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ОбложкаBioseparations science and engineering / R.G.Harrison et al. - 2nd ed. - Oxford; New York: Oxford university press, 2015. - xxii, 547 p.: ill., tab. - (Topics in chemical engineering: a series of textbooks and monographs). - Bibliogr. at the end of the chapters. - Ind.: p.535-547. - ISBN 978-0-19-539181-7
Шифр: (И/Л8-B60) 02
 

Место хранения: 02 | Отделение ГПНТБ СО РАН | Новосибирск

Оглавление / Contents
 
Preface ....................................................... xix

1    Introduction to Bioproducts and Bioseparations ............. 1
1.1  Instructional Objectives ................................... 3
1.2  Broad Classification of Bioproducts ........................ 3
1.3  Small Biomolecules ......................................... 4
     1.3.1  Primary Metabolites ................................. 4
     1.3.2  Secondary Metabolites ............................... 9
     1.3.3  Summary of Small Biomolecules ...................... 12
1.4  Macromolecules: Proteins .................................. 13
     1.4.1  Primary Structure .................................. 13
     1.4.2  Secondary Structure ................................ 14
     1.4.3  Tertiary Structure ................................. 14
     Example 1.1. Effect of a Reducing Agent on Protein
     Structure and Mobility .................................... 17
     1.4.4  Quaternary Structure ............................... 17
     1.4.5  Prosthetic Groups and Hybrid Molecules ............. 17
     1.4.6  Functions and Commercial Uses of Proteins .......... 19
     1.4.7  Stability of Proteins .............................. 21
     1.4.8  Recombinant Protein Expression ..................... 25
1.5  Macromolecules: Nucleic Acids and Oligonucleotides ........ 31
1.6  Macromolecules: Polysaccharides ........................... 33
1.7  Particulate Products ...................................... 34
1.8  Introduction to Bioseparations: Engineering Analysis ...... 35
     1.8.1  Stages of Downstream Processing .................... 35
     Example 1.2. Initial Selection of Purification Steps ...... 36
     1.8.2  Basic Principles of Engineering Analysis ........... 37
     1.8.3  Process and Product Quality ........................ 39
     1.8.4  Criteria for Process Development ................... 39
1.9  The Route to Market ....................................... 40
     1.9.1  The Chemical and Applications Range of the
            Bioproduct ......................................... 40
     1.9.2  Documentation of Pharmaceutical Bioproducts ........ 41
     1.9.3  GLP and cGMP ....................................... 42
     1.9.4  Formulation ........................................ 42
1.10 Summary ................................................... 42
     Nomenclature .............................................. 43
     Problems .................................................. 44
     References ................................................ 46

2    Analytical Methods and Bench Scale Preparative
     Bioseparations ............................................ 48
2.1  Instructional Objectives .................................. 49
2.2  Specifications ............................................ 49
2.3  Assay Attributes .......................................... 51
     2.3.1  Precision .......................................... 51
     2.3.2  Accuracy ........................................... 52
     2.3.3  Specificity ........................................ 52
     2.3.4  Linearity, Limit of Detection, and Limit of
            Quantitation ....................................... 53
     2.3.5  Range .............................................. 54
     2.3.6  Robustness ......................................... 55
2.4  Analysis of Biological Activity ........................... 55
     2.4.1  Animal Model Assays ................................ 55
     2.4.2  Cell-Line-Derived Bioassays ........................ 56
     2.4.3  In vitro Biochemical Assays ........................ 57
     Example 2.1. Coupled Enzyme Assay for Alcohol Oxidase ..... 58
2.5  Analysis of Purity ........................................ 59
     2.5.1  Electrophoretic Analysis ........................... 60
            Example 2.2. Estimation of the Maximum Temperature
            in an Electrophoresis Gel .......................... 63
     2.5.2  High-Performance Liquid Chromatography (HPLC) ...... 76
     2.5.3  Mass Spectrometry .................................. 79
     2.5.4  Coupling of HPLC with Mass Spectrometry ............ 80
     2.5.5  Ultraviolet Absorbance ............................. 80
            Example 2.3. Determination of Molar Absorptivity ... 81
     2.5.6  CHNO/Amino Acid Analysis (AAA) ..................... 82
            Example 2.4. Calculations Based on CHNO Analysis ... 82
     2.5.7  Protein Assays ..................................... 83
     2.5.8  Enzyme-Linked Immunosorbent Assay .................. 84
     2.5.9  Gas Chromatography ................................. 86
     2.5.10 DNA Hybridization .................................. 86
     2.5.11 ICP/MS(AES) ........................................ 87
     2.5.12 Dry Weight ......................................... 87
2.6  Microbiology Assays ....................................... 88
     2.6.1  Sterility .......................................... 88
     2.6.2  Bioburden .......................................... 88
     2.6.3  Endotoxin .......................................... 89
     2.6.4  Virus, Mycoplasma, and Phage ....................... 89
2.7  Bench Scale Preparative Separations ....................... 90
     2.7.1  Preparative Electrophoresis ........................ 90
     2.7.2  Magnetic Bioseparations ............................ 96
2.8  Summary .................................................. 101
     Nomenclature ............................................. 103
     Problems ................................................. 104
     References ............................................... 108

3    Cell Lysis and Flocculation .............................. 111
3.1  Instructional Objectives ................................. 111
3.2  Some Elements of Cell Structure .......................... 112
     3.2.1  Prokaryotic Cells ................................. 112
     3.2.2  Eukaryotic Cells .................................. 113
3.3  Cell Lysis ............................................... 114
     3.3.1  Osmotic and Chemical Cell Lysis ................... 116
     3.3.2  Mechanical Methods of Lysis ....................... 117
3.4  Flocculation ............................................. 120
     3.4.1  The Electric Double Layer ......................... 121
            Example 3.1. Dependence of the Debye Radius on
            the Type of Electrolyte ........................... 124
     3.4.2  Forces Between Particles and Flocculation by
            Electrolytes ...................................... 125
            Example 3.2. Sensitivity of Critical Flocculation
            Concentration to Temperature and Counterion
            Charge Number ..................................... 127
     3.4.3  The Schulze-Hardy Rule ............................ 128
     3.4.4  Flocculation Rate ................................. 129
     3.4.5  Polymeric Flocculants ............................. 129
3.5  Summary .................................................. 131
     Nomenclature ............................................. 131
     Problems ................................................. 133
     References ............................................... 133

4    Filtration ............................................... 135
4.1  Instructional Objectives ................................. 136
4.2  Filtration Principles .................................... 137
     4.2.1  Conventional Filtration ........................... 137
            Example 4.1. Batch Filtration ..................... 138
     4.2.2  Crossflow Filtration .............................. 143
            Example 4.2. Concentration Polarization in
            Ultrafiltration ................................... 146
            Example 4.3. Comparison of Mass Transfer
            Coefficient Calculated by Boundary Layer Theory
            Versus by Shear-Induced Diffusion Theory .......... 150
4.3  Filter Media and Equipment ............................... 152
     4.3.1  Conventional Filtration ........................... 152
     4.3.2  Crossflow Filtration .............................. 156
4.4  Membrane Fouling ......................................... 160
4.5  Scale-up and Design of Filtration Systems ................ 162
     4.5.1  Conventional Filtration ........................... 163
            Example 4.4. Rotary Vacuum Filtration ............. 164
            Example 4.5. Washing of a Rotary Vacuum Filter
            Cake .............................................. 166
     4.5.2  Crossflow Filtration .............................. 171
            Example 4.6. Diafiltration Mode in Crossflow
            Filtration ........................................ 173
4.6  Summary .................................................. 176
     Nomenclature ............................................. 178
     Problems ................................................. 179
     References ............................................... 184

5    Sedimentation ............................................ 185
5.1  Instructional Objectives ................................. 185
5.2  Sedimentation Principles ................................. 186
     5.2.1  Equation of Motion ................................ 186
     5.2.2  Sensitivities ..................................... 187
5.3  Methods for Analysis of Sedimentation .................... 189
     5.3.1  Equilibrium Sedimentation ......................... 190
     5.3.2  Sedimentation Coefficient ......................... 191
            Example 5.1. Application of the Sedimentation
            Coefficient ....................................... 191
     5.3.3  Equivalent Time ................................... 192
            Example 5.2. Scale-up Based on Equivalent Time .... 193
     5.3.4  Sigma Analysis .................................... 193
5.4  Production Centrifuges: Comparison and Engineering
     Analysis ................................................. 194
     5.4.1  Tubular Bowl Centrifuge ........................... 195
            Example 5.3. Complete Recovery of Bacterial Cells
            in a Tubular Bowl Centrifuge ...................... 199
     5.4.2  Disk Centrifuge ................................... 200
5.5  Ultracentrifugation ...................................... 203
     5.5.1 Determination of Molecular Weight .................. 204
5.6  Flocculation and Sedimentation ........................... 205
5.7  Sedimentation at Low Accelerations ....................... 206
     5.7.1  Diffusion, Brownian Motion ........................ 206
     5.7.2  Isothermal Settling ............................... 207
     5.7.3  Convective Motion and Pйclet Analysis ............. 207
     5.7.4  Inclined Sedimentation ............................ 207
     5.7.5  Field-Flow Fractionation .......................... 209
5.8  Centrifugal Elutriation .................................. 210
5.9  Summary .................................................. 210
     Nomenclature ............................................. 212
     Problems ................................................. 214
     References ............................................... 217

6    Extraction ............................................... 219
6.1  Instructional Objectives ................................. 219
6.2  Extraction Principles .................................... 220
     6.2.1  Phase Separation and Partitioning Equilibria ...... 220
     6.2.2  Countercurrent Stage Calculations ................. 226
            Example 6.1. Separation of a Bioproduct and an
            Impurity by Countercurrent Extraction ............. 230
            Example 6.2. Effect of Solvent Rate in
            Countercurrent Staged Extraction of an
            Antibiotic ........................................ 230
6.3  Scale-up and Design of Extractors ........................ 232
     6.3.1 Reciprocating-Plate Extraction Columns ............. 233
            Example 6.3. Scale-up of a Reciprocating-Plate
            Extraction Column ................................. 235
     6.3.2 Centrifugal Extractors ............................. 237
            Example 6.4. Increase in Feed Rate to
            a Podbielniak Centrifugal Extractor ............... 238
6.4  Summary .................................................. 239
     Nomenclature ............................................. 240
     Problems ................................................. 241
     References ............................................... 243

7    Liquid Chromatography and Adsorption ..................... 245
7.1  Instructional Objectives ................................. 247
7.2  Adsorption Equilibrium ................................... 248
7.3  Adsorption Column Dynamics ............................... 251
     7.3.1  Fixed-Bed Adsorption .............................. 251
            Example 7.1. Determination of the Mass Transfer
            Coefficient from Adsorption Breakthrough Data ..... 256
     7.3.2  Agitated-Bed Adsorption ........................... 258
7.4  Chromatography Column Dynamics ........................... 259
     7.4.1  Plate Models ...................................... 260
     7.4.2  Moment Analysis ................................... 262
     7.4.3  Chromatography Column Mass Balance with
            Negligible Dispersion ............................. 264
            Example 7.2. Chromatographic Separation of Two
            Solutes ........................................... 264
            Example 7.3. Calculation of the Shock Wave
            Velocity for a Nonlinear Isotherm ................. 266
            Example 7.4. Calculation of the Elution Profile ... 267
     7.4.4  Dispersion Effects in Chromatography .............. 269
     7.4.5  Computer Simulation of Chromatography
            Considering Axial Dispersion, Fluid-Phase Mass
            Transfer, Intraparticle Diffusion, and
            Nonlinear Equilibrium ............................. 275
     7.4.6  Gradients and Modifiers ........................... 277
            Example 7.5. Equilibrium for a Protein Anion in
            the Presence of Chloride Ion ...................... 277
7.5  Membrane Chromatography .................................. 279
     Example 7.6. Comparison of Time for Diffusion Mass
     Transfer in Conventional Chromatography and Membrane
     Chromatography ........................................... 282
7.6  Simulated Moving Bed Chromatography ...................... 284
7.7  Adsorbent Types .......................................... 288
     7.7.1  Silica-Based Resins ............................... 288
     7.7.2  Polymer-Based Resins .............................. 289
     7.7.3  Ion Exchange Resins ............................... 290
     7.7.4  Reversed-Phase Chromatography ..................... 291
     7.7.5  Hydrophobic Interaction Chromatography ............ 292
     7.7.6  Affinity Chromatography ........................... 292
     7.7.7  Immobilized Metal Affinity Chromatography (IMAC) .. 293
     7.7.8  Size Exclusion Chromatography ..................... 293
7.8  Particle Size and Pressure Drop in Fixed Beds ............ 294
7.9  Equipment ................................................ 295
     7.9.1  Columns ........................................... 295
     7.9.2  Chromatography Column Packing Procedures .......... 296
     7.9.3  Detectors ......................................... 297
     7.9.4  Chromatography System Fluidics .................... 298
7.10 Scale-up ................................................. 299
     7.10.1 Adsorption ........................................ 299
            Example 7.7. Scale-up of the Fixed-Bed
            Adsorption of a Pharmaceutical Product ............ 302
     7.10.2 Chromatography .................................... 306
            Example 7.8. Scale-up of a Protein
            Chromatography .................................... 308
            Example 7.9.  Scale-up of Protein Chromatography
            Using Standard Column Sizes ....................... 309
            Example 7.10. Scale-up of Elution Buffer Volumes
            in Protein Chromatography ......................... 310
            Example 7.11. Consideration of Pressure Drop in
            Column Scaling .................................... 311
7.11 Summary .................................................. 311
     Nomenclature ............................................. 314
     Problems ................................................. 317
     References ............................................... 324

8    Precipitation ............................................ 327
8.1  Instructional Objectives ................................. 327
8.2  Protein Solubility ....................................... 328
     8.2.1  Structure and Size ................................ 328
     8.2.2  Charge ............................................ 329
     8.2.3  Solvent ........................................... 331
            Example 8.1. Salting Out of a Protein with
            Ammonium Sulfate .................................. 333
8.3  Precipitate Formation Phenomena .......................... 334
     8.3.1  Initial Mixing .................................... 335
     8.3.2  Nucleation ........................................ 335
     8.3.3  Growth Governed by Diffusion ...................... 336
            Example 8.2. Calculation of Concentration of
            Nuclei in a Protein Precipitation ................. 337
            Example 8.3. Diffusion-Limited Growth of
            Particles ......................................... 340
     8.3.4  Growth Governed by Fluid Motion ................... 341
            Example 8.4. Growth of Particles Limited by
            Fluid Motion ...................................... 342
     8.3.5  Precipitate Breakage .............................. 343
     8.3.6  Precipitate Aging ................................. 343
8.4  Particle Size Distribution in a Continuous-Flow Stirred
     Tank Reactor ............................................. 344
     Example 8.5. Dependence of Population Density
     on Particle Size and Residence Time in a CSTR ............ 348
8.5  Methods of Precipitation ................................. 348
8.6  Design of Precipitation Systems .......................... 352
8.7  Summary .................................................. 354
     Nomenclature ............................................. 356
     Problems ................................................. 358
     References ............................................... 360

9    Crystallization .......................................... 362
9.1  Instructional Objectives ................................. 363
9.2  Crystallization Principles ............................... 363
     9.2.1  Crystals .......................................... 363
     9.2.2  Nucleation ........................................ 364
     9.2.3  Crystal Growth .................................... 366
     9.2.4  Crystallization Kinetics from Batch Experiments ... 367
9.3  Batch Crystallizers ...................................... 368
     9.3.1  Analysis of Dilution Batch Crystallization ........ 369
            Example 9.1. Batch Crystallization with Constant
            Rate of Change of Diluent Concentration ........... 371
9.4  Process Crystallization of Proteins ...................... 373
9.5  Crystallizer Scale-up and Design ......................... 375
     9.5.1  Experimental Crystallization Studies as a Basis
            for Scale-up ...................................... 375
     9.5.2  Scale-up and Design Calculations .................. 377
            Example 9.2. Scale-up of Crystallization Based
            on Constant Power per Volume ...................... 378
9.6  Summary .................................................. 379
     Nomenclature ............................................. 379
     Problems ................................................. 381
     References ............................................... 383

10   Evaporation .............................................. 384
10.1 Instructional Objectives ................................. 384
10.2 Evaporation Principles ................................... 385
     10.2.1 Heat Transfer ..................................... 385
            Example 10.1. Evaporation of a Butyl Acetate
            Stream Containing a Heat-Sensitive Antibiotic
            in a Falling-Film Evaporator ...................... 388
     10.2.2 Vapor-Liquid Separation ........................... 394
10.3 Evaporation Equipment .................................... 396
     10.3.1 Climbing-Film Evaporators ......................... 397
     10.3.2 Falling-Film Evaporators .......................... 398
     10.3.3 Forced-Circulation Evaporators .................... 398
     10.3.4 Agitated-Film Evaporators ......................... 399
10.4 Scale-up and Design of Evaporators ....................... 399
10.5 Summary .................................................. 402
     Nomenclature ............................................. 403
     Problems ................................................. 404
     References ............................................... 405

11   Drying ................................................... 407
11.1 Instructional Objectives ................................. 407
11.2 Drying Principles ........................................ 408
     11.2.1 Water in Biological Solids and in Gases ........... 408
            Example 11.1. Drying of Antibiotic Crystals ....... 411
     11.2.2 Heat and Mass Transfer ............................ 412
            Example 11.2. Conductive Drying of Wet Solids in
            a Tray ............................................ 414
            Example 11.3. Mass Flux During the Constant Rate
            Drying Period in Convective Drying ................ 420
            Example 11.4. Time to Dry Nonporous Biological
            Solids by Convective Drying ....................... 421
11.3 Dryer Description and Operation .......................... 422
     11.3.1 Vacuum-Shelf Dryers ............................... 422
     11.3.2 Batch Vacuum Rotary Dryers ........................ 423
     11.3.3 Freeze Dryers ..................................... 424
     11.3.4 Spray Dryers ...................................... 426
11.4 Scale-up and Design of Drying Systems .................... 427
     11.4.1 Vacuum-Shelf Dryers ............................... 427
     11.4.2 Batch Vacuum Rotary Dryers ........................ 428
     11.4.3 Freeze Dryers ..................................... 428
     11.4.4 Spray Dryers ...................................... 431
            Example 11.5. Sizing of a Spray Dryer ............. 432
11.5 Summary .................................................. 435
     Nomenclature ............................................. 436
     Problems ................................................. 437
     References ............................................... 440

12   Bioprocess Design and Economics .......................... 441
12.1 Instructional Objectives ................................. 441
12.2 Definitions and Background ............................... 442
12.3 Synthesis of Bioseparation Processes ..................... 445
     12.3.1 Primary Recovery Stages ........................... 445
     12.3.2 Intermediate Recovery Stages ...................... 450
     12.3.3 Final Purification Stages ......................... 451
     12.3.4 Pairing of Unit Operations in Process Synthesis ... 453
12.4 Process Analysis ......................................... 454
     12.4.1 Spreadsheets ...................................... 454
     12.4.2 Process Simulators and Their Benefits ............. 454
     12.4.3 Using a Biochemical Process Simulator ............. 457
12.5 Process Economics ........................................ 460
     12.5.1 Capital Cost Estimation ........................... 461
     12.5.2 Operating Cost Estimation ......................... 466
     12.5.3 Profitability Analysis ............................ 471
12.6 Illustrative Examples .................................... 472
     12.6.1 Citric Acid Production ............................ 472
     12.6.2 Human Insulin Production .......................... 479
     12.6.3 Therapeutic Monoclonal Antibody Production ........ 495
12.7 Summary .................................................. 502
     Problems ................................................. 503
     References ............................................... 507

13   Laboratory Exercises in Bioseparations ................... 511
13.1 Flocculant Screening ..................................... 511
     13.1.1 Background ........................................ 512
     13.1.2 Objectives ........................................ 512
     13.1.3 Procedure ......................................... 512
     13.1.4 Report ............................................ 513
     13.1.5 Some Notes and Precautions ........................ 514
13.2 Crossflow Filtration ..................................... 514
     13.2.1 Background ........................................ 514
     13.2.2 Objectives ........................................ 515
     13.2.3 Procedure ......................................... 515
     13.2.4 Report ............................................ 515
13.3 Centrifugation of Flocculated and Unflocculated
     Particulates ............................................. 516
     13.3.1 Background ........................................ 516
     13.3.2 Objectives ........................................ 517
     13.3.3 Procedure ......................................... 517
     13.3.4 Report ............................................ 519
13.4 Aqueous Two-Phase Extraction ............................. 520
     13.4.1 Physical Measurements ............................. 520
     13.4.2 Procedure ......................................... 521
     13.4.3 Calculations and Report ........................... 522
     13.4.4 Inverse Lever Rule ................................ 524
13.5 Chromatography Scale-up .................................. 525
     13.5.1 Background ........................................ 525
     13.5.2 Objectives ........................................ 525
     13.5.3 Procedure ......................................... 526
     13.5.4 Report ............................................ 528
     References ............................................... 530

APPENDIX: Table of Units and Constants ........................ 531
Index ......................................................... 535

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