Plan 368 7.3.4 Pre-CMC Data 369 7.4 Workflows in the Environment of the Crystallization Laboratory 369 7.4.1 Micro-Project Management 369 7.4.2 Dependencies 370 7.4.3 Material Flow 371 7.4.4 Designations and Code Assignment 371 7.4.5 Analytic Database System 373 7.4.6 Physical Sample Transfer 375 7.4.7 Analytic Transfer Tool 375 7.4.8 Analytical Processes – Timely Measurement 376 7.4.9 Sample Storage Processes 377 7.4.10 Documentation 378 7.4.11 Review Process for ELN Documents 379 7.4.11.1 Document Status 379 7.4.11.2 Manual ELN Review Process 380 7.4.11.3 Archive Process 381 7.4.12 Communication with CROs 381 7.4.13 Fundamental Lab Processes 382 7.5 Processes in the Solid-State Lab 382 7.5.1 Initial Testing 382 7.5.2 Solubility Estimation 384 7.5.3 Manual Screening 384 7.5.4 High-Throughput Screening 385 7.5.5 Processes for Replica Experiments and Scale-Up of Solid Forms 387 7.6 Development of Crystallization Processes 387 7.7 Support Processes 388 7.7.1 Route Scouting Process 389 7.7.2 Crystallization of Impurities and Intermediates 389 7.7.3 Downstream Processes 389 7.7.4 Scale-Up and Technology Transfer Process 390 7.7.5 Analytical Development 390 7.7.6 Preformulation 391 7.7.7 Formulation 391 7.8 Conclusion 392 List of Abbreviations 393 References 393 8 Digitalization in Laboratories of the Pharmaceutical Industry 397Tanja S. Picker 8.1 Introduction 397 8.2 Motivation of Digitalization in the Laboratory 398 8.2.1 Expectations of the Staff 398 8.2.2 Increasing Throughput 400 8.2.3 Repeatability 400 8.2.4 Enhanced Requirements on Data Integrity 400 8.2.5 Centralized Archiving 401 8.2.6 Ad Hoc Analysis 401 8.2.7 The Value of Data 402 8.3 Categories of Laboratory IT Systems 403 8.3.1 Devices 403 8.3.2 Lab Execution Systems (LES) and Scientific Data Management Systems (SDMS) 404 8.3.3 Lab Data Systems 404 8.3.4 Enterprise Resource Planning (ERP) 405 8.3.5 Further Use of Data 405 8.3.5.1 Data Analysis and Reporting 405 8.3.5.2 Big Data Analytics and Artificial Intelligence 406 8.4 System Interfaces for Data Exchange 406 8.4.1 Adapters 407 8.4.1.1 Serial Port (RS232) 407 8.4.1.2 Universal Series Bus (USB) 407 8.4.1.3 Ethernet 407 8.4.1.4 Cable Less Connections 407 8.4.2 Communication Medium and Protocols 408 8.4.2.1 File-Based Communication 408 8.4.2.2 ANSI/ISA-88 Batch Control (S-88) 408 8.4.2.3 Open Platform Communications Unified Architecture (OPC UA) 408 8.4.2.4 Standards in Lab Automation (SiLA) 408 8.4.3 Data Formats 409 8.4.3.1 Common Data Formats (e.g. TXT, XML, JSON) 409 8.4.3.2 Analytical Information Markup Language (AnIML) 409 8.4.3.3 Allotrope Data Format (ADF) 410 8.5 Implementation of IT Solutions 411 8.5.1 Identification of Digital Gaps in the Lab Processes 411 8.5.1.1 Contextual Inquiry 411 8.5.1.2 Interaction Room 411 8.5.2 Implementation Approach 412 8.5.2.1 Design 413 8.5.2.2 Realization 415 8.5.2.3 Verification 415 8.5.2.4 Rollout 416 8.6 Conclusion 416 List of Abbreviations 416 References 417 9.1 Polymorphs and Patents – the US Perspective 421Kristi McIntyre 9.1.1 Introduction 421 9.1.2 What is a Patent? 421 9.1.3 How Are Patents Obtained? 422 9.1.4 United States Patent Law 422 9.1.4.1 Tapentadol Hydrochloride 423 9.1.4.1.1 Tapentadol Hydrochloride Form A Held Not Obvious 423 9.1.4.1.2 Tapentadol Hydrochloride Form AWas Found to Have Utility 424 9.1.4.2 Paroxetine Hydrochloride Hemihydrate 424 9.1.4.2.1 PHC Hemihydrate History 425 9.1.4.2.2 Meaning of “Crystalline Paroxetine Hydrochloride Hemihydrate” 425 9.1.4.2.3 PHC Hemihydrate: Infringed, But Invalid for Anticipation 426 9.1.4.3 Ranitidine Hydrochloride 426 9.1.4.3.1 History of RHCl Form 2 426 9.1.4.3.2 RHCl Form 2 Not Anticipated by Example 32 427 9.1.4.4 Cefdinir 427 9.1.4.5 Amlodipine Besylate 428 9.1.4.5.1 History of Amlodipine Besylate 428 9.1.4.5.2 Amlodipine Besylate Found Obvious 428 9.1.4.6 Concluding Remarks 429 Notes 429 References 430 9.2 Polymorphs and Patents – The EU Perspective 431Oliver Brosch 9.2.1 European Patent Applications and European Patents 431 9.2.1.1 Introduction 431 9.2.1.2 Summary of the Processing of Applications and Patents Before the European Patent Office (EPO) 431 9.2.1.3 Economic Factors 432 9.2.1.4 Unitary Patents 433 9.2.1.5 Protection of Polymorphs and Solid Forms in General 433 9.2.1.6 Polymorph Screening 434 9.2.2 Decisions of Technical Boards of Appeal of the EPO 435 9.2.2.1 Decision T 777/08 of 24 May 2011 435 9.2.2.2 Decision T 1555/12 Dated 29 April 2015 435 9.2.2.3 Decision T 2114/13 Dated 12 October 2016 442 9.2.2.4 Decision T 2397/12 Dated 12 March 2018 442 9.2.2.5 Decision T 246/15 Dated 13 November 2018 442 9.2.3 Jurisdiction of the Federal Patent Court and the German Federal Supreme Court 443 9.2.3.1 Decision “Kristallformen” German Federal Court 443 9.2.3.2 Decision X ZR 58/08 Dated 15 March 15 2011 443 9.2.3.3 Decision X ZR 98/09 Dated 15 May 2012 444 9.2.3.4 Decision X ZR 110/16 Dated 7 August 2018 444 9.2.4 Assessing Validity of a Patent or the Chances of Success 445 9.2.5 Interaction with Patent Professionals 446 List of Abbreviations 447 References 447 10 Regulatory Frameworks Affecting Solid-State Development 449Christoph Saal 10.1 Introduction – The Need for Regulation in Pharmaceutical Industry 449 10.2 Solid-State Forms to Be Used for Drugs 451 10.3 General Regulatory Considerations for Pharmaceutical Solid-State Forms 453 10.4 Regulatory Framework for Pharmaceutical Salts 454 10.4.1 Pharmaceutical Equivalence and Pharmaceutical Alternatives 454 10.4.2 Bioequivalence 456 10.4.3 Therapeutic Equivalence 458 10.4.4 Biowaivers 458 10.4.5 Regulatory Approval for Pharmaceutical Salts 460 10.4.5.1 Regulatory Approval Pathways in the United States 460 10.4.5.2 Regulatory Approval Pathways in the European Union 461 10.4.6 Regulatory Approval for Polymorphs 463 10.4.7 Polymorphism in Pharmacopoeias 469 10.5 Regulatory Framework for Co-crystals 471 10.6 Summary 476 List of Abbreviations 476 References 477 11 Opportunities and Challenges for Generic Development from a Solid-state Perspective 481Judith Aronhime and Mike Teiler 11.1 The Birth of a New Drug and the Generic Siblings that Will Follow – Two Different Mindsets 481 11.1.1 Generics 481 11.1.2 Proprietary Products 482 11.1.3 API and Solid State 483 11.1.3.1 Generics 483 11.1.3.2 Proprietary 483 11.2 Portfolio Management – How is a Portfolio Constructed and Maintained? 484 11.2.1 Activities and Timelines 484 11.2.1.1 Strategy 484 11.2.1.2 Value 484 11.2.1.3 Factors Impacting on Timing – When and How Does a Product Show Up on a Generic Company’s Radar Screen? 485 11.2.2 Timing 487 11.2.2.1 When is “On-time?” 487 11.2.3 Market-specific Considerations Based on Local Legislation and Administration (OB, PIV, Various Exclusivities – US, EU, JP, etc.) 489 11.2.3.1 Patents Through the Eyes of the Regulatory Authorities 489 11.2.3.2 Data Exclusivity (Data Protection) 489 11.2.3.3 Salts and Esters 490 11.2.3.4 Think Global, Act Local 490 11.2.4 Sources to Evaluate a Project 491 11.2.4.1 Government and Regulatory Agencies 491 11.2.4.2 Analyst Reports and Company Financial Reports 492 11.2.4.3 Pay Data Sources 492 11.2.5 Evaluation Tools 493 11.2.5.1 Business Case 493 11.2.5.2 Quality Target Project Profile (QTPP) 493 11.2.6 Criteria for Identifying Promising Projects 493 11.2.7 Criteria for Building a Robust Portfolio 494 11.3 Challenges in Developing a Generic Product from the Solid-state Perspective 495 11.3.1 Implications in Developing Formulation with a Metastable API 496 11.3.2 The Stability Question 497 11.3.2.1 Polymorphic Stability in Dry Conditions 497 11.3.2.2 Polymorphic Stability inWet Conditions (Slurry) 498 11.4 Generic Solid-state Development 498 11.4.1 General 498 11.4.2 Predevelopment Phase: Solid-state Strategy 499 11.4.2.1 Review of the Solid State, Especially the Polymorph Patent Landscape 499 11.4.2.2 Design-around Considerations 500 11.4.3 Crystal Forms Discovery 503 11.4.3.1 Importance of the Crystal Forms Discovery Stage 503 11.4.3.2 New Crystal Forms Unpredictability 503 11.4.3.3 Pragmatic Questions About Crystal Forms Search 504 11.4.3.4 Late-appearing Polymorphs 505 11.4.3.5 Irreproducibility of Procedures 506 11.4.3.6 Analytical Focus 507 11.4.4 Target Selection 507 11.4.4.1 Solubility 508 11.4.4.2 Morphology 509 11.4.4.3 Solid-state Stability 509 11.4.4.4 Additional Factors 509 11.4.5 Process Development in the Laboratory Scale 510 11.4.5.1 Process Development 510 11.4.5.2 Thermodynamic Stability Relationships 510 11.4.5.3 Solubility Curves 510 11.4.5.4 API Target 511 11.4.5.5 Analytical Methods for Polymorphic Purity 512 11.4.6 Scale-up Challenges 512 11.4.6.1 Control of Crystal Form 512 11.4.6.2 Control of Particle Size and Morphology 513 11.4.6.3 Lot-to-Lot Variability 513 11.4.6.4 Analytical Focus 514 11.4.7 Pharma Development 515 11.4.7.1 The Tetrahedron Principle and Consistency Among Lots 516 11.4.7.2 The Effect of Micronization on Amorphous Content in Crystalline APIs 516 11.4.7.3 Solid-state Stability upon Storage 517 11.4.8 Impact on Formulation 517 11.4.9 Summary of Timelines for Solid-state Activity 518 11.4.10 Intellectual Property (IP) Strategies and Activities 519 11.5 Success Factors 520 11.5.1 Successful Biostudy 520 11.5.2 Successful Launch 521 11.5.3 Generic Commercial Success 522 List of Abbreviations 523 References 524 Index 531

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Book SynopsisLearn to master a powerful technology to enable a faster drug discovery workflow The ultimate dream for medicinal chemists is the ability to synthesize new drug-like compounds with the push of a button. The key to synthesizing chemical compounds more quickly and accurately lies in computer-controlled technologies that can be optimized by machine learning. Recent developments in computer-controlled automated syntheses that rely on miniature flow reactors—with integrated analysis of the resulting products—provide a workable technology for synthesizing new chemical substances very quickly and with minimal effort. In Flow and Microreactor Technology in Medicinal Chemistry, early adopters of this ground-breaking technology describe its current and potential uses in medicinal chemistry. Based on successful examples of the use of flow and microreactor synthesis for drug-like compounds, the book introduces current as well as emerging uses for automated synthesis in a drug discovery context. Flow and Microreactor Technology in Medicinal Chemistry readers will also find: Numerous case studies that address the most common applications of this technology in the day-to-day work of medicinal chemists How to integrate flow synthesis with drug discovery How to perform enantioselective reactions under continuous flow conditions Flow and Microreactor Technology in Medicinal Chemistry is a valuable practical reference for medicinal chemists, organic chemists, and natural products chemists, whether they are working in academia or in the pharmaceutical industry.Table of ContentsINTRODUCTION Continuous flow technology for the fine chemical and pharmaceutical Industries. CASE STUDIES Novel (forbidden) chemistry towards NCE to increase chemical space Enantioselective catalysis in continuous flow to improve throughput Synthesis in continuous flow of important drugs and APIs TECHNOLOGIES HTE in continuous flow to speed library synthesis Integration systems with continuous synthesis and biological screening Microreactors for target validation (organ on a chip) Process Analytical Technologies (PAT) and tools for controlled process design Artificial Intelligence, Machine Learning and automatization in drug discovery Emerging market challenges and on demand manufacturing

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Book SynopsisUnites a biological and a biotechnological perspective on cyanobacteria, and includes the industrial aspects and applications of cyanobacteria Cyanobacteria Biotechnology offers a guide to the interesting and useful features of cyanobacteria metabolism that keeps true to a biotechnology vision. In one volume the book brings together both biology and biotechnology to illuminate the core acpects and principles of cyanobacteria metabolism. Designed to offer a practical approach to the metabolic engineering of cyanobacteria, the book contains relevant examples of how this metabolic "module" is currently being engineered and how it could be engineered in the future. The author includes information on the requirements and real-world experiences of the industrial applications of cyanobacteria. This important book: Brings together biology and biotechnology in order to gain insight into the industrial relevant topic of cyanobacteria Introduces the key aspects of the metabolism of cyanobacteria Presents a grounded, practical approach to the metabolic engineering of cyanobacteria Offers an analysis of the requirements and experiences for industrial cyanobacteria Provides a framework for readers to design their own processes Written for biotechnologists, microbiologists, biologists, biochemists, Cyanobacteria Biotechnology provides a systematic and clear volume that brings together the biological and biotechnological perspective on cyanobacteria.Table of ContentsForeword: Cyanobacteria Biotechnology xv Acknowledgments xviii Part I Core Cyanobacteria Processes 1 1 Inorganic Carbon Assimilation in Cyanobacteria: Mechanisms, Regulation, and Engineering 3Martin Hagemann, Shanshan Song, and Eva-Maria Brouwer 1.1 Introduction – The Need for a Carbon-Concentrating Mechanism 3 1.2 The Carbon-Concentrating Mechanism (CCM) Among Cyanobacteria 4 1.2.1 Ci Uptake Proteins/Mechanisms 5 1.2.2 Carboxysome and RubisCO 8 1.3 Regulation of Ci Assimilation 10 1.3.1 Regulation of the CCM 10 1.3.2 Further Regulation of Carbon Assimilation 13 1.3.3 Metabolic Changes and Regulation During Ci Acclimation 14 1.3.4 Redox Regulation of Ci Assimilation 15 1.4 Engineering the Cyanobacterial CCM 16 1.5 Photorespiration 17 1.5.1 Cyanobacterial Photorespiration 17 1.5.2 Attempts to Engineer Photorespiration 19 1.6 Concluding Remarks 20 Acknowledgments 21 References 21 2 Electron Transport in Cyanobacteria and Its Potential in Bioproduction 33David J. Lea-Smith and Guy T. Hanke 2.1 Introduction 33 2.2 Electron Transport in a Bioenergetic Membrane 34 2.2.1 Linear Electron Transport 34 2.2.2 Cyclic Electron Transport 37 2.2.3 ATP Production from Linear and Cyclic Electron Transport 37 2.3 Respiratory Electron Transport 38 2.4 Role of Electron Sinks in Photoprotection 41 2.4.1 Terminal Oxidases 41 2.4.2 Hydrogenase and Flavodiiron Complexes 41 2.4.3 Carbon Fixation and Photorespiration 43 2.4.4 Extracellular Electron Export 44 2.5 Regulating Electron Flux into Different Pathways 45 2.5.1 Electron Flux Through the Plastoquinone Pool 45 2.5.2 Electron Flux Through Fdx 46 2.6 Spatial Organization of Electron Transport Complexes 47 2.7 Manipulating Electron Transport for Synthetic Biology Applications 48 2.7.1 Improving Growth of Cyanobacteria 49 2.7.2 Production of Electrical Power in BPVs 49 2.7.3 Hydrogen Production 50 2.7.4 Production of Industrial Compounds 50 2.8 Future Challenges in Cyanobacterial Electron Transport 51 References 52 3 Optimizing the Spectral Fit Between Cyanobacteria and Solar Radiation in the Light of Sustainability Applications 65Klaas J. Hellingwerf, Que Chen, and Filipe Branco dos Santos 3.1 Introduction 65 3.2 Molecular Basis and Efficiency of Oxygenic Photosynthesis 67 3.3 Fit Between the Spectrum of Solar Radiation and the Action Spectrum of Photosynthesis 72 3.4 Expansion of the PAR Region of Oxygenic Photosynthesis 74 3.5 Modulation and Optimization of the Transparency of Photobioreactors 79 3.6 Full Control of the Light Regime: LEDs Inside the PBR 81 3.7 Conclusions and Prospects 82 References 83 Part II Concepts in Metabolic Engineering 89 4 What We Can Learn from Measuring Metabolic Fluxes in Cyanobacteria 91Xiang Gao, Chao Wu, Michael Cantrell, Melissa Cano, Jianping Yu, and Wei Xiong 4.1 Central Carbon Metabolism in Cyanobacteria: An Overview and Renewed Pathway Knowledge 91 4.1.1 Glycolytic Routes Interwoven with the Calvin Cycle 91 4.1.2 Tricarboxylic Acid Cycling 94 4.2 Methodologies for Predicting and Quantifying Metabolic Fluxes in Cyanobacteria 95 4.2.1 Flux Balance Analysis and Genome-Scale Reconstruction of Metabolic Network 95 4.2.2 13C-Metabolic Flux Analysis 96 4.2.3 Thermodynamic Analysis and Kinetics Analysis 99 4.3 Cyanobacteria Fluxome in Response to Altered Nutrient Modes and Environmental Conditions 101 4.3.1 Autotrophic Fluxome 101 4.3.2 Photomixotrophic Fluxome 104 4.3.3 Heterotrophic Fluxome 105 4.3.4 Photoheterotrophic Fluxome 105 4.3.5 Diurnal Metabolite Oscillations 106 4.3.6 Nutrient States’ Impact on Metabolic Flux 107 4.4 Metabolic Fluxes Redirected in Cyanobacteria for Biomanufacturing Purposes 108 4.4.1 Restructuring the TCA Cycle for Ethylene Production 108 4.4.2 Maximizing Flux in the Isoprenoid Pathway 109 4.4.2.1 Measuring Precursor Pool Size to Evaluate Potential Driving Forces for Isoprenoid Production 109 4.4.2.2 Balancing Intermediates for Increased Pathway Activity 110 4.4.2.3 Kinetic Flux Profiling to Detect Bottlenecks in the Pathway 111 4.5 Synopsis and Future Directions 112 Acknowledgments 112 References 112 5 Synthetic Biology in Cyanobacteria and Applications for Biotechnology 123Elton P. Hudson 5.1 Introduction 123 5.2 Getting Genes into Cyanobacteria 123 5.2.1 Transformation 123 5.2.2 Expression from Episomal Plasmids 125 5.2.3 Delivery of Genes to the Chromosome 127 5.3 Basic Synthetic Control of Gene Expression in Cyanobacteria 129 5.3.1 Quantifying Transcription and Translation in Cyanobacteria 130 5.3.2 Controlling Transcription with Synthetic Promoters 134 5.3.2.1 Constitutive Promoters 136 5.3.2.2 Regulated Promoters that Are Sensitive to Added Compounds (Inducible) 137 5.3.2.3 CRISPR Interference for Transcriptional Repression 139 5.3.3 Controlling Translation 141 5.3.3.1 Ribosome Binding Sites (Cis-Acting) 141 5.3.3.2 Riboswitches (Cis-Acting) 142 5.3.3.3 Small RNAs (Trans-Acting) 143 5.4 Exotic Signals for Controlling Expression 143 5.4.1 Oxygen 144 5.4.2 Light Color 144 5.4.3 Cell Density or Growth Phase 145 5.4.4 Engineering Regulators for Altered Sensing Properties: State of the Art 147 5.5 Advanced Regulation: The Near Future 148 5.5.1 Logic Gates and Timing Circuits 148 5.5.2 Orthogonal Transcription Systems 151 5.5.3 Synthetic Biology Solutions to Increase Stability 152 5.5.4 Synthetic Biology Solutions for Cell Separation and Product Recovery 154 5.6 Conclusions 157 Acknowledgments 158 References 158 6 Sink Engineering in Photosynthetic Microbes 171María Santos-Merino, Amit K. Singh, and Daniel C. Ducat 6.1 Introduction 171 6.2 Source and Sink 172 6.3 Regulation of Sink Energy in Plants 177 6.3.1 Sucrose and Other Signaling Carbohydrates 178 6.3.2 Hexokinases 179 6.3.3 Sucrose Non-fermenting Related Kinases 180 6.3.4 TOR Kinase 181 6.3.5 Engineered Pathways as Sinks in Photosynthetic Microbes 182 6.3.6 Sucrose 183 6.3.7 2,3-Butanediol 187 6.3.8 Ethylene 187 6.3.9 Glycerol 188 6.3.10 Isobutanol 188 6.3.11 Isoprene 189 6.3.12 Limonene 189 6.3.13 P450, an Electron Sink 190 6.4 What Are Key Source/Sink Regulatory Hubs in Photosynthetic Microbes? 191 6.5 Concluding Remarks 194 Acknowledgment 195 References 195 7 Design Principles for Engineering Metabolic Pathways in Cyanobacteria 211Jason T. Ku and Ethan I. Lan 7.1 Introduction 211 7.2 Cofactor Optimization 212 7.2.1 Recruiting NADPH-Dependent Enzymes Wherever Possible 215 7.2.2 Engineering NADH-Specific Enzymes to Utilize NADPH 217 7.2.3 Increasing NADH Pool in Cyanobacteria Through Expression of Transhydrogenase 218 7.3 Incorporation of Thermodynamic Driving Force into Metabolic Pathway Design 219 7.3.1 ATP Driving Force in Metabolic Pathways 220 7.3.2 Increasing Substrate Pool Supports the Carbon Flux Toward Products 222 7.3.3 Product Removal Unblocks the Limitations of Product Titer 223 7.4 Development of Synthetic Pathways for Carbon Conserving Photorespiration and Enhanced Carbon Fixation 225 7.5 Summary and Future Perspective on Cyanobacterial Metabolic Engineering 229 References 229 8 Engineering Cyanobacteria for Efficient Photosynthetic Production: Ethanol Case Study 237Guodong Luan and Xuefeng Lu 8.1 Introduction 237 8.2 Pathway for Ethanol Synthesis in Cyanobacteria 238 8.2.1 Pyruvate Decarboxylase and Type II Alcohol Dehydrogenase 238 8.2.2 Selection of Better Enzymes in the Pdc–AdhII Pathway 240 8.2.3 Systematic Characterization of the PdcZM–Slr1192 Pathway 241 8.3 Selection of Optimal Cyanobacteria “Chassis,” Strain for Ethanol Production 242 8.3.1 Synechococcus PCC 6803 and Synechococcus PCC 7942 243 8.3.2 Synechococcus PCC 7002 245 8.3.3 Anabaena PCC 7120 245 8.3.4 Nonconventional Cyanobacteria Species 246 8.4 Metabolic Engineering Strategies Toward More Efficient and Stable Ethanol Production 246 8.4.1 Enhancing the Carbon Flux via Overexpression of Calvin Cycle Enzymes 248 8.4.2 Blocking Pathways that Are Competitive to Ethanol 248 8.4.3 Arresting Biomass Formation 249 8.4.4 Engineering Cofactor Supply 249 8.4.5 Engineering Strategies Guided by In Silico Simulation 250 8.4.6 Stabilizing Ethanol Synthesis Capacity in Cyanobacterial Cell Factories 251 8.5 Exploring the Response in Cyanobacteria to Ethanol 253 8.5.1 Response of Cyanobacterial Cells Toward Exogenous Added Ethanol 254 8.5.2 Response of Cyanobacteria to Endogenous Synthesized Ethanol 255 8.6 Metabolic Engineering Strategies to Facilitate Robust Cultivation Against Biocontaminants 256 8.6.1 Engineering Cyanobacteria Cell Factories to Adapt for Selective Environmental Stresses 256 8.6.2 Engineering Cyanobacteria Cell Factories to Utilize Uncommon Nutrients 258 8.7 Conclusions and Perspectives 258 References 259 9 Engineering Cyanobacteria as Host Organisms for Production of Terpenes and Terpenoids 267João S. Rodrigues and Pia Lindberg 9.1 Terpenoids and Industrial Applications 267 9.2 Terpenoid Biosynthesis in Cyanobacteria 270 9.2.1 Methylerythritol-4-Phosphate Pathway 270 9.2.2 Formation of Terpene Backbones 272 9.3 Natural Occurrence and Physiological Roles of Terpenes and Terpenoids in Cyanobacteria 274 9.4 Engineering Cyanobacteria for Terpenoid Production 275 9.4.1 Metabolic Engineering 277 9.4.1.1 Terpene Synthases 277 9.4.1.2 Increasing Supply of Terpene Backbones 285 9.4.1.3 Engineering the Native MEP Pathway 286 9.4.1.4 Implementing the MVA Pathway 287 9.4.1.5 Enhancing Precursor Supply 288 9.4.2 Optimizing Growth Conditions for Production 289 9.4.3 Product Capture and Harvesting 291 9.5 Summary and Outlook 292 Acknowledgments 293 References 293 10 Cyanobacterial Biopolymers 301Moritz Koch and Karl Forchhammer 10.1 Polyhydroxybutryate 301 10.1.1 Introduction 301 10.1.2 PHB Metabolism in Cyanobacteria 302 10.1.3 Industrial Applications of PHB 305 10.1.3.1 Physical Properties of PHB and Its Derivatives 305 10.1.3.2 Biodegradability 306 10.1.3.3 Application of PHB as a Plastic 306 10.1.3.4 Reactor Types 306 10.1.3.5 Production Process 307 10.1.3.6 Downstream Processing 308 10.1.4 Metabolic Engineering of PHB Biosynthesis 308 10.1.5 Limitations and Potential of PHB Production in Cyanobacteria 310 10.2 Cyanophycin Granules in Cyanobacteria 311 10.2.1 Biology of Cyanophycin 311 10.2.2 Genes and Enzymes of CGP Metabolism 315 10.2.2.1 Cyanophycin Synthetase 315 10.2.2.2 Cyanophycin Degrading Enzymes 316 10.2.3 Regulation of Cyanophycin Metabolism 317 10.2.4 Cyanophycin Overproduction and Potential Industrial Applications 318 Acknowledgement 319 References 319 11 Biosynthesis of Fatty Acid Derivatives by Cyanobacteria: From Basics to Biofuel Production 331Akihito Kawahara and Yukako Hihara 11.1 Introduction 331 11.2 Overview of Fatty Acid Metabolism 332 11.2.1 Fatty Acid Biosynthesis 332 11.2.2 Fatty Acid Degradation and Turnover 335 11.2.3 Accumulation of Storage Lipids 336 11.3 Basic Technologies for Production of Free Fatty Acids 337 11.3.1 Production of Free Fatty Acids in E. coli 337 11.3.2 Production of Free Fatty Acids in Cyanobacteria 338 11.4 Advanced Technologies for Enhancement of Free Fatty Acid Production 339 11.4.1 Enhancement of Fatty Acid Biosynthesis 339 11.4.2 Enhancement of Carbon Fixation Activity 345 11.4.3 Engineering of Carbon Flow: Modification of Key Regulatory Factors 345 11.4.4 Engineering of Carbon Flow: Deletion of Competitive Pathways 346 11.4.5 Mitigation of the Toxicity of FFAs 347 11.4.6 Enhancement of FFA Secretion 348 11.4.7 Induction of Cell Lysis 349 11.4.8 Recovery of Produced FFAs from Medium 350 11.4.9 Identification of Cyanobacterial Strains Suitable for FFA Production 350 11.5 Hydrocarbon Production in Cyanobacteria 351 11.6 Advanced Technologies for Enhancement of Hydrocarbon Production 353 11.6.1 Enhancement of Alk(a/e)ne Biosynthesis 353 11.6.2 Improvement of the Performance of Alkane Biosynthetic Enzymes 354 11.7 Basic Technologies for Production of Fatty Alcohols 355 11.8 Advanced Technologies for Enhancement of Fatty Alcohol Production 355 11.9 Basic Technologies for Production of Fatty Acid Alkyl Esters 356 11.10 Perspectives 357 References 358 12 Product Export in Cyanobacteria 369Cátia F. Gonçalves, Steeve Lima, and Paulo Oliveira 12.1 Introduction 369 12.2 Secretion Mediated by Membrane-Embedded Systems 373 12.2.1 Proteins 373 12.2.2 Extracellular Polymeric Substances (EPS) 377 12.2.3 Soluble Sugars and Organic Acids 379 12.2.4 Fatty Acids 381 12.2.5 Alcohols 382 12.2.6 Terpenes 384 12.3 MV-Mediated Secretion 386 12.3.1 Structure and Biogenesis of Bacterial MVs 386 12.3.1.1 Cyanobacterial MVs 388 12.3.2 MVs as Novel Biotechnological Tools 389 12.4 Concluding Remarks 391 Acknowledgments 392 References 392 Part III Frontiers of Cyanobacteria Biotechnology 407 13 Harnessing Solar-Powered Oxic N2-fixing Cyanobacteria for the BioNitrogen Economy 409James Young, Liping Gu, William Gibbons, and Ruanbao Zhou 13.1 Introduction 409 13.2 Physiology and Implications of Oxic Nitrogen Fixation 410 13.2.1 Ecological Range 411 13.2.2 Balancing Photosynthesis and Nitrogen Fixation 412 13.2.3 Energetic Demands and How the Cells Adapt 412 13.2.4 Impacts of Continuous Light vs Dark–Light Cycles 416 13.3 Major Biotechnology Applications for Diazotrophic Cyanobacteria 417 13.3.1 General Economic and Environmental Considerations of Diazotrophic Cyanobacteria 417 13.3.2 Metabolic Engineering of N2-Fixing Cyanobacteria for Carbon Compound Production 420 13.3.2.1 Direct Production of Biofuels 420 13.3.2.2 Cyanobacteria as a Fermentable Substrate 420 13.3.3 Metabolic Engineering of Nitrogen Fixing Cyanobacteria for Nitrogen-Rich Compound Production 422 13.3.3.1 Ammonia 422 13.3.3.2 Guanidine 423 13.3.3.3 Cyanophycin 423 13.3.3.4 Amino Acids and Proteins 423 13.3.4 Application of Diazotrophic Cyanobacteria in Agriculture 425 13.4 Conclusions 428 References 428 14 Traits of Fast-Growing Cyanobacteria 441Meghna Srivastava, Elton P. Hudson, and Pramod P. Wangikar 14.1 Introduction 441 14.2 Why is Growth Rate Significant? 442 14.3 An Overview of Factors Affecting the Growth Rates of Cyanobacteria 446 14.3.1 Light Intensity and Quality 448 14.3.2 Mixotrophic Growth 451 14.3.3 Circadian Rhythm 451 14.3.4 Additional Factors Relating to Growth Rates in Cyanobacteria 452 14.3.4.1 Cell Morphology 453 14.3.4.2 Genome Size 453 14.3.4.3 Saltwater Tolerance 454 14.3.4.4 Nutrient Supplementation 454 14.3.5 Carbon Storage 455 14.4 Overview of the Fast-Growing Model Cyanobacteria 455 14.4.1 Synechococcus elongatus UTEX 2973 455 14.4.2 Synechococcus elongatus PCC 11801 456 14.4.3 Synechococcus sp. PCC 11901 456 14.4.4 Synechococcus sp. PCC 7002 457 14.5 Relationship Between Light Usage and Growth Rate in Model Strains 458 14.5.1 Case Study: The pmgA Mutant of Synechocystis 458 14.5.2 Case Study: The S. elongatus 7942 and S. elongatus 2973 Strains 460 14.6 Molecular Determinants of Fast Growth of S. elongatus UTEX 2973 460 14.7 Carbon Fluxes in Fast-Growing Strains Determined Using Metabolic Flux Analysis 463 14.8 Engineering Cyanobacteria for Fast Growth 465 14.8.1 Calvin Cycle Enzymes 465 14.8.2 PEP Carboxylase 466 14.8.3 Carbon and Light Uptake Proteins 467 14.9 Conclusion 468 References 468 15 Cyanobacterial Biofilms in Natural and Synthetic Environments 477Christian David, Rohan Karande, and Katja Bühler 15.1 Motivation 477 15.2 Introduction to Biofilms: Biology and Applications 478 15.3 Cyanobacteria in Natural Biofilms and Microbial Mats 483 15.4 Introduction to (Photo-)biotechnology 484 15.5 Benefits of Microscale Systems for (Photo-)biofilm Cultivation 487 15.6 Oxygen Accumulation and Its Impacts 488 15.7 Resource Management in Biofilms 491 15.8 Applications of Photosynthetic Biofilms 493 15.8.1 Biofilms Enable High Cell Densities 497 15.8.2 Biofilms Enable Continuous Production 498 15.9 Outlook 499 References 499 16 Growth of Photosynthetic Microorganisms in Different Photobioreactors Operated Outdoors 505Eleftherios Touloupakis and Pietro Carlozzi 16.1 Background 505 16.1.1 Photobiological Hydrogen Production 506 16.1.2 Polyhydroxyalkanoate Production by Photosynthetic Microbes 508 16.1.3 Photobioreactors 509 16.2 Case Studies of Outdoor Cultivations of Photosynthetic Microorganisms 513 16.2.1 Outdoor Cultures of Purple Non-Sulfur Bacteria for H2 and PHB Production 513 16.2.2 Outdoor Cultures of Cyanobacteria 516 16.3 Conclusion 517 Acknowledgments 519 References 519 Index 531

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Book SynopsisModel-Based Optimization for Petroleum Refinery Configuration Design An accessible, easy-to-read introduction to the methods of mixed-integer optimization, with practical applications, real-world operational data, and case studies Interest in model-based approaches for optimizing the design of petroleum refineries has increased throughout the industry in recent years. Mathematical optimization based on mixed-integer programming has brought about the superstructure optimization method for synthesizing petroleum refinery configurations from multiple topological alternatives. Model-Based Optimization for Petroleum Refinery Configuration Design presents a detailed introduction to the use of mathematical optimization to solve both linear and nonlinear problems in the refining industry. The book opens with an overview of petroleum refining processes, basic concepts in mathematical programming, and applications of mathematical programming for refinery optimization. Subsequent chapters address superstructure representations of topological alternatives, mathematical formulation, solution strategies, and various modeling frameworks. Practical case studies demonstrate refinery configuration design, refinery retrofitting, and real-world issues and considerations. Presents linear, nonlinear, and mixed-integer programming approaches applicable to both new and existing petroleum refineries Highlights the benefits of model-based solutions to refinery configuration design problems Features detailed case studies of the development and implementation of optimization models Discusses economic considerations of heavy oil processing, including cash flow analysis of refinery costs and return on capital Includes numerical examples based on real-world operational data and various commercial technologies Model-Based Optimization for Petroleum Refinery Configuration Design is an invaluable resource for researchers, chemical engineers, process and energy engineers, other refining professionals, and advanced chemical engineering students.Table of Contents1 Introduction to Optimization Modeling for Petroleum Refineries 1 1.1 Background 1 1.2 Overview of Refining Processes 4 1.2.1 Atmospheric Crude Oil Distillation 5 1.2.2 Hydroprocessing 5 1.2.3 Sulfur Recovery 9 1.2.4 Reforming 9 1.2.5 Isomerization 10 1.2.6 Blending 11 1.3 Overview of Refinery Optimization Modeling 12 1.3.1 Refinery Optimization Systems, Techniques, and Tools 12 1.3.2 Modeling for Advanced Process Control 14 1.3.3 Modeling for Real-Time Optimization 15 1.3.4 Modeling for Process Simulation 17 1.3.4.1 Modeling for Dynamic Simulation 18 1.3.4.2 Modeling for Operator Training Simulation 19 1.3.5 Modeling for Planning and Scheduling 19 1.3.5.1 Systems Implementation 23 1.3.5.2 Optimization of Crude Oil Scheduling 24 1.3.5.3 Refinery Management 25 1.4 Concluding Remarks 25 References 26 2 Basic Petroleum Refinery Economics 31 2.1 Refinery Economics Overview 31 2.1.1 Refinery Profitability 31 2.1.2 Refinery Margins 32 2.1.3 Refinery Margin Calculations 33 2.1.4 Refinery Margin Trends 34 2.1.5 Refinery Margin Improvement 34 2.2 Marginal Economics for Incremental Optimization 34 2.3 Refinery Economic Analysis 36 2.3.1 Refinery Value Determination 36 2.3.2 Refinery Economic Evaluation 37 2.3.2.1 Simple Example 37 2.3.2.2 Advanced Example 38 2.3.2.3 Further Example 40 2.3.3 Refinery Contracts 41 2.4 Concluding Remarks 41 References 41 3 Superstructure Representation 43 3.1 Introduction to Superstructures 43 3.2 Types of Superstructure Representation 43 3.3 State–Task Network Superstructure Representation 44 3.4 State–Equipment Network Superstructure Representation 45 3.5 Resource–Task Network Superstructure Representation 46 3.6 Superstructure Generation 47 3.7 Other Superstructure Representations 48 3.7.1 State–Space Network Superstructure Representation 48 3.7.2 Unit Operation–Port–State Superstructure Representation 48 3.7.3 Bond Graph Superstructure Representation 48 3.8 Superstructure Representation Example for Naphtha Processing 49 3.9 Chapter Summary 53 References 53 4 Modeling Framework 57 4.1 Modeling of Mixed Continuous and Integer Decision Variables 57 4.2 Superstructure Optimization Modeling 58 4.3 Constructing Superstructures 58 4.4 Modeling of Superstructure Representations 59 4.5 Modeling of Discrete Decisions and Logical Relations 60 4.5.1 Propositional Logics for Superstructure Optimization Modeling 61 4.5.2 Logical Binary Variables 62 4.5.3 Yes/No Type Binary Variables 62 4.5.4 Disjunctive Optimization Modeling 63 4.6 Modeling of Process Units and Operations 67 4.6.1 Process Design Procedure 67 4.6.2 Selecting Modeling Variables 67 4.6.3 Formulating Simple Models 68 4.6.4 Basic Unit Models 68 4.6.4.1 Mixer 68 4.6.4.2 Splitter 69 4.6.4.3 Separator 70 4.6.4.4 Valve 70 4.6.4.5 Multicomponent Splitter 70 4.6.5 Unit Operation Models 72 4.6.5.1 Compressor 72 4.6.5.2 Furnace 72 4.6.5.3 Conversion Reactor 72 4.6.5.4 Heat Exchanger 75 4.6.6 Information Flow Modeling 75 4.6.6.1 Information Flow Diagram 77 4.6.6.2 Choice of Design Variables 79 4.6.6.3 Equation Ordering 79 4.7 Modeling for Numerical Studies 84 4.8 Chapter Summary 86 References 86 5 Model Formulation and Implementation 89 5.1 Mathematical Formulation 89 5.2 Generic Optimization Model Formulation for Refinery Planning 90 5.2.1 Objective Function 91 5.2.2 Production Capacity and Expansion Constraints 91 5.2.3 Mass Balances 92 5.2.4 Demand Constraints 92 5.2.5 Availability Constraints 92 5.2.6 Non-Negativity Constraints 92 5.3 Generic Optimization Model Formulation for Refinery Design 93 5.3.1 Material Balances 93 5.3.2 Mixed-Integer Logical Constraints 93 5.3.3 Logical Constraints on Design and Structural Specifications 94 5.3.4 Logic Propositional Constraints on Design Specifications 95 5.3.4.1 Example 1 95 5.3.4.2 Example 2 100 5.3.5 Logic Propositional Constraints on Structural Specifications 101 5.3.6 Generalized Disjunctive Programming 101 5.4 Numerical Implementation for Computational Experiments 106 5.5 Computational Experiment Examples 110 5.5.1 MILP Model Results 113 5.5.2 GDP Model Results 114 5.6 Chapter Summary 123 References 123 6 Solution Strategies 125 6.1 Convex Relaxation 125 6.2 Lagrangean Decomposition 126 6.3 Global Optimization Techniques 126 6.3.1 Branch and Reduce 128 6.3.2 Spatial Branch and Bound 128 6.3.3 Hybrid Branch and Bound 128 6.3.4 Interval Analysis 129 6.3.5 Extended Cutting Plane 129 6.4 Advancements in Commercial Integer Optimization Solvers 130 6.4.1 Overview 130 6.4.2 Computational Performance of Commercial Integer Optimization Solvers 130 6.4.3 A Commercial Success Story: CPLEX Integer Optimization Solver 130 6.4.4 Solution Methods and Algorithms 131 6.4.4.1 Integer Optimization Algorithms 131 6.4.4.2 Branch and Bound 132 6.4.4.3 Presolve and Cutting Planes 134 6.4.4.4 Heuristics 135 6.4.4.5 Combined Local Search and Heuristics 136 6.4.4.6 Parallelization 136 6.4.4.7 Solution Pools 136 6.4.4.8 Tuning Tools 136 6.4.5 Application Examples 136 6.4.5.1 Example 1: Energy Optimization 137 6.4.5.2 Example 2: Financial Optimization 137 6.4.5.3 Example 3: Manufacturing Optimization 137 6.4.5.4 Concluding Remarks 138 6.5 Chapter Summary 139 References 139 7 Industrial Case Studies with Business-Centric Techno-Commercial Considerations 145 7.1 Industrial Case Study 1: Refinery Configuration for Heavy Oil Processing 145 7.1.1 Background 145 7.1.2 Problem Statement 146 7.1.3 Model Formulation 147 7.1.4 Numerical Example 148 7.1.5 Concluding Remarks 151 7.2 Industrial Case Study 2: Refinery Configuration for Whole Complex Processing 152 7.2.1 Model Formulation 152 7.2.1.1 Superstructure Representation 156 7.2.1.2 Logic Propositions 162 7.2.1.3 Objective Function 164 7.2.2 Computational Results 165 7.2.2.1 Computational Results and Discussion 166 7.2.2.2 Model Validation 171 7.2.2.3 Application Extension to Refinery Upgrade Studies 176 7.2.2.4 Sensitivity Analysis 176 7.2.3 Concluding Remarks 176 7.3 Industrial Case Study 3: Refinery Configuration for Naphtha Upgrading 177 7.3.1 Problem Statement 178 7.3.2 Propositional Logics and Logic Cuts in Process Synthesis Problems 178 7.3.3 Logical Constraints 178 7.3.3.1 General Formulation 178 7.3.3.2 Logical Constraints on Processing Alternatives of Naphtha for Petroleum Refineries 182 7.3.4 Computational Experience 182 7.3.5 Concluding Remarks 183 7.4 Chapter Summary 186 References 186 8 Industrial Case Studies with Environmental-Centric Techno-Commercial Considerations 191 8.1 Industrial Case Study 1: Refinery Configuration with Environmental Considerations 191 8.1.1 Background 191 8.1.2 Problem Statement 192 8.1.3 Model Formulation 192 8.1.3.1 Superstructure Representation 192 8.1.3.2 Material Balance Constraints 192 8.1.3.3 Logical Constraints 194 8.1.3.4 Logic Propositions 194 8.1.3.5 Environmental Performance Assessment for Risk Evaluation of Flowsheets 196 8.1.3.6 Objective Function 197 8.1.4 Numerical Example 197 8.1.5 Concluding Remarks 198 8.2 Industrial Case Study 2: Refinery Configuration with Heat Integration 198 8.2.1 Problem Statement 198 8.2.2 Superstructure Representation 199 8.2.3 Modeling and Computational Strategy 201 8.2.4 Model Formulation 202 8.2.4.1 Flowsheet Optimization 202 8.2.4.2 Heat Integration Constraints 205 8.2.4.3 Objective Function 206 8.2.5 Computational Results 206 8.2.6 Concluding Remarks 209 8.3 Chapter Summary 211 References 212 9 Industrial Case Studies with Engineering-Centric Techno-Commercial Considerations 215 9.1 Industrial Case Study 1: Refinery Configuration for High-Octane Fuel Production 215 9.1.1 Catalytic Reforming Process 216 9.1.2 Data Reconciliation Method 216 9.1.3 Problem Statement 217 9.1.4 Model Formulation 217 9.1.4.1 Data Reconciliation Model 218 9.1.4.2 Feed Characterization 219 9.1.4.3 Reactor Representation 220 9.1.4.4 Reactor Pressure Balance 221 9.1.4.5 Reaction Kinetic Tuning 221 9.1.4.6 Reactor Switch in Cyclic Reformer 221 9.1.4.7 Measurement Models 223 9.1.5 Results and Discussion 224 9.1.5.1 Key Process Variables 224 9.1.5.2 Tuning Strategies 225 9.1.5.3 Reformate Yields 226 9.1.5.4 Reactor Total Endotherms 226 9.1.6 Concluding Remarks 226 9.2 Industrial Case Study 2: Refinery Configuration for Low-Benzene Fuel Production 227 9.2.1 Problem Statement 227 9.2.2 Superstructure Representation 227 9.2.3 Model Formulation 229 9.2.4 Preliminary Computational Results 234 9.3 Chapter Summary 234 References 234 Summary and Conclusions 237 Index 239

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Book SynopsisProcess Control, Intensification, and Digitalisation in Continuous Biomanufacturing Explore new trends in continuous biomanufacturing with contributions from leading practitioners in the field With the increasingly widespread acceptance and investment in the ??technology, the last decade has demonstrated the utility of continuous ??processing in the pharmaceutical industry. In Process Control, Intensification, and Digitalisation in Continuous Biomanufacturing, distinguished biotechnologist Dr. Ganapathy Subramanian delivers a comprehensive exploration of the potential of the continuous processing of biological products and discussions of future directions in advancing continuous processing to meet new challenges and demands in the manufacture of therapeutic products. A stand-alone follow-up to the editor’s Continuous Biomanufacturing: Innovative Technologies and Methods published in 2017, this new edited volume focuses on critical aspects of process intensification, process control, and the digital transformation of biopharmaceutical processes. In addition to topics like the use of multivariant data analysis, regulatory concerns, and automation processes, the book also includes: Thorough introductions to capacitance sensors to control feeding strategies and the continuous production of viral vaccines Comprehensive explorations of strategies for the continuous upstream processing of induced microbial systems Practical discussions of preparative hydrophobic interaction chromatography and the design of modern protein-A-resins for continuous biomanufacturing In-depth examinations of bioprocess intensification approaches and the benefits of single use for process intensification Perfect for biotechnologists, bioengineers, pharmaceutical engineers, and process engineers, Process Control, Intensification, and Digitalisation in Continuous Biomanufacturing is also an indispensable resource for chemical engineers seeking a one-stop reference on continuous biomanufacturing.Table of ContentsPreface xiii Part I Continuous Biomanufacturing 1 1 Strategies for Continuous Processing in Microbial Systems 3Julian Kopp, Christoph Slouka, Frank Delvigne, and Christoph Herwig 1.1 Introduction 3 1.1.1 Microbial Hosts and Their Applications in Biotechnology 3 1.1.2 Regulatory Demands for Their Applied Cultivation Mode 5 1.2 Overview of Applied Cultivation Methods in Industrial Biotechnology 6 1.2.1 Batch and Fed-Batch Cultivations 7 1.2.1.1 Conventional Approaches and Their Technical Limitations 7 1.2.1.2 Feeding and Control Strategies Using E. coli as a Model Organism 8 1.2.2 Introduction into Microbial Continuous Biomanufacturing (CBM) 9 1.2.2.1 General Considerations 9 1.2.2.2 Mass Balancing and the Macroscopic Effects in Chemostat Cultures 11 1.2.3 Microbial CBM vs. Mammalian CBM 13 1.2.3.1 Differences in Upstream of Microbial CBM Compared with Cell Culture 13 1.2.3.2 Downstream in Microbial CBM 14 1.3 Monitoring and Control Strategies to Enable CBM with Microbials 16 1.3.1 Subpopulation Monitoring and Possible PAT Tools Applicable for Microbial CBM 16 1.3.2 Modeling and Control Strategies to Enable CBM with Microbials 19 1.4 Chances and Drawbacks in Continuous Biomanufacturing with E. coli 21 1.4.1 Optimization of Plant Usage Using CBM with E. coli 21 1.4.2 Reasons Why CBM with E. coli Is Not State of the Art (Yet) 23 1.4.2.1 Formation of Subpopulation Following Genotypic Diversification 23 1.4.2.2 Formation of Subpopulation Following Phenotypic Diversification 25 1.4.2.3 Is Genomic Integration of the Target Protein an Enabler for CBM with E. coli? 26 1.4.3 Solutions to Overcome the Formation of Subpopulations and How to Realize CBM with E. coli in the Future 27 1.5 Conclusion and Outlook 29 References 30 2 Control of Continuous Manufacturing Processes for Production of Monoclonal Antibodies 39Anurag S. Rathore, Garima Thakur, Saxena Nikita, and Shantanu Banerjee 2.1 Introduction 39 2.2 Control of Upstream Mammalian Bioreactor for Continuous Production of mAbs 40 2.3 Integration Between Upstream and Downstream in Continuous Production of mAbs 46 2.3.1 Continuous Clarification as a Bridge Between Continuous Upstream and Downstream 46 2.3.2 Considerations for Process Integration 48 2.4 Control of Continuous Downstream Unit Operations in mAb Manufacturing 49 2.4.1 Control of Continuous Dead-End Filtration 49 2.4.2 Control of Continuous Chromatography 50 2.4.3 Control of Continuous Viral Inactivation 53 2.4.4 Control of Continuous Precipitation 54 2.4.5 Control of Continuous Formulation 56 2.5 Integration Between Adjacent Unit Operations Using Surge Tanks 57 2.6 Emerging Approaches for High-Level Monitoring and Control of Continuous Bioprocesses 59 2.6.1 Artificial Intelligence (AI) and Machine Learning (ML) Control 60 2.6.2 Statistical Process Control 61 2.6.3 Process Digitalization 62 2.7 Conclusions 63 References 63 3 Artificial Intelligence and the Control of Continuous Manufacturing 75Steven S. Kuwahara 3.1 Introduction 75 3.2 Continuous Monitoring and Validation 84 3.3 Choosing Other Control Charts 84 3.4 Information Awareness 85 3.5 Management and Personnel 86 References 90 Part II Intensified Biomanufacturing 93 4 Bioprocess Intensification: Technologies and Goals 95William G. Whitford 4.1 Introduction 95 4.2 Bioprocess Intensification 98 4.2.1 Definition 98 4.2.2 New Directions 100 4.2.3 Sustainability Synergy 102 4.3 Intensification Techniques 103 4.3.1 Enterprise Resource Management 103 4.3.2 Synthetic Biology and Genetic Engineering 104 4.3.3 New Expression Systems 105 4.3.4 Bioprocess Optimization 106 4.3.5 Bioprocess Simplification 107 4.3.6 Continuous Bioprocessing 108 4.4 Materials 109 4.4.1 Media Optimization 109 4.4.2 Variability 110 4.5 Digital Biomanufacturing 110 4.5.1 Data 111 4.5.2 Bioprocess Control 112 4.5.3 Digital Twins 113 4.5.4 Artificial Intelligence 114 4.5.5 Cloud/Edge Computing 114 4.6 Bioprocess Modeling 114 4.7 Automation and Autonomation 115 4.8 Bioprocess Monitoring 117 4.9 Improved Process and Product Development 118 4.9.1 Design of Experiments 118 4.9.2 QbD and PAT 119 4.9.3 High-Throughput Systems 119 4.9.4 Methods 120 4.9.5 Commercialized Systems 120 4.10 Advanced Process Control 121 4.11 Bioreactor Design 121 4.12 Single-Use Systems 122 4.13 Facilities 123 4.14 Conclusion 126 Abbreviations and Acronyms 126 Acknowledgment 129 References 129 5 Process Intensification Based on Disposable Solutions as First Step Toward Continuous Processing 137Stefan R. Schmidt 5.1 Introduction 137 5.1.1 Theory and Practice of Process Intensification 137 5.1.2 Current Bioprocessing 140 5.1.3 General Aspects of Disposables 140 5.2 Technical Solutions 141 5.2.1 Process Development 141 5.2.2 Upstream Processing Unit Operations 142 5.2.2.1 High-Density, Large-Volume Cell Banking in Bags 143 5.2.2.2 Seed Train Intensification 144 5.2.2.3 Cell Retention and Harvest 145 5.2.3 Downstream Processing Unit Operations 149 5.2.3.1 Depth Filtration 149 5.2.3.2 In-line Virus Inactivation 151 5.2.3.3 In-line Buffer Blending and Dilution 152 5.2.3.4 Chromatography 153 5.2.3.5 Tangential Flow Filtration 159 5.2.3.6 Drug Substance Freezing 161 5.3 Process Analytical Technology and Sensors 162 5.3.1 Sensors for USP Applications 163 5.3.2 Sensors for DSP Applications 164 5.4 Conclusions 165 5.4.1 Transition from Traditional to Intensified Processes 165 5.4.2 Impact on Cost 169 5.4.3 Influence on Time 170 References 171 6 Single-Use Continuous Manufacturing and Process Intensification for Production of Affordable Biological Drugs 179Ashish K. Joshi and Sanjeev K. Gupta 6.1 Background 179 6.2 State of Upstream and Downstream Processes 180 6.2.1 Sizing Upstream Process 181 6.2.2 Sizing Downstream Process 182 6.2.3 Continuous Process Retrofit into the Existing Facility 184 6.2.3.1 Upstream Process 184 6.2.3.2 Downstream Process 184 6.2.4 Learning from Chemical Industry 185 6.3 Cell Line Development and Manufacturing Role 186 6.3.1 Speeding Up Upstream and Downstream Development 188 6.3.2 The State of Manufacturing 189 6.4 Process Integration and Intensification 190 6.4.1 Intensification of a Multiproduct Perfusion Platform 190 6.4.2 Upstream Process Intensification Using Perfusion Process 192 6.5 Process Intensification and Integration in Continuous Manufacturing 192 6.6 Single-Use Manufacturing to Maximize Efficiency 194 6.6.1 The Benefits of SUT in the New Era of Biomanufacturing 195 6.6.2 Managing an SUT Cost Profile 195 6.6.3 In-Line Conditioning (ILC) 196 6.6.4 Impact of Single-Use Strategy on Manufacturing Cost of Goods 197 6.6.5 Limitations of SUT 198 6.7 Process Economy 199 6.7.1 Biopharma Market Dynamics 200 6.7.2 Management of the Key Risks of a Budding Market 201 6.8 Future Perspective 202 References 203 Part III Digital Biomanufacturing 209 7 Process Intensification and Industry 4.0: Mutually Enabling Trends 211Marc Bisschops and Loe Cameron 7.1 Introduction 211 7.2 Enabling Technologies for Process Intensification 213 7.2.1 Process Intensification in Biomanufacturing 213 7.2.2 Process Intensification in Cell Culture 214 7.2.3 Process Intensification in Downstream Processing 214 7.2.4 Process Integration: Manufacturing Platforms 216 7.2.5 The Two Elephants in the (Clean) Room 217 7.3 Digital Opportunities in Process Development 220 7.4 Digital Opportunities in Manufacturing 222 7.5 Digital Opportunities in Quality Assurance 223 7.6 Considerations 224 7.6.1 Challenges 224 7.6.2 Gene Therapy 226 7.7 Conclusions 227 References 227 8 Consistent Value Creation from Bioprocess Data with Customized Algorithms: Opportunities Beyond Multivariate Analysis 231Harini Narayanan, Moritz von Stosch, Martin F. Luna, M.N. Cruz Bournazou, Alessandro Buttè, and Michael Sokolov 8.1 Motivation 231 8.2 Modeling of Process Dynamics 232 8.2.1 Hybrid Models 234 8.2.2 Conclusion 238 8.3 Predictive Models for Critical Quality Attributes 238 8.3.1 Historical Product Quality Prediction 238 8.3.2 Synergistic Prediction of Process and Product Quality 242 8.4 Extrapolation and Process Optimization 242 8.5 Bioprocess Monitoring Using Soft Sensors 247 8.5.1 Static Soft Sensor 248 8.5.2 Dynamic Soft Sensors 250 8.5.3 Concluding Remarks 251 8.6 Scale-Up and Scale-Down 251 8.6.1 Differences Between Lab and Manufacturing Scales 252 8.6.2 Scale-Up 253 8.6.3 Scale-Down 254 8.6.4 Conclusions 255 8.7 Digitalization as an Enabler for Continuous Manufacturing 255 References 257 9 Digital Twins for Continuous Biologics Manufacturing 265Axel Schmidt, Steffen Zobel-Roos, Heribert Helgers, Lara Lohmann, Florian Vetter, Christoph Jensch, Alex Juckers, and Jochen Strube 9.1 Introduction 265 9.2 Digital Twins in Continuous Biomanufacturing 269 9.2.1 USP Fed Batch and Perfusion 273 9.2.2 Capture, LLE, Cell Separation, and Clarification 273 9.2.2.1 Fluid Dynamics (Red) 277 9.2.2.2 Phase Equilibrium (Blue) 277 9.2.2.3 Kinetics (Green) 277 9.2.3 UF/DF, SPTFF for Concentration, and Buffer Exchange 278 9.2.4 Precipitation/Crystallization 282 9.2.5 Chromatography and Membrane Adsorption 282 9.2.5.1 General Rate Model Chromatography 282 9.2.5.2 SEC 284 9.2.5.3 Adsorption Mechanism 284 9.2.5.4 IEX-SMA 284 9.2.5.5 HIC-SMA 285 9.2.5.6 Modified Mixed-Mode SMA 285 9.2.5.7 Modified HIC-SMA Process Model Exemplification by mab Purification 287 9.2.5.8 Model Parameter Determination 289 9.2.5.9 Phase Equilibrium Isotherms 290 9.2.5.10 Mass Transfer Kinetics 292 9.2.6 Lyophilization 293 9.2.6.1 Thermal Conductivity of the Vial 293 9.2.6.2 Product Resistance 293 9.2.6.3 Product Temperature 295 9.2.6.4 Water Properties 295 9.3 Process Integration and Demonstration 295 9.3.1 USP Fed Batch and Perfusion 301 9.3.2 Capture, LLE, Cell Separation, and Clarification 306 9.3.3 UF/DF, SPTFF for Concentration, and Buffer Exchange 309 9.3.4 Precipitation/Crystallization 311 9.3.5 Chromatography and Membrane Adsorption 314 9.3.6 Lyophilization 314 9.3.7 Comparison Between Conceptual Process Design and Experimental Data 319 9.4 PAT in Continuous Biomanufacturing 320 9.4.1 State-of-the-Art PAT 321 9.4.2 QbD-based PAT Control Strategy 322 9.4.3 Process Simulation Toward APC-Based Autonomous Operation 323 9.4.4 Applicability of Spectroscopic Methods in Continuous Biomanufacturing 328 9.4.5 Proposed Control Strategy Including PAT 332 9.4.6 Evaluation and Summary of PAT 337 9.5 Conclusion 338 Acknowledgments 339 References 339 10 Regulatory and Quality Considerations of Continuous Bioprocessing 351Britta Manser and Martin Glenz 10.1 Introduction 351 10.2 Integrated Processing 352 10.3 Process Traceability 353 10.3.1 Batch and Lot Definition 353 10.3.2 Lot Traceability and Deviation Management 354 10.4 Process Consistency 355 10.4.1 Process Control 356 10.4.1.1 Automation 356 10.4.1.2 Process Analytical Technologies (PAT) 357 10.4.1.3 Data Analysis 359 10.4.1.4 Real-Time Release Testing 360 10.4.2 Quality by Design 360 10.4.2.1 Multicolumn Protein A Chromatography 361 10.4.2.2 Continuous Virus Inactivation 362 10.4.2.3 Bind/Elute Cation Exchange Chromatography 362 10.4.2.4 Flow-Through Anion Exchange Chromatography 363 10.4.2.5 Ultrafiltration and Diafiltration 363 10.4.2.6 Sterile Filtration 363 10.4.2.7 Virus Reduction Filtration 363 10.4.2.8 Connection of Unit Operations 364 10.5 Patient Safety 365 10.5.1 Contamination Control 365 10.5.2 Virus Safety 366 10.5.2.1 Virus Reduction in Chromatography 367 10.5.2.2 Low-pH Virus Inactivation 367 10.5.2.3 Virus Reduction Filtration 368 10.6 Equipment Design 369 10.7 Conclusion 370 References 371 Index 377

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Book SynopsisExplore modern waste heat recovery technology across a variety of industries In Waste Heat Recovery in Process Industries, esteemed thermal engineer Hussam Jouhara delivers an organized and comprehensive exploration of waste heat recovery systems with a focus on industrial applications in different temperature ranges. The author describes various waste heat recovery systems, like heat exchangers, waste heat boilers, air preheaters, direct electrical conversion devices, and thermal storage. The book also offers discussions of the technologies and applications relevant to different temperature ranges present in industrial settings along with revealing case studies from various industries. Waste Heat Recovery in Process Industries examines a variety of industries, from steel to ceramics, chemicals, and food, and how plants operating in these sectors can use waste heat to improve their energy efficiency, reduce energy costs, and minimize their carbon footprint. The book also offers: A thorough introduction to waste heat recovery systems, including recuperative and regenerative burners, heat exchangers, waste heat boilers, air preheaters, and heat pumps Comprehensive explorations of low temperature applications, below 100°C, including advantages and drawbacks, as well as illustrative case studies Practical discussions of medium temperature applications, between 100°C and 400°C, including case studies In-depth examination of high temperature applications, above 400°C, including several case studies Perfect for chemical, mechanical, process, and power engineers, Waste Heat Recovery in Process Industries is also an ideal resource for professionals working in the chemical, metal processing, pharmaceutical, and food industries. Table of ContentsPreface xiii 1 Thermodynamic Cycles 1 1.1 Introduction to Thermodynamic Cycles 1 1.2 Rankine Cycle 1 1.2.1 Introduction 1 1.2.2 Thermodynamic Diagrams 2 1.2.3 The Carnot Cycle 10 1.2.4 Ideal and Actual Rankine Cycles 12 1.2.4.1 Ideal Cycle 13 1.2.4.2 Superheated Rankine Cycle 15 1.2.4.3 Actual Rankine Cycle 17 1.2.4.4 Improvements to the Rankine Cycle 19 1.2.4.5 Regenerative Rankine Cycles 22 1.2.4.6 Cogeneration 26 1.2.5 Other Configurations of the Rankine Cycle 29 1.2.5.1 Supercritical Rankine Cycles 29 1.2.5.2 Reverse Rankine Cycles 30 1.2.6 Rankine Cycles in Power Plants 31 1.2.6.1 Fossil Fuel Power Plants 31 1.2.6.2 Nuclear Power Plants 32 1.2.6.3 Overall Efficiency of a Power Plant 32 1.2.6.4 Case Studies 33 1.3 Organic Rankine Cycle 34 1.3.1 Configurations of ORC 35 1.3.1.1 Basic ORC Configuration 35 1.3.1.2 ORC with Preheating 36 1.3.1.3 Recuperative ORC 38 1.3.1.4 Recuperative ORC with Preheating 39 1.3.2 Organic Working Fluids 40 1.3.3 Organic Working Fluid Selection 42 1.3.4 Applications of the ORC 45 1.3.4.1 Waste Heat Recovery 45 1.4 Kalina Cycle 46 1.4.1 Cycle Fundamentals 46 1.4.1.1 Why Use Ammonia–Water Solution in Kalina Cycle? 48 1.4.2 Advantages and Drawbacks 49 1.4.2.1 Advantages 49 1.4.2.2 Drawbacks 50 1.4.3 Applications of the Kalina Cycle 50 1.4.3.1 The Different Configurations of the Cycle 51 1.4.4 Case Studies 53 1.5 Brayton Cycle 53 1.5.1 Regenerative Brayton Cycle (Regenerator) 57 1.5.1.1 Compressor Analysis 58 1.5.1.2 Turbine Analysis 58 1.5.1.3 Heat Supplied to the Cycle 59 1.5.2 Regenerative Brayton Cycle (Reheater and Intercooler) 59 1.5.2.1 Intercooling 60 1.5.2.2 Reheating 60 1.6 Chapter Summary 61 References 62 2 Waste Heat Recovery 67 2.1 Burner and Air Preheaters 67 2.1.1 Recuperators 67 2.1.1.1 Recuperative Burners 68 2.1.1.2 Classifying Recuperative Burners 71 2.1.1.3 Efficiency Improvement and Fuel Savings 72 2.1.2 Regenerators 74 2.1.2.1 Rotary Regenerators 74 2.1.2.2 Static Regenerators 75 2.1.2.3 Regenerative Burners 75 2.1.3 Burner Technology Comparison 76 2.1.4 No X Formation 77 2.1.5 Run-Around Coil 78 2.2 Heat Exchangers 79 2.2.1 Shell and Tube HEXs 79 2.2.1.1 Construction 80 2.2.1.2 Applications and Limitations 82 2.2.2 Plate Heat Exchanger 82 2.2.2.1 Spiral Plate Heat Exchanger 83 2.2.3 Heat Pipe Heat Exchanger 83 2.2.4 Compact HEX 85 2.3 Waste Heat Boilers 86 2.3.1 Different WHB Designs 87 2.3.2 WHB Methodologies 88 2.3.2.1 Feed Water Preheating Effect 88 2.3.2.2 Optimising Thermodynamic Cycles 89 2.3.2.3 Heat Recovery Boiler with Water Spray Systems 91 2.3.3 Failure Modes 92 2.3.3.1 Failure Modes Analysis 92 2.4 Heat Recovery Steam Generators 93 2.4.1 Construction of Waste HRSG 94 2.4.1.1 HRSG Design and Construction 95 2.4.1.2 Evaporator 95 2.4.1.3 Superheater 96 2.4.1.4 Economiser 96 2.4.1.5 Steam Drum 96 2.4.1.6 Evaporator Types 96 2.4.1.7 Horizontal Tube HEXs 98 2.4.1.8 Natural Circulation HRSGs 98 2.4.1.9 Assisted (or Forced) Circulation HRSGs 99 2.4.1.10 Tube Materials 99 2.4.1.11 The ‘Pinch Point’ and Other Effects 100 2.5 Heat Pumps 100 2.5.1 Fundamental Principles of Heat Pumps 100 2.5.1.1 Cooling Mode 101 2.5.1.2 Heating Mode 101 2.5.2 Variation of Heat Pump System 102 2.5.2.1 Air Source Heat Pump System 103 2.5.2.2 Ground Source Heat Pump System 103 2.5.2.3 Water Source Heat Pump System 105 2.5.2.4 Water Loop Heat Pump System 105 2.5.2.5 Exhaust Air System 106 2.5.2.6 Hybrid Heat Pump 106 2.5.2.7 Solar-Assisted Heat Pumps 106 2.6 Direct Electrical Conversion Device 107 2.6.1 TEG – Working Principle 108 2.6.2 The Seebeck Effect 109 2.6.3 The Peltier Effect 109 2.6.3.1 Applications of the Peltier Effect 110 2.6.4 Thomson Effect 110 2.6.5 Joule Heating 111 2.6.6 Theoretical Principle 112 2.6.7 Figure of Merit 112 2.6.8 Fermi Level 113 2.6.9 Nano-Sizing 114 2.6.10 Efficiency of TEG 115 2.7 Thermal Storage 116 2.7.1 Sensible Heat Storage 117 2.7.2 Latent Heat Storage 120 2.7.3 Thermochemical Storage 123 2.7.4 Phase Change Materials 123 2.7.5 Organic Material 125 2.7.6 Inorganic PCMs 128 2.7.7 Eutectic PCMs 128 2.7.8 PCM Methodologies 129 2.7.8.1 Encapsulation of PCMs 129 2.7.8.2 Microencapsulated PCMs 129 2.7.8.3 Macroencapsulation of the PCMs 132 2.7.8.4 Nanomaterial PCMs 132 2.7.8.5 Shape Stabilisation 135 2.8 Design Development Methods 135 2.8.1 Introduction 135 2.8.2 Heat Exchangers 140 2.8.2.1 Local Heat Transfer 140 2.8.2.2 LMTD Method 147 2.8.2.3 Effectiveness-Number of Transfer Units (ε-NTU) Method 151 2.8.3 Regenerative and Recuperative Burners 152 2.8.3.1 Regenerative Burners 154 2.8.3.2 Recuperative Burners 156 2.8.4 Waste Heat Boilers 157 2.8.5 Air Preheaters 160 2.8.6 Heat Recovery Steam Generator 166 2.8.7 Heat Pumps 170 2.8.8 Direct Electrical Conversion Device 173 2.8.9 Thermal Storage 176 References 178 3 Low-Temperature Applications 191 3.1 Refrigeration 191 3.2 Cryogenics 198 3.2.1 Loop Heat Pipe 199 3.3 HVAC 204 References 209 4 Medium-Temperature Applications 213 4.1 Food Industry 213 4.1.1 Energy Use in the Industry 213 4.1.2 Case Study 1: Heat Recovery Potential of the Crisps Manufacturing Process 214 4.1.3 Case Study 2: Temperature and Energy Performance of Open Refrigerated Display Cabinets Using Heat Pipe Shelves 215 4.2 Ventilation 221 4.2.1 Applications 221 4.3 Solar Energy 223 4.4 Geothermal Energy 230 4.5 Automotive Industry 233 4.5.1 Industrial Processes 235 4.6 Aviation 237 References 239 5 High-Temperature Applications 245 5.1 Steel Industry 245 5.1.1 TEG Modules 246 5.1.2 Heat Exchangers 246 5.1.2.1 Application 1: Slag Particles Blast Furnace Retrofit 246 5.1.2.2 Application 2: Flat Heat Pipe Heat Exchanger 247 5.1.3 Recuperators 249 5.1.3.1 Application 1: Heat Recuperator for Steel Slag 249 5.2 Ceramic Industry 251 5.2.1 Introduction 251 5.2.2 Heat Exchangers 251 5.2.2.1 Application 1: Radiative Heat Pipe 251 5.2.2.2 Application 2: Multi-Pass Heat Pipe 252 5.2.2.3 Application 3: Forced Convection Heat Pipe 253 5.3 Cement Industry 254 5.3.1 Gas Suspension Preheaters 255 5.3.1.1 Application 1 255 5.3.1.2 Application 2 256 5.3.2 Heat Pipe Thermoelectric Generator 256 5.4 Aluminium Industry 258 5.4.1 Rotary Regenerator 258 5.4.2 Heat Exchangers 258 5.4.3 Heat Pumps 258 5.4.4 Recuperators 260 5.4.4.1 Radiative Recuperator 260 5.4.4.2 Convective Recuperator 261 5.4.4.3 Hybrid Recuperator 262 5.4.5 Thermoelectric Device 262 5.4.6 Regenerative Burner 262 5.4.7 Preheating Scrap 264 5.4.8 De-coating 265 References 265 Index 269

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Book SynopsisAn eye-opening exploration of membrane contactors from a group of industry leaders In Membrane Contactor Technology: Water Treatment, Food Processing, Gas Separation, and Carbon Capture, an expert team of researchers delivers an up-to-date and insightful explanation of membrane contactor technology, including transport phenomena, design aspects, and diverse process applications. The book also includes explorations of membrane synthesis, process, and module design, as well as rarely discussed process modeling and simulation techniques. The authors discuss the technical and economic aspects of this increasingly important technology and examine the geometry, flow, energy and mass transport, and design aspects of membrane contactor modules. They also cover a wide range of application opportunities for this technology, from the materials sciences to process engineering. Membrane Contactor Technology also includes: A thorough introduction to the membrane contactor extraction process, including dispersion-free membrane extraction processes and supported liquid membrane processes Comprehensive explorations of membrane transport theory, including discussions of diffusional mass and heat transfer modeling, as well as numerical modeling In-depth examinations of module configuration and geometry, including design and flow configuration Practical discussions of modes or operation, including membrane distillation, osmotic evaporation, and forward osmosis Perfect for process engineers, biotechnologists, water chemists, and membrane scientists, Membrane Contactor Technology also belongs in the libraries of chemical engineers, polymer chemists, and chemists working in the environmental industry.Table of ContentsPreface xv About the Authors xvii 1 Introduction to Membrane Technology 1 Mohammad Younas and Mashallah Rezakazemi 1.1 Overview of Membrane Technology 1 1.2 Conventional Membrane Separation Processes 2 1.2.1 Microfiltration (MF) 2 1.2.2 Ultrafiltration (UF) 2 1.2.3 Nanofiltration (NF) 3 1.2.4 Reverse Osmosis (RO) 3 1.2.5 Electrodialysis (ED) 4 1.2.6 Pervaporation (PV) 5 1.3 Molecular Weight Cutoff (MWCO) 8 1.4 Concentration Polarization 9 1.5 Membrane Fouling 10 1.6 Diafiltration 11 1.7 Historical Perspective 11 1.8 Concluding Remarks and Future Challenges 12 References 14 2 Introduction to Membrane Contactor Technology 17 Mohammad Younas and Mashallah Rezakazemi 2.1 Membrane Contactor Separation Processes 17 2.1.1 Membrane Contactors 17 2.1.2 History and Background of Membrane Contactors 20 2.1.3 Types of Membrane Contactor Systems 21 2.1.3.1 Solid Porous Membrane as Medium of Contact in Membrane Contactors 21 2.1.3.2 Liquid Membrane Contactors 30 2.1.4 Membrane Contactor Integrated Systems 34 2.1.5 Potential of Membrane Contactor in Concentration, Temperature Polarization, Wetting, and Fouling of Membranes 35 2.2 Conclusion and Future Trends of Membrane Contactors 37 References 38 3 Transport Theory in Membrane Contactor: Operational Principle 45 Mohammad Younas, Waheed Ur Rehman, and Mashallah Rezakazemi 3.1 Diffusional Mass and Heat Transfer Modeling 45 3.2 Membrane Characterization Models 46 3.2.1 Contact Angle and Liquid Entry Pressure 46 3.2.2 Liquid Entry Pressure (LEP) 49 3.2.3 Permporometry (Pore Size Distribution) 52 3.2.4 Electron Microscopy 52 3.3 Transport Models in Liquid–Liquid Contactor 52 3.3.1 Resistance in Series Model 55 3.3.1.1 Model Approach 56 3.3.1.2 Two Film Theory 56 3.3.1.3 Phase Equilibrium in Liquid–Liquid System 58 3.3.1.4 Overall Mass Transfer Coefficient 59 3.4 Transport Model in Gas–Liquid Systems 60 3.4.1 Phase Equilibrium for Gas–Liquid System 61 3.4.2 Resistance in Series Model 61 3.5 Reactive Diffusion in Liquid-Side Boundary Layer 62 3.6 Mass Transfer Resistance Analysis 63 3.7 Correlations for Mass Transfer Coefficients 65 3.7.1 Correlation for Flow in Shell Side 66 3.7.2 Correlation for Flow in Tube Side 66 3.7.3 Correlation for Mass Transfer in Membrane Pores 68 3.8 Correlations for Heat Transfer Coefficients 69 3.9 Interfacial Transfer Area 70 3.10 Axial Pressure Drop in Membrane Contactor Module 71 3.11 Dynamic Modeling 71 3.12 Transfer Units and Module Design Length 72 3.13 Numerical Modeling of Mass Transport in Membrane Contactor Modules 73 3.13.1 Mass Transfer in Shell Side 75 3.13.2 Mass Transfer Inside Fibers 77 3.13.3 Mass Transfer in Membrane Pores 78 3.13.4 Numerical Modeling Term in the Case of Membrane Wetting 79 3.14 Numerical Modeling of Heat Transport in Membrane Contactor Modules 81 3.14.1 Governing Equation in Cold and Hot Channels 82 3.14.2 Governing Equation Inside Membrane 82 3.15 Model Solution Algorithm 83 3.16 Conclusions and Perspectives 84 3.A Membrane Transport Theory: Operational Principle 84 3.A.1 Steady-State Resistance-in-Series Model Across Liquid–Liquid Contactor 84 3.A.1.1 Hydrophobic Membrane Based on Aqueous-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 84 3.A.1.2 Hydrophobic Membrane Based on Organic-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 85 3.A.1.3 Hydrophobic Membrane Based on Organic-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 85 3.A.1.4 Hydrophobic Membrane Based on Aqueous-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 85 3.A.1.5 Hydrophilic Membrane Based on Aqueous-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 86 3.A.1.6 Hydrophilic Membrane Based on Organic-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 86 3.A.1.7 Hydrophilic Membrane Based on Organic-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 86 3.A.1.8 Hydrophilic Membrane Based on Aqueous-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 87 3.A.1.9 Composite Membrane Based on Aqueous-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 87 3.A.1.10 Composite Membrane Based on Organic-Phase Side (Species Transfers from Aqueous Phase to Organic Phase) 87 3.A.1.11 Composite Membrane Based on Organic-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 87 3.A.1.12 Composite Membrane Based on Aqueous-Phase Side (Species Transfers from Organic Phase to Aqueous Phase) 88 3.A.2 Steady-State Resistance-in-Series Model Across Gas–Liquid Contactor 88 3.A.2.1 Hydrophobic Membrane Based on Gas-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 88 3.A.2.2 Hydrophobic Membrane Based on Liquid-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 88 3.A.2.3 Hydrophobic Membrane Based on Liquid-Phase Side (Species Transfers from Liquid Phase to Gas Phase) 89 3.A.2.4 Hydrophobic Membrane Based on Gas-Phase Side (Species Transfers from Liquid Phase to Gas Phase) 89 3.A.2.5 Hydrophilic Membrane Based on Gas-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 89 3.A.2.6 Hydrophilic Membrane Based on Liquid-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 90 3.A.2.7 Hydrophilic Membrane Based on Liquid-Phase Side (Species Transfers from Liquid Phase to Gas Phase) 90 3.A.2.8 Hydrophilic Membrane Based on Gas-Phase Side (Species Transfers from Liquid Phase to Gas Phase) 91 3.A.2.9 Composite Membrane Based on Gas-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 91 3.A.2.10 Composite Membrane Based on Liquid-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 91 3.A.2.11 Composite Membrane Based on Liquid-Phase Side (Species Transfers from Gas Phase to Liquid Phase) 91 3.A.2.12 Composite Membrane Based on Gas-Phase Side (Species Transfers from Liquid Phase to Gas Phase) 92 3.A.3 Dynamic Modeling Across the Storage Tank 92 References 93 4 Module Design and Membrane Materials 99 Nabilah Fazil, Sidra Saqib, Ahmad Mukhtar, Mohammad Younas, and Mashallah Rezakazemi 4.1 Introduction 99 4.2 Membrane Module Design Configuration 100 4.2.1 Plate-and-Frame Modules 100 4.2.2 Spiral Wound Modules 103 4.2.3 Tubular Modules 104 4.2.4 Hollow Fiber Modules 106 4.3 Membrane Contactor Module Housing 111 4.4 Membrane Module Flow Configuration 116 4.5 Membrane Materials 116 4.5.1 Polymer Materials 118 4.5.2 Inorganic Fillers 125 4.6 Membrane and Membrane Module for Membrane Distillation (MD) and Osmotic Membrane Distillation (OMD) 126 4.7 Solvents Used in Membrane Synthesis 128 4.8 Membrane Synthesis Techniques 128 4.9 Conclusions 130 4.10 Future Perspective 131 References 131 5 Mode of Operation in Membrane Contactors 143 Waheed Ur Rehman, Zarrar Salahuddin, Sarah Farrukh, Muhammad Younas, and Mashallah Rezakazemi 5.1 Membrane Distillation (MD) 143 5.1.1 Basic Principles of MD Process 143 5.1.2 MD Configurations 144 5.1.3 Overall Driving Force 145 5.1.4 Overall Mass Transfer Coefficient, K 147 5.1.4.1 Feed-Side Mass Transfer 148 5.1.4.2 Membrane Mass Transfer 150 5.1.4.3 Strip-Side Mass Transfer 151 5.1.5 Vapor Pressure Polarization Coefficient, Θv 152 5.1.5.1 DCMD 152 5.1.5.2 Feed–Side and Strip–Side Heat Transfer 153 5.1.5.3 Membrane Heat Transfer 153 5.1.6 AGMD 154 5.1.6.1 SGMD 156 5.1.7 VMD 157 5.1.8 Membranes for MD Process 157 5.1.9 Pros and Cons of MD Process 158 5.1.10 Future Prospects of MD Process 161 5.2 Osmotic Membrane Distillation (OMD) 161 5.2.1 Basic Principles of OMD Process 161 5.2.2 Overall Mass Transfer 163 5.2.2.1 Mass Transfer Across Feed Boundary Layer 163 5.2.2.2 Mass Transfer Across Stripper Boundary Layer 163 5.2.2.3 Mass Transfer Across Membrane 164 5.2.2.4 Mass Transfer Coefficient for Feed and Stripper Side 164 5.2.2.5 Mass Transfer Coefficient Across Membrane 164 5.2.3 Stripping Solutions for OMD 165 5.2.4 Membranes for OMD Process 166 5.2.5 Pros and Cons of OMD Process 166 5.3 Forward Osmosis 167 5.3.1 Basic Principles of FO Process 167 5.3.2 Calculation of the Osmotic Pressures 167 5.3.3 Reverse Solute Flux in FO 170 5.3.4 Membranes for FO Process 170 5.3.5 Draw Solutes for FO Process 171 5.3.6 Pros and Cons of FO Process 172 5.4 Pressure-Retarded Osmosis 172 5.4.1 Basic Principles of PRO Process 172 5.4.2 Membranes for PRO Process 175 5.4.3 Pros and Cons of PRO Process 176 5.5 Conclusions 176 References 176 6 Applications of Membrane Contactor Technology in Wastewater Treatment 185 Ayesha Rehman, Xianhui Li, Sarah Farrukh, Mohammad Younas, and Mashallah Rezakazemi 6.1 Introduction 185 6.2 Common Toxic Substances in Wastewater 187 6.2.1 Phenols 187 6.2.2 Heavy Metals 188 6.2.3 Ammonia 188 6.2.4 Hydrogen Sulfide 188 6.2.5 Carbon Dioxide 188 6.2.6 Petroleum Hydrocarbons 188 6.2.7 Polycyclic Aromatic Hydrocarbons 189 6.2.8 Nitrobenzene 189 6.3 Environmental Risks of Wastewater 189 6.4 Membrane Technology for Wastewater Treatment 190 6.5 Membrane Contactor Technology for Removal of Organic Contaminants from Wastewater 193 6.6 Removal of Inorganic Contaminants from Wastewater 200 6.7 Polymer-Based Adsorption Membranes 202 6.8 Ion-Exchange Nanoporous Membrane 204 6.9 Micellar-Enhanced Ultrafiltration Membrane 204 6.10 Membrane Materials for Water Treatment 205 6.11 Membrane Materials for Microfiltration (MF) and Ultrafiltration (UF) 206 6.12 Membrane Materials for Nanofiltration (NF) 206 6.13 Membrane Materials for Reverse Osmosis (RO) 207 6.14 Membrane Materials for Forward Osmosis (FO) 207 6.15 Challenges in Membrane Materials to Prevent Fouling 208 6.16 Conclusions and Perspectives 209 References 210 7 Applications of Membrane Contactors in Food Industry 219 Waheed Ur Rehman, Bazla Sarwar, Sidra Saqib, Ahmad Mukhtar, Mohammad Younas, and Mashallah Rezakazemi 7.1 Introduction 219 7.2 Membrane Distillation (MD) Applications in Food Industry 219 7.2.1 MD in the Concentration of Apple Juice 221 7.2.2 MD in the Concentration of Orange Juice 222 7.2.3 MD in the Concentration of Milk 222 7.2.4 MD in the Treatment of Saline Dairy Waste Water 223 7.2.5 MD in the Concentration of Muscadine Grape Pomace 224 7.2.6 MD in the Recovery of Phenols from Olive Mill Wastewater 225 7.2.7 MD in the Concentration of Sucrose Solution 225 7.2.8 Effect of Operating Parameters on MD Flux 225 7.3 Application of Osmotic Membrane Distillation (OMD) in Food Industry 227 7.3.1 Effect of Operating Conditions on OMD Water Flux 228 7.3.2 OMD in the Concentration of Apple Juice 231 7.3.3 OMD in the Concentration of Grape Juice 232 7.3.4 OMD in the Concentration of Pomegranate Juice 233 7.3.5 OMD in the Concentration of Orange Juice 235 7.3.6 OMD in the Concentration of Cranberry and Noni Juices 235 7.3.7 OMD in the Concentration of Kiwi and Pineapple Juices 236 7.3.8 OMD in the Concentration of Tea Extracts 236 7.3.9 Dealcoholization of Beer and Wine 237 7.4 Coupled Operation of Osmotic Distillation and Membrane Distillation 238 7.5 Conclusions 239 7.6 Future Perspectives 239 References 240 8 Applications of Membrane Contactor Technology for Pre-combustion Carbon Dioxide (CO2) Capture 247 Zarrar Salahuddin, Sarah Farrukh, Mohammad Younas, and Mashallah Rezakazemi 8.1 Introduction 247 8.2 Why Pre-combustion Carbon Capture? 250 8.3 Membranes for Pre-combustion Carbon Capture 250 8.3.1 Hydrogen (H2)-Selective Membranes 250 8.3.2 CO2 -Selective Membranes 255 8.4 Advantages and Limitations of Pre-combustion Carbon Capture Using Membrane Technology 262 8.5 Applications of Pre-combustion Carbon Capture 263 8.6 Current Trends and Future Prospects 263 8.7 Concluding and Future Directions 269 References 269 9 Application of Membrane Contactor Technology for Post-combustion Carbon Dioxide (CO2) Capture 281 Muhammad B. Wazir, Muhammad Daud, Mohammad Younas, and Mashallah Rezakazemi 9.1 Introduction 281 9.2 Membranes for Post-combustion CO2 Capture 282 9.2.1 Membrane Types 282 9.2.2 Membrane Modules 285 9.3 Experimental Membrane Materials for Post-combustion CO2 Sequestration 285 9.4 Commercial Membranes for Post-combustion CO2 Separation 288 9.5 Cost of Post-combustion CO2 Capture in Membrane Contactors 289 9.6 Absorbents for Post-combustion CO2 Separation 291 9.6.1 Amine-Based Absorbents 291 9.6.2 Ammonia 293 9.6.3 Salt Solutions 294 9.6.4 Ionic Liquids 295 9.7 Conclusion and Future Perspective 295 References 296 10 Market Prospects of Membrane Contactors 305 Zahra Pezeshki, Mohammad Younas, and Mashallah Rezakazemi 10.1 Membrane Contactor Market Dynamics 305 10.2 Market Overview 306 10.3 Membrane Contactor Market by Application 313 10.3.1 Water and Wastewater Treatment Market 313 10.3.2 Food Processing Market 315 10.3.3 Gas Separation Market 318 10.3.4 Carbon Capture Market 321 10.4 Membrane Contactor Market, by Membrane 321 10.5 Membrane Contactor Market, by Region 325 10.6 Recent Developments of Membrane Contactor Companies 328 10.6.1 3M Company 328 10.6.2 Cobetter Filtration Equipment Pvt. Ltd. 329 10.6.3 Eurowater 329 10.6.4 JU.CLA.S Srl 329 10.6.5 Veolia Environnement SA 329 10.6.6 PTI Pacific Pty. Ltd. 330 10.6.7 Kværner ASA 330 10.6.8 Lenntech B.V. 330 10.6.9 Pure Water Group 330 10.6.10 TNO Company 330 10.6.11 Euwa H. H. Eumann GmbH (Euwa) 330 10.6.12 Hydro-Elektrik GmbH 331 10.6.13 KH TEC GmbH 331 10.6.14 Romfil GmbH 331 10.7 Future Directions 331 10.8 Conclusion 332 References 332 11 Conclusions and Perspective 337 Mohammad Younas and Mashallah Rezakazemi 11.1 Future Directions 340 Index 342

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Book SynopsisNovel Membrane Emulsification Comprehensive resource presenting state-of-the-art of membrane emulsification technology, from principle to practice, with focus on biomedical applications Novel Membrane Emulsification: Principles, Preparation, Processes, and Bioapplications provides comprehensive coverage of membrane emulsification technology by summarizing the principle, preparation, and bioapplications through utilizing uniform particle size, introducing recent development in preparation and applications in the controlled release and delivery of protein/peptide, anticancer drugs and vaccines, and in the bioseparation media and cell culture carriers, and discussing direct, rapid, and rotary membrane emulsification equipments. Novel Membrane Emulsification includes information on: Preparation of hydrophobic microspheres from O/W emulsion, hydrophilic microspheres from W/O emulsion, and microcapsules/composite microspheres from double emulsions, covering preparation from monomer and preformed polymer systems Preparation of small particles by rapid membrane emulsification process Applications of uniform particles in sustained release of protein/peptide drugs, covering strategies to improve encapsulation efficiency and maintain bioactivity of drugs Applications of uniform particles in anticancer drug and vaccine delivery including personalized therapeutic vaccine Applications of uniform particles in protein separation, covering uniform agarose microsphere for protein separation and super-porous microsphere for vaccine separation Novel Membrane Emulsification is an essential resource for scientists and researchers in multiple fields, particularly chemistry, chemical engineering, and materials science, to advance this technique and produce novel materials with controlled characteristics. The text is also a valuable learning resource for biomedical science and bioengineering researchers and students.Table of ContentsPreface xv 1 Membrane Emulsification Process: Principle and Model 1 1.1 Introduction 1 1.2 Cross-Flow Membrane Emulsification 2 1.2.1 Mechanism of Droplet Formation 2 1.2.2 Force Balance Model 6 1.2.3 Torque Balance Model 8 1.2.3.1 Associating the Dispersed-Phase Parameters 9 1.2.3.2 Associating the Continuous Phase Parameters 10 1.2.3.3 Torque Balance Model Associating Operation Parameters 10 1.2.3.4 Evaluation of Controlling Factors on Droplets Uniformity by Torque Balance Model 11 1.2.4 Computational Fluid Dynamics 16 1.2.5 Models by Surface Evolver Tool 19 1.2.6 Models by Lattice Boltzmann Method 20 1.3 Premix Membrane Emulsification 21 1.4 Summary 23 References 23 2 Preparation of Hydrophobic Microspheres From O/W Emulsion 27 2.1 Introduction 27 2.2 Preparation from Monomer System 28 2.2.1 PST–DVB Microspheres 28 2.2.2 PST-DMAEMA Microspheres 29 2.2.3 PGMA Microspheres 31 2.2.4 PST-HEMA Microspheres 32 2.2.5 PMMA Microspheres 34 2.3 Preparation from Performed Polymer System 37 2.3.1 PST–PMMA Microspheres 37 2.3.2 Polyurethane Urea Microspheres 39 2.3.3 Polyimide Prepolymer (PIP) Microspheres 40 2.3.4 Biodegradable Poly(Lactide) Microspheres 41 2.3.5 Microcapsules Containing Inorganic Materials 43 2.3.6 Pickering Emulsion 43 2.4 Morphology Control of Microspheres 45 2.4.1 Effect of Crosslinker on Morphology of Microspheres 45 2.4.2 Effect of Inert Diluents on Morphology of Microspheres 46 2.4.2.1 Nonsolvating Diluent Effects on Microsphere Morphology 47 2.4.2.2 Solvating Diluent Effects on Microsphere Morphology 49 2.4.3 Effect of Emulsifier/Stabilizer on Morphology of Microspheres 52 2.4.4 Effect of Cosurfactant on Morphology of Composite Microspheres 52 2.5 Summary 56 References 57 3 Preparation of Hydrophilic Polymer Microspheres from W/O Emulsion 61 3.1 Introduction 61 3.2 Membrane Modification and Preparation 62 3.2.1 Hydrophobic Modification of the Membrane 62 3.2.2 Preparation of Hydrophobic Membrane 67 3.3 Preparation Microparticles from Monomer System 73 3.3.1 Preparation of Poly(N-isopropylacrylamide) (PNIPAM) Microspheres and Microcapsules 73 3.4 Preparation Microparticles from Preformed Polymer System 77 3.4.1 Chitosan Microspheres 77 3.4.2 Agarose Microspheres 83 3.4.3 Alginate Microspheres 89 3.4.4 Cellulose Microspheres 93 3.4.5 Glucomannan Microspheres 94 3.5 Other Hydrophilic Microspheres Prepared by Membrane Emulsification 95 3.5.1 PVA Microspheres 95 3.5.2 Protein Microspheres 98 3.6 Summary 99 References 100 4 Preparation of Uniform Microcapsules and Microspheres from W/O/W Double Emulsion 105 4.1 Introduction 105 4.2 Preparation of Uniform Microcapsules 107 4.2.1 Oil-Soluble Emulsifier on the Size Distribution of Microcapsules 109 4.2.2 PVA Concentration in the Outer Aqueous Phase 110 4.2.3 Transmembrane Pressure on the Size Distribution of Microcapsules 110 4.2.4 The Membrane with Different Pore Size 112 4.2.5 Microcapsules for Drug Encapsulation 113 4.2.5.1 Composition of Polymers 113 4.2.5.2 The Inner Aqueous Phase Volume 114 4.2.5.3 NaCl Concentration in Outer Aqueous Phase 115 4.2.5.4 Drug-Loading Amount 116 4.2.5.5 pH Value in Outer Aqueous Phase 117 4.2.5.6 Microcapsules Size 117 4.2.6 Microcapsules with Controllable Structure 119 4.2.6.1 Polymer Concentrations in Oil Phase 119 4.2.6.2 Solidification Rate of the Droplets 119 4.2.6.3 Stabilizer Type 121 4.2.6.4 Volume Fraction of the Inner Aqueous Phase 121 4.3 Preparation of Composite Microspheres 121 4.3.1 Water-Soluble Inhibitor 123 4.3.2 Stabilizer in Outer Aqueous Phase 123 4.3.3 Cross-Linking Agent 124 4.4 Summary 126 References 126 5 Rapid Membrane Emulsification Process for Preparation of Small Microspheres 129 5.1 Introduction 129 5.2 Preparation of Hydrophobic Microspheres from O/W Emulsion 130 5.2.1 Preparation of Polylactide-Based Particles from O/W Emulsion 130 5.2.2 Preparation of PST Particles from O/W Emulsion 132 5.2.3 Preparation of Drug-Loaded Particles from O/W Emulsion 132 5.2.3.1 Preparation of Drug-Loaded Particles via Adsorption 133 5.2.3.2 Preparation of Drug-Loaded Particles via Encapsulation 133 5.2.3.3 Preparation of Polydopamine Microcapsules 135 5.3 Preparation of Hydrophilic Microspheres from W/O Emulsion 136 5.3.1 Preparation of Chitosan Particles 136 5.3.1.1 Preparation of Chitosan Solid Particles 136 5.3.1.2 Preparation of Chitosan gel Particles 138 5.3.2 Preparation of Stimuli-Responsive PNIPAM Particles 139 5.3.3 Preparation of Agarose Particles 139 5.3.4 Preparation of Alginate Particles 141 5.3.5 Preparation of Konjac Glucomannan Particles 143 5.4 Preparation of Microcapsule from Double Emulsion 144 5.4.1 Preparation of Drug/Antigen-Loaded Microcapsules via W/O/W Emulsions 144 5.4.1.1 Preparation of Particles for Encapsulating Water-Soluble Antigen 144 5.4.1.2 Preparation of Particles for Encapsulating Water-Soluble Drugs 145 5.4.1.3 Preparation of Hollow Particles for Encapsulating Antigen/Drug 147 5.4.2 Preparation of Microspheres with Unique Structure via W/O/W Emulsion 147 5.4.2.1 Preparation of PLA/PLGA Microspheres with Single-Core Structure 147 5.4.2.2 Preparation of PMMA/PLGA Microspheres with Gigaporous Structures 149 5.4.2.3 Preparation of PLGA Microspheres with Nonspherical Structures 151 5.4.3 Preparation of Microspheres via O/W/O Emulsion 152 5.4.3.1 HTCC Chitosan Microspheres for Oral Administration via O/W/O 153 5.4.3.2 CMCC Chitosan Microspheres for Encapsulating Water-Insoluble Drugs 154 5.4.3.3 Chitosan Microspheres for Combined Drug Delivery and Specific Administration 155 5.4.3.4 Preparation of Biomimetic Chitosan Microsphere with Cell Membrane 157 5.5 Summary 158 References 158 6 Applications of Uniform Particles in Sustained Release of Drugs 163 6.1 Introduction 163 6.2 Synthetic Polymer (PLA, PLGA, and PELA) 164 6.2.1 Pla 164 6.2.2 Plga 166 6.2.3 Pela 167 6.2.4 Strategy to Improve Encapsulation Efficiency 168 6.2.4.1 Effect of Additives on Encapsulation Efficiency 168 6.2.4.2 Effect of pH in the External Phase 169 6.2.4.3 Effect of Polymer 170 6.2.4.4 Effect of Solidification Technique 171 6.2.4.5 Using Post-loading Mode Instead of Pre-loading Mode 174 6.2.5 Strategy to Maintain Bioactivity of Drugs 175 6.2.5.1 Adding Additives to Prevent Proteins from Denaturation 175 6.2.5.2 Designing Amphiphilic Block Polymer PELA Instead of PLA 178 6.2.5.3 Effect of Preparation and Solidification Method 180 6.3 Natural Polymer (Polysaccharide) Chitosan 181 6.3.1 Strategies to Improve Encapsulation Efficiency 182 6.3.1.1 Using Step-wise Crosslinking Method to Avoid Shrinkage Stage 183 6.3.1.2 Using Chitosan Derivatives as Polymer to Adjust Microsphere Structure to Avoid Drug Crosslinking and Leakage 184 6.3.1.3 Preparing Chitosan/Alginate Complex Microsphere by Two-step Solidification Method to Avoid Drug Leakage 185 6.3.1.4 Controlling Morphologies of Microspheres to Increase Drug Loading 187 6.3.2 Strategies to Maintain Bioactivity of Drugs 188 6.3.2.1 Step-wise Crosslinking Method 189 6.3.2.2 Using Chitosan Derivatives as Polymer to Protect Protein from the Crosslinking Process 189 6.3.2.3 Self-solidification System Instead of Using Chemical Crosslinker 192 6.3.2.4 Preparing Chitosan/Alginate Complex Microsphere Instead of Chemical Crosslinking of Chitosan 193 6.4 Summary 194 References 195 7 Applications of Uniform Particles for Targeted Delivery of Anticancer Drugs 201 7.1 Introduction 201 7.2 Influence of Physical and Chemical Particle Properties on Antitumor Efficacy 202 7.2.1 Size 203 7.2.2 Surface Charge 203 7.2.3 Surface Hydrophobicity 206 7.2.4 Morphology 207 7.2.5 Flexibility 210 7.3 Classical Strategies for Targeting Tumor Tissues 211 7.3.1 Ligand/Receptor-Induced Targeting 211 7.3.2 Tumor Microenvironment Sensitive Targeting 212 7.3.2.1 pH- Sensitive Drug Delivery 213 7.3.2.2 Enzyme Responsive Drug Delivery 215 7.3.2.3 Hypoxia-Targeted Drug Delivery 215 7.3.3 Externally Activated Targeting 217 7.3.3.1 Magnetism-Based Tumor Targeting 217 7.3.3.2 Photosensitive Tumor Targeting 219 7.3.3.3 Thermal-Responsive Targeting 220 7.3.3.4 Ultrasonic-Induced Targeting 221 7.4 Novel Biomimetic Delivery Strategies 222 7.5 Summary 224 References 225 8 Applications of Uniform Particles in Vaccine Formulations 231 8.1 Introduction 231 8.2 Adjuvant and Delivery System: Assembling the Vaccine Components 232 8.2.1 Particulate Vaccine Platforms 233 8.2.1.1 Polymeric Particles 233 8.2.1.2 Polysaccharide Particles 234 8.2.1.3 Inorganic Particles 235 8.2.1.4 Liposome 236 8.2.1.5 Lipid Nanoparticle 236 8.2.2 Modularizing Strategies for Vaccine Delivery System 237 8.2.2.1 Encapsulation 237 8.2.2.2 Adsorption 238 8.2.2.3 Conjugation 239 8.3 Physicochemical Traits for the Enhanced Vaccination 240 8.3.1 Size 240 8.3.2 Charge 241 8.3.3 Shape 243 8.3.4 Hydrophobicity 245 8.3.5 Softness 246 8.4 Connecting the Dots: Strengthening on the Multi-Scale Delivery of Vaccines 248 8.4.1 Distribution 249 8.4.2 Internalization 252 8.4.3 Presentation 254 8.5 Summary 257 References 257 9 Applications of Uniform Microspheres and Super-porous Microspheres in Biochemical Engineering 267 9.1 Introductions 267 9.2 Uniform Microspheres for Chromatographic Media 268 9.2.1 Significance of Particle Size Uniformity in Chromatography 268 9.2.2 Agarose Microspheres 270 9.2.3 Konjac Glucomannan Microspheres 276 9.2.4 PST Microspheres 280 9.2.5 PGMA Microspheres 290 9.2.6 PHEMA Microspheres 292 9.2.7 Silica Microspheres 293 9.3 Super-Porous Microspheres for Vaccine Separation 297 9.3.1 Significance of Super-Porous Microspheres for Vaccine Separation 297 9.3.2 Preparation Methods for Super-Porous Microspheres 297 9.3.2.1 Super-Porous P(ST–DVB) Microspheres 299 9.3.2.2 Super-Porous P(GMA–DVB) Microspheres 299 9.3.2.3 Super-Porous Agarose Microspheres 300 9.3.2.4 Application of Membrane Emulsification Technology in the Preparation of Super-Porous Polymeric Microspheres 301 9.3.3 Surface Hydrophilization and Chemical Derivatization of Polymeric Microspheres 304 9.3.3.1 Physical Adsorption of Modified Agarose on Super-Porous P(ST-DVB) Microspheres 304 9.3.3.2 Chemical Modification with Poly(Vinyl Alcohol) of Super-Porous P(ST-DVB) Microspheres 304 9.3.3.3 Surface Hydrophilization of Super-Porous PGMA Microspheres 305 9.3.4 Applications in Biomolecules Separation 306 9.3.4.1 Excellent Flow Hydrodynamics 306 9.3.4.2 Application in Virus-Like Particles (VLPs) Separation 308 9.4 Uniform Microspheres for Cell Culture 312 9.5 Summary 316 References 317 10 Membrane Emulsification Equipment and Industrialization 323 10.1 Introduction 323 10.2 Cross-flow Membrane Emulsification Equipment 324 10.3 Premix Membrane Emulsification Equipment 326 10.4 Rotary Membrane Emulsification Equipment 329 10.5 Industrialization – Case Report 331 10.6 Summary 333 References 333 Index 335

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Book SynopsisBiotechnology for Zero Waste The use of biotechnology to minimize waste and maximize resource valorization In Biotechnology for Zero Waste: Emerging Waste Management Techniques, accomplished environmental researchers Drs. Chaudhery Mustansar Hussain and Ravi Kumar Kadeppagari deliver a robust exploration of the role of biotechnology in reducing waste and creating a zero-waste environment. The editors provide resources covering perspectives in waste management like anaerobic co-digestion, integrated biosystems, immobilized enzymes, zero waste biorefineries, microbial fuel cell technology, membrane bioreactors, nano biomaterials, and more. Ideal for sustainability professionals, this book comprehensively sums up the state-of-the-art biotechnologies powering the latest advances in zero-waste strategies. The renowned contributors address topics like bioconversion and biotransformation and detail the concept of the circular economy. Biotechnology for Zero Waste effectively guides readers on the path to creating sustainable products from waste. The book also includes: A thorough introduction to modern perspectives on zero waste drives, including anaerobic co-digestion as a smart approach for enhancing biogas production Comprehensive explorations of bioremediation for zero waste, biological degradation systems, and bioleaching and biosorption of waste Practical discussions of bioreactors for zero waste and waste2energy with biotechnology An in-depth examination of emerging technologies, including nanobiotechnology for zero waste and the economics and commercialization of zero waste biotechnologies Perfect for process engineers, natural products, environmental, soil, and inorganic chemists, Biotechnology for Zero Waste: Emerging Waste Management Techniques will also earn a place in the libraries of food technologists, biotechnologists, agricultural scientists, and microbiologists.Table of ContentsForeword xxvii Preface xxix Part I Modern Perspective of Zero Waste Drives 1 1 Anaerobic Co-digestion as a Smart Approach for Enhanced Biogas Production and Simultaneous Treatment of Different Wastes 3S. Bharathi and B. J. Yogesh 1.1 Introduction 3 1.2 Anaerobic Co-digestion (AcD) 5 1.3 Digester Designs 13 1.4 Digestate/Spent Slurry 14 1.5 Conclusion 15 References 15 2 Integrated Approaches for the Production of Biodegradable Plastics and Bioenergy from Waste 19Chandan Kumar Sahu, Mukta Hugar, and Ravi Kumar Kadeppagari 2.1 Introduction 19 2.2 Food Waste for the Production of Biodegradable Plastics and Biogas 19 2.3 Dairy and Milk Waste for the Production of Biodegradable Plastics and Biogas 22 2.4 Sugar and Starch Waste for the Production of Biodegradable Plastics and Biogas 23 2.5 Wastewater for the Production of Biodegradable Plastics and Bioenergy 25 2.6 Integrated Approaches for the Production of Biodegradable Plastics and Bioenergy from Waste 27 2.7 Conclusions 28 References 28 3 Immobilized Enzymes for Bioconversion of Waste to Wealth 33Angitha Balan, Vaisiri V. Murthy, and Ravi Kumar Kadeppagari 3.1 Introduction 33 3.2 Enzymes as Biocatalysts 34 3.3 Immobilization of Enzymes 35 3.4 Bioconversion of Waste to Useful Products by Immobilized Enzymes 38 3.5 Applications of Nanotechnology for the Immobilization of Enzymes and Bioconversion 41 3.6 Challenges and Opportunities 43 Acknowledgments 43 References 44 Part II Bioremediation for Zero Waste 47 4 Bioremediation of Toxic Dyes for Zero Waste 49Venkata Krishna Bayineni 4.1 Introduction 49 4.2 Background to Dye(s) 50 4.3 The Toxicity of Dye(s) 50 4.4 Bioremediation Methods 51 4.5 Conclusion 63 References 63 5 Bioremediation of Heavy Metals 67Tanmoy Paul and Nimai C. Saha 5.1 Introduction 67 5.2 Ubiquitous Heavy Metal Contamination – The Global Scenario 68 5.3 Health Hazards from Heavy Metal Pollution 69 5.4 Decontaminating Heavy Metals – The Conventional Strategies 71 5.5 Bioremediation – The Emerging Sustainable Strategy 72 5.6 Conclusion 78 References 79 6 Bioremediation of Pesticides Containing Soil and Water 83Veena S. More, Allwin Ebinesar Jacob Samuel Sehar, Anagha P. Sheshadri, Sangeetha Rajanna, Anantharaju Kurupalya Shivram, Aneesa Fasim, Archana Rao, Prakruthi Acharya, Sikandar Mulla, and Sunil S. More 6.1 Introduction 83 6.2 Pesticide Biomagnification and Consequences 84 6.3 Ill Effects of Biomagnification 84 6.4 Bioremediation 85 6.5 Methods Used in Bioremediation Process 86 6.6 Bioremediation Process Using Biological Mediators 88 6.7 Factors Affecting Bioremediation 90 6.8 Future Perspectives 91 References 91 7 Bioremediation of Plastics and Polythene in Marine Water 95Tarun Gangar and Sanjukta Patra 7.1 Introduction 95 7.2 Plastic Pollution: A Threat to the Marine Ecosystem 96 7.3 Micro- and Nanoplastics 96 7.4 Microbes Involved in the Degradation of Plastic and Related Polymers 99 7.5 Enzymes Responsible for Biodegradation 101 7.6 Mechanism of Biodegradation 102 7.7 Biotechnology in Plastic Bioremediation 104 7.8 Future Perspectives: Development of More Refined Bioremediation Technologies as a Step Toward Zero Waste Strategy 106 Acknowledgment 106 Conflict of Interest 107 References 107 Part III Biological Degradation Systems 111 8 Microbes and their Consortia as Essential Additives for the Composting of Solid Waste 113Mansi Rastogi and Sheetal Barapatre 8.1 Introduction 113 8.2 Classification of Solid Waste 113 8.3 Role of Microbes in Composting 114 8.4 Effect of Microbial Consortia on Solid Waste Composting 116 8.5 Benefits of Microbe-Amended Compost 119 References 119 9 Biodegradation of Plastics by Microorganisms 123Md. Anisur R. Mazumder, Md. Fahad Jubayer, and Thottiam V. Ranganathan 9.1 Introduction 123 9.2 Definition and Classification of Plastics 124 9.3 Biodegradation of Plastics 128 9.4 Current Trends and Future Prospects 136 List of Abbreviations 137 References 138 10 Enzyme Technology for the Degradation of Lignocellulosic Waste 143Swarrna Haldar and Soumitra Banerjee 10.1 Introduction 143 10.2 Enzymes Required for the Degradation of Lignocellulosic Waste 144 10.3 Utilizing Enzymes for the Degradation of Lignocellulosic Waste 150 10.4 Conclusion 150 References 150 11 Usage of Microalgae: A Sustainable Approach to Wastewater Treatment 155Kumudini B. Satyan, Michael V. L. Chhandama, and Dhanya V. Ranjit 11.1 Introduction 155 11.2 Microalgae for Wastewater Treatment 158 11.3 Cultivation of Microalgae in Wastewater 162 11.4 Algae as a Source of Bioenergy 164 11.5 Conclusion 166 References 166 Part IV Bioleaching and Biosorption of Waste: Approaches and Utilization 171 12 Microbes and Agri-Food Waste as Novel Sources of Biosorbents 173Simranjeet Singh, Praveen C. Ramamurthy, Vijay Kumar, Dhriti Kapoor, Vaishali Dhaka, and Joginder Singh 12.1 Introduction 173 12.2 Conventional Methods for Agri-Food Waste Treatment 175 12.3 Application of the Biosorption Processes 176 12.4 Use of Genetically Engineered Microorganisms and Agri-Food Waste 178 12.5 Biosorption Potential of Microbes and Agri-Food Waste 179 12.6 Modification, Parameter Optimization, and Recovery 180 12.7 Immobilization of Biosorbent 182 12.8 Conclusions 183 References 185 13 Biosorption of Heavy Metals and Metal-Complexed Dyes Under the Influence of Various Physicochemical Parameters 189Allwin Ebinesar Jacob Samuel Sehar, Veena S. More, Amrutha Gudibanda Ramesh, and Sunil S. More 13.1 Introduction 189 13.2 Mechanisms Involved in Biosorption of Toxic Heavy Metal Ions and Dyes 191 13.3 Chemistry of Heavy Metals in Water 191 13.4 Chemistry of Metal-Complexed Dyes 192 13.5 Microbial Species Used for the Removal of Metals and Metal-Complexed Dyes 192 13.6 Industrial Application on the Biosorption of Heavy Metals 195 13.7 Biosorption of Reactive Dyes 198 13.8 Metal-Complexed Dyes 199 13.9 Biosorption of Metal-Complexed Dyes 200 13.10 Conclusion 203 References 203 14 Recovery of Precious Metals from Electronic and Other Secondary Solid Waste by Bioleaching Approach 207Dayanand Peter, Leonard Shruti Arputha Sakayaraj, and Thottiam Vasudevan Ranganathan 14.1 Introduction 207 14.2 What Is Bioleaching? 208 14.3 E-Waste, What Are They? 210 14.4 Role of Microbes in Bioleaching of E-Waste 212 14.5 Application of Bioleaching for Recovery of Individual Metals 214 14.6 Large-Scale Bioleaching of E-Waste 215 14.7 Future Aspects 215 List of Abbreviations 216 References 216 Part V Bioreactors for Zero Waste 219 15 Photobiological Reactors for the Degradation of Harmful Compounds in Wastewaters 221Naveen B. Kilaru, Nelluri K. Durga Devi, and Kondepati Haritha 15.1 Introduction 221 15.2 Photobiological Agents and Methods Used in PhotoBiological Reactors 222 15.3 Conclusion 238 Acknowledgment 238 References 239 16 Bioreactors for the Production of Industrial Chemicals and Bioenergy Recovery from Waste 241Gargi Ghoshal 16.1 Introduction 241 16.2 Basic Biohydrogen-Manufacturing Technologies and their Deficiency 244 16.3 Overview of Anaerobic Membrane Bioreactors 246 16.4 Factors Affecting Biohydrogen Production in AnMBRs 248 16.5 Techniques to Improve Biohydrogen Production 252 16.6 Environmental and Economic Assessment of BioHydrogen Production in AnMBRs 253 16.7 Future Perspectives of Biohydrogen Production 253 16.8 Products Based on Solid-State Fermenter 253 16.9 Koji Fermenters for SSF for Production of Different Chemicals 257 16.10 Recent Research on Biofuel Manufacturing in Bioreactors Other than Biohydrogen 258 References 259 Part VI Waste2Energy with Biotechnology: Feasibilities and Challenges 263 17 Utilization of Microbial Potential for Bioethanol Production from Lignocellulosic Waste 265Manisha Rout, Bithika Sardar, Puneet K. Singh, Ritesh Pattnaik, and Snehasish Mishra 17.1 Introduction 265 17.2 Processing of Lignocellulosic Biomass to Ethanol 268 17.3 Biological Pretreatment 271 17.4 Enzymatic Hydrolysis 276 17.5 Fermentation 277 17.6 Conclusion and Future Prospects 279 References 280 18 Advancements in Bio-hydrogen Production from Waste Biomass 283Shyamali Sarma and Sankar Chakma 18.1 Introduction 283 18.2 Routes of Production 285 18.3 Biomass as Feedstock for Biohydrogen 286 18.4 Factors Affecting Biohydrogen 288 18.5 Strategies to Enhance Microbial Hydrogen Production 292 18.6 Future Perspectives and Conclusion 297 References 297 19 Reaping of Bio-Energy from Waste Using Microbial Fuel Cell Technology 303Senthilkumar Kandasamy, Naveenkumar Manickam, and Samraj Sadhappa 19.1 Introduction 303 19.2 Microbial Fuel Cell Components and Process 306 19.3 Application of Microbial Fuel Cell to the Social Relevance 309 19.4 Conclusion and Future Perspectives 311 References 311 20 Application of Sustainable Micro-Algal Species in the Production of Bioenergy for Environmental Sustainability 315Senthilkumar Kandasamy, Jayabharathi Jayabalan, and Balaji Dhandapani 20.1 Introduction 315 20.2 Cultivation and Processing of Microalgae 317 20.3 Genetic Engineering for the Improvement of Microalgae 326 20.4 Conclusion and Challenges in Commercializing Microalgae 327 References 327 Part VII Emerging Technologies (Nano Biotechnology) for Zero Waste 329 21 Nanomaterials and Biopolymers for the Remediation of Polluted Sites 331Minchitha K. Umesha, Sadhana Venkatesh, and Swetha Seshagiri 21.1 Introduction 331 21.2 Water Remediation 332 21.3 Soil Remediation 336 References 339 22 Biofunctionalized Nanomaterials for Sensing and Bioremediation of Pollutants 343Satyam and S. Patra 22.1 Introduction 343 22.2 Synthesis and Surface Modification Strategies for Nanoparticles 345 22.3 Binding Techniques for Biofunctionalization of Nanoparticles 345 22.4 Commonly Functionalized Biomaterials and Their Role in Remediation 348 22.5 Biofunctionalized Nanoparticle-Based Sensors for Environmental Application 354 22.6 Limitation of Biofunctionalized Nanoparticles for Environmental Application 355 22.7 Future Perspective 356 22.8 Conclusion 356 Acknowledgment 357 References 357 23 Biogeneration of Valuable Nanomaterials from Food and Other Wastes 361Amrutha B. Mahanthesh, Swarrna Haldar, and Soumitra Banerjee 23.1 Introduction 361 23.2 Green Synthesis of Nanomaterials by Using Food and Agricultural Waste 362 23.3 Synthesis of Bionanoparticles from Food and Agricultural Waste 362 23.4 Conclusion 365 Acknowledgments 365 References 365 24 Biosynthesis of Nanoparticles Using Agriculture and Horticulture Waste 369Vinayaka B. Shet, Keshava Joshi, Lokeshwari Navalgund, and Ujwal Puttur 24.1 Introduction 369 24.2 Agricultural and Horticultural Waste 370 24.3 Biosynthesis of Nanoparticle 370 24.4 Characterization of Biosynthesized Nanoparticles 373 24.5 Applications of Biosynthesized Nanoparticles 375 References 377 25 Nanobiotechnology – A Green Solution 379Baishakhi De and Tridib K. Goswami 25.1 Introduction 379 25.2 Nanotechnology and Nanobiotechnology – The Green Processes and Technologies 381 25.3 The Versatile Role of Nanotechnology and Nanobiotechnology 385 25.4 Nanotechnologies inWaste Reduction and Management 390 25.5 Conclusion 393 References 393 26 Novel Biotechnological Approaches for Removal of Emerging Contaminants 397Sangeetha Gandhi Sivasubramaniyan, Senthilkumar Kandasamy, and Naveen kumar Manickam 26.1 Introduction 397 26.2 Classification of Emerging Contaminants 397 26.3 Various Sources of ECs 399 26.4 Need of Removal of ECs 400 26.5 Methods of Treatment of EC 400 26.6 Biotechnological Approaches for the Removal of ECs 401 26.7 Conclusion 406 References 407 Part VIII Economics and Commercialization of Zero Waste Biotechnologies 409 27 Bioconversion of Waste to Wealth as Circular Bioeconomy Approach 411Dayanand Peter, Jaya Rathinam, and Ranganathan T. Vasudevan 27.1 Introduction 411 27.2 Biovalorization of Organic Waste 413 27.3 Bioeconomy Waste Production and Management 414 27.4 Concerns About Managing Food Waste in Achieving Circular Bioeconomy Policies 416 27.5 Economics of Bioeconomy 417 27.6 Entrepreneurship in Bioeconomy 417 27.7 Conclusion 418 List of Abbreviations 418 References 418 28 Bioconversion of Food Waste to Wealth – Circular Bioeconomy Approach 421Rajam Ramasamy and Parthasarathi Subramanian 28.1 Introduction 421 28.2 Circular Bioeconomy 422 28.3 Food Waste Management Current Practices 424 28.4 Techniques for Bioconversion of Food Waste Toward Circular Bioeconomy Approach 425 28.5 Conclusion 435 References 435 29 Zero-Waste Biorefineries for Circular Economy 439Puneet K. Singh, Pooja Shukla, Sunil K. Verma, Snehasish Mishra, and Pankaj K. Parhi 29.1 Introduction 439 29.2 Bioenergy, Bioeconomy, and Biorefineries 440 29.3 Bioeconomic Strategies Around the World 443 29.4 Challenging Factors and Impact on Bioeconomy 445 29.5 Effect of Increased CO2 Concentration, Sequestration, and Circular Economy 447 29.6 Carbon Sequestration in India 447 29.7 Methods for CO2 Capture 448 29.8 Conclusion and Future Approach 451 References 452 30 Feasibility and Economics of Biobutanol from Lignocellulosic and Starchy Residues 457Sandesh Kanthakere 30.1 Introduction 457 30.2 Opportunities and Future of Zero Waste Biobutanol 458 30.3 Generation of Lignocellulosic and Starchy Wastes 459 30.4 Value Added Products from Lignocellulose and Starchy Residues 462 30.5 Conclusion 468 References 468 31 Critical Issues That Can Underpin the Drive for Sustainable Anaerobic Biorefinery 473Spyridon Achinas 31.1 Introduction 473 31.2 Biogas – An Energy Vector 474 31.3 Anaerobic Biorefinery Approach 475 31.4 Technological Trends and Challenges in the Anaerobic Biorefinery 477 31.5 Perspectives Toward the Revitalization of the Anaerobic Biorefineries 482 31.6 Conclusion 485 Conflict of Interest 485 References 485 32 Microbiology of Biogas Production from Food Waste: Current Status, Challenges, and Future Needs 491Vanajakshi Vasudeva, Inchara Crasta, and Sandeep N. Mudliar 32.1 Introduction 491 32.2 Fundamentals for Accomplishing National Biofuel Policy 492 32.3 Significances of Anaerobic Microbiology in Biogas Process 493 32.4 Microbiology and Physico-Chemical Process in AD 493 32.5 Pretreatment 496 32.6 Variations in Anaerobic Digestion 496 32.7 Factors Influencing Biogas Production 497 32.8 Application of Metagenomics 502 32.9 Conclusions and Future Needs 504 List of Abbreviations 504 References 505 Part IX Green and Sustainable future (Zero Waste and Zero Emissions) 507 33 Valorization of Waste Cooking Oil into Biodiesel, Biolubricants, and Other Products 509Murlidhar Meghwal, Harita Desai, Sanchita Baisya, Arpita Das, Sanghmitra Gade, Rekha Rani, Kalyan Das, and Ravi Kumar Kadeppagari 33.1 Introduction 509 33.2 Treatment 510 33.3 Evaluation of Waste Cooking Oil and Valorized Cooking Oil 511 33.4 Versatile Products as an Outcome of Valorized Waste Cooking Oil 512 33.5 Conclusion 516 References 517 34 Agri and Food Waste Valorization Through the Production of Biochemicals and Packaging Materials 521A. Jagannath and Pooja J. Rao 34.1 Introduction 521 34.2 Importance 522 34.3 Worldwide Initiatives 522 34.4 Composition-Based Solutions and Approaches 523 34.5 Biochemicals 523 34.6 Biofuels 526 34.7 Packaging Materials and Bioplastics 526 34.8 Green Valorization 531 34.9 Conclusion 531 References 532 35 Edible Coatings and Films from Agricultural and Marine Food Wastes 543C. Naga Deepika, Murlidhar Meghwal, Pramod K. Prabhakar, Anurag Singh, Rekha Rani, and Ravi Kumar Kadeppagari 35.1 Introduction 543 35.2 Sources of Food Waste 544 35.3 Film/Coating Made from Agri-Food Waste 545 35.4 Film/Coating Materials from Marine Biowaste 548 35.5 Film/Coating Formation Methods 550 35.6 Conclusion 552 References 553 36 Valorization of By-Products of Milk Fat Processing 557Menon R. Ravindra, Monika Sharma, Rajesh Krishnegowda, and Amanchi Sangma 36.1 Introduction 557 36.2 Processing of Milk Fat and Its By-Products 558 36.3 Valorization of Buttermilk 558 36.4 Valorization of Ghee Residue 562 36.5 Conclusion 565 References 565 Index 569

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Book SynopsisNanotechnology for Environmental Remediation Comprehensive resource on using nanomaterials to alleviate environmental pollution Contaminated land, soil and water pose a threat to the environment and health. These sites require immediate action in terms of assessing pollution and new remediation strategies. Nanotechnology for Environmental Remediation helps readers understand the potential of nanotechnology in resolving the growing problem of environmental contamination. The specific aim of this book is to provide comprehensive information relating to the progress in the development of functional nanomaterials and nanocomposites which are used for the environmental remediation of a variety of contaminants. The work deals with the different aspects of nanotechnology in water, air and soil contamination and presents the recent advances with a focus on remediation. Core topics discussed in the work include: Nanotechnology that can be used to engineer and tailor particles for specific environmental remediation applications A big-picture conceptual understanding of environmental remediation methods for researchers, environmentalists and professionals involved in assessing and developing new nano-based strategies A detailed approach towards the different remediation procedures by various nanomaterials such as metal nanoparticles, polymeric nanoparticles, carbon nanotubes, and dendrimers The societal impact that nanotechnology has on the environment Chemists and biotechnologists can use Nanotechnology for Environmental Remediation as a comprehensive reference work for thoroughly understanding this new type of technology and why it is so important when considering environmental remediation efforts. Due to the practical application of nanotechnologies, environmental organizations and agencies can also both utilize the work to explore new and more effective ways of doing things, both now and into the future as nanotechnology becomes more common.Table of Contents1.Science and Technology of Nanomaterials: Introduction 2.Nanobioremediation 3.Nanotechnology in soil remediation 4.Nanotechnology in water treatment 5.Nanotechnology in air pollution remediation 6.Nanomaterials in filtration 7.Nanoadsorbents for environmental remediation 8.Iron nanoparticles for environmental remediation 9.Metal oxide nanoparticles for environmental remediation 10.Biopolymeric nanoparticles for environmental remediation 11.Functionalized nanoparticles for environmental remediation 12.Dendrimers for environmental remediation 13.Nanocrystals for environmental remediation 14.Carbon nanotubes for environmental remediation 15.Enzyme nanoparticles for environmental remediation 16.Nanofibres for environmental remediation 17.Nanocomposites for environmental remediation 18.Nanocatalysts in environmental applications 19.Aerogels for environmental remediation 20.Nanomaterials based environmental sensors 21.Intelligent nanomaterials for environmental remediation 22.Environmental Toxicology of Nanomaterials: Challenges 23.Societal impact of nanomaterials 24.LCA of nanomaterials for bioremediation

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Book SynopsisChemically Modified Carbon Nanotubes for Commercial Applications Discover the go-to handbook for developers and application-oriented researchers who use carbon nanotubes in real products Carbon nanotubes have held much interest for researchers since their discovery in 1991. Due to their low mass density, large aspect ratio, and unique physical, chemical, and electronic properties, they provide a fertile ground for innovation in nanoscale applications. The development of chemical modifications that can enhance the poor dispersion of carbon nanotubes in solvents and improve interactions with other materials have enabled extensive industrial applications in a variety of fields. As the chemistry of carbon nanotubes and their functionalization becomes better understood, Chemically Modified Carbon Nanotubes for Commercial Applications presents the most recent developments of chemically modified carbon nanotubes and emphasizes the broad appeal for commercial purposes along many avenues of interest. The book reviews their already realized and prospective applications in fields such as electronics, photonics, separation science, food packaging, environmental monitoring and protecting, sensing technology, and biomedicine. By focusing on their commercialization prospects, this resource offers a unique approach to a significant and cutting-edge discipline. In Chemically Modified Carbon Nanotubes for Commercial Applications readers will also find: Case studies that emphasize the information presented in each chapter Each chapter includes important websites and suggested reading materials Discussion of current applications of the relevant methodologies in every chapter A look at future perspectives in each application area to highlight the scope for next steps within the industry Chemically Modified Carbon Nanotubes for Commercial Applications is a valuable reference for material scientists, chemists (especially those focused on environmental concerns), and chemical and materials engineering scientists working in R&D and academia who want to learn more about chemically modified carbon nanotubes for various scalable commercial applications. It is also a useful resource for a broad audience: anyone interested in the fields of nanomaterials, nanoadsorbents, nanomedicine, bioinspired nanomaterials, nanotechnology, nanodevices, nanocomposites, biomedical application of nanomaterials, nano-engineering, and high energy applications.Table of ContentsPART 1: CHEMICALLY MODIFIED CARBON NANOTUBES: OVERVIEW AND ECONOMIC ASPECTS Chapter 1: Overview and fundamentals of Chemically Modified Carbon Nanotubes Chapter 2: Synthesis and Properties of Chemically Modified Carbon Nanotubes Chapter 3: Different Chemical Modification Methods of Carbon Nanotubes Chapter 4: Economics of Chemically Modified Carbon Nanotubes PART 2: CHEMICALLY MODIFIED CARBON NANOTUBES: CURRENT APPLICATIONS Chapter 5: Chemically Modified Carbon Nanotubes for Advanced Fibers and Wires Applications Chapter 6: Chemically Modified Carbon Nanotubes for Membranes for Purification and Desalination of Water Chapter 7: Chemically Modified Carbon Nanotubes for Electronics and Photonic Applications Chapter 8: Chemically Modified Carbon Nanotubes for Biosensors Applications Chapter 9: Chemically Modified Carbon Nanotubes in Cancer Therapy Chapter 10: Chemically Modified Carbon Nanotubes in Drug Delivery Chapter 11: Chemically Modified Carbon Nanotubes in 3D and 4D Printing Chapter 12: Chemically Modified Carbon Nanotubes in Food Packaging Chapter 13: Chemically Modified Carbon Nanotubes for Tribology Applications Chapter 14: Chemically Modified Carbon Nanotubes in Tissue engineering Chapter 15: Chemically Modified Carbon Nanotubes in Transportation Chapter 16: Chemically Modified Carbon Nanotubes in Energy Production and Storage Chapter 17: Chemically Modified Carbon Nanotubes for High Energy Applications Chapter 18: Chemically Modified Carbon Nanotubes in Lubricants (Eco-lubricants) Chapter 19: Chemically Modified Carbon Nanotubes for Pollutants Adsorption Chapter 20: Chemically Modified Carbon Nanotubes in Environmental Protection Chapter 21: Chemically Modified Carbon Nanotubes in Membrane Separation Chapter 22: Chemically Modified Carbon Nanotubes in Cement and Concrete Field Chapter 23: Chemically Modified Carbon Nanotubes for Gas-Sensing Application Chapter 24: Chemically Modified Carbon Nanotubes for Corrosion Protection

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Book Synopsis

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