Abhinav A. Shukla, Mark R. Etzel, Shishir Gadam1-57444-517-0, 978-1-57444-517-6
Table of contents :
Process Scale Bioseparations for the Biopharmaceutical Industry……Page 1
BIOTECHNOLOGY AND BIOPROCESSING SERIES……Page 3
Preface……Page 5
Editors……Page 10
Contents……Page 15
Table of Contents……Page 0
CONTENTS……Page 18
1.1 INTRODUCTION……Page 19
1.2.1 CENTRIFUGATION……Page 23
1.2.1.1 Solid– Liquid Separation Theory……Page 24
1.2.1.1.1 Driving Forces and Stokes’ Equation……Page 25
1.2.1.1.2 Sigma Factor……Page 28
1.2.1.2.2 DensityDifference……Page 29
1.2.1.2.4 Viscosity……Page 30
1.2.1.2.5 Flow Rate and Residence Time……Page 31
1.2.1.4 Definition of Key Parameters……Page 32
1.2.1.4.1 Operational Parameters……Page 33
1.2.1.4.2 Performance Parameters……Page 34
1.2.2.1.1 Depth Filtration……Page 36
1.2.2.1.2 Cake Filtration……Page 37
1.2.2.1.2.1 Constant Flow Filtration……Page 38
1.2.2.1.2.3 Variable Pressure and Flow Rate Filtration……Page 40
1.2.2.1.3 Filter Aid Assisted Depth Filtration……Page 41
1.2.2.2 Tangential Flow Filtration……Page 42
1.2.2.2.1 Pressure Controlled Model……Page 43
1.2.2.2.2 Mass Transfer Model……Page 45
1.2.2.3.1 Pore Blockage Model……Page 47
1.2.2.4.1 Operational Parameters……Page 48
1.2.2.4.2 Performance Parameters……Page 49
1.3.1 MATERIALS……Page 51
1.3.2 METHODS……Page 52
1.3.3.1 Centrifugation……Page 55
1.3.3.2.1 Filter Screening……Page 59
1.3.3.2.2 Optimization and Scale- Up……Page 61
1.3.3.4 Microfiltration ( Option 2)……Page 63
1.4 CONCLUSIONS……Page 68
ACKNOWLEDGMENTS……Page 70
NOMENCLATURE……Page 71
REFERENCES……Page 72
CONTENTS……Page 76
2.1 INTRODUCTION……Page 77
2.2.1 FLUIDIZATION……Page 78
2.2.1.1 Experimental Methodology……Page 79
2.2.1.2 Stability of Fluidized Beds……Page 80
2.2.1.2.1 Residence Time Distribution Using Pulse Response Experiments……Page 81
2.2.1.2.2 Model to Describe the Phenomena Observed……Page 82
2.2.1.3.1 Screening Tests……Page 83
2.2.2.1 Fluid Side Transport……Page 84
2.3.1 INTEGRATING FLUID AND PARTICLE SIDE TRANSPORT……Page 85
2.4.1 DENSITY DISPLACEMENT……Page 86
2.5.1 TRADITIONAL PLATE DISTRIBUTION SYSTEMS……Page 87
2.5.2 ALTERNATE DISTRIBUTION SYSTEMS……Page 88
2.6.1.2 Bed Stability……Page 89
2.6.1.3.2 Buffer Washout Strategies……Page 90
2.6.2.1 Fluidization……Page 91
2.6.2.3.1 Without Biomass……Page 92
2.6.2.3.2 With Biomass……Page 93
2.6.2.4.2 Load Optimization……Page 95
2.7 CONCLUSIONS AND OUTLOOK……Page 96
REFERENCES……Page 98
CONTENTS……Page 99
3.1.1 BATCH ADSORPTION WITH NONPOROUS MAGNETIC ADSORBENT PARTICLES……Page 100
3.1.2 CASE STUDY I: SIMPLE CHARACTERIZATION OF A MAGNETIC ADSORBENT’S PRODUCT BINDING BEHAVIOR……Page 101
3.1.3 HIGH- GRADIENT MAGNETIC SEPARATION……Page 102
3.1.4 HIGH- GRADIENT MAGNETIC FISHING……Page 104
3.1.5 DESIGN OF AN HGMF PROCESS……Page 107
3.2.1 MAGNETIC SUPPORT MATERIALS……Page 109
3.2.2 LIGAND SELECTION……Page 112
3.3 DESIGN AND SET- UP OF MAGNETIC SEPARATOR SYSTEMS……Page 115
3.4.1 INTRODUCTION……Page 118
3.4.2 SIMPLIFIED YIELD ESTIMATION……Page 120
3.4.3 MULTI- COMPONENT SYSTEMS……Page 122
3.4.4 CASE STUDY III: OPTIMIZATION OF THE CAPACITY RATIO USED……Page 125
3.4.5 PROCESS PRODUCTIVITY……Page 126
3.4.6 CASE STUDY IV: INFLUENCE OFWASHING AND ELUTION STEPS……Page 130
3.4.7 ADSORBENT REUSE……Page 131
3.4.8 CASE STUDY V: PILOT PLANT EFFICIENCIES……Page 133
REFERENCES……Page 135
CONTENTS……Page 138
4.1 INTRODUCTION……Page 139
4.2.1 SOLUBILIZATION……Page 140
4.2.3 DISULFIDE BONDS……Page 141
4.3.2 DO YOU HAVE PURIFIED PROTEIN?……Page 143
4.3.3.2 Refolding Proteins Containing Disulfide Bonds……Page 147
4.3.4 ANALYSIS OF THE REFOLD……Page 148
4.3.5.2 Soluble Product……Page 149
4.3.6 PREMADE KITS……Page 150
4.3.7.3 Solid Phase Refolding……Page 151
4.4.1.1 Components That Lead to Protein Microheterogeneities……Page 152
4.4.1.2 Components and Environmental Health and Safety Concerns……Page 155
4.4.2 ADDITION AND MIXING OF COMPONENTS……Page 156
4.4.3 DISULFIDE BONDING AND OXYGEN MASS TRANSFER……Page 157
4.4.4 MIXING AND TYPE OF TANK……Page 164
4.4.5 SUMMARY……Page 166
4.5.1.1 Mechanism of High Pressure Refolding……Page 168
REFERENCES……Page 169
5.1 INTRODUCTION……Page 174
5.2 PRINCIPLES OF PROTEIN CRYSTALLIZATION……Page 175
5.3 PRACTICAL CONSIDERATIONS IN DEVELOPING A PROTEIN CRYSTALLIZATION PROCESS……Page 178
5.3.1 DATA ANALYSIS METHOD 1……Page 182
5.3.2 DATA ANALYSIS METHOD 2……Page 183
5.4.1 RUBISCO……Page 185
5.4.2 SUBTILISIN……Page 187
5.4.3 APROTININ……Page 188
5.4.4 INSULIN……Page 189
5.5 THE FUTURE……Page 190
REFERENCES……Page 191
CONTENTS……Page 194
6.2 LINEAR AND NONLINEAR RETENTION IN CHROMATOGRAPHY……Page 195
6.3 AFFINITY CHROMATOGRAPHY……Page 198
6.3.2 DYE LIGAND CHROMATOGRAPHY……Page 199
6.3.4 BIOMIMETIC LIGANDS……Page 200
6.3.6 AFFINITY TAG LIGANDS……Page 201
6.4.1.2 Resins for Ion Exchange Chromatography……Page 203
6.4.1.3 Loading and Binding Capacity……Page 206
6.4.1.4 Buffers for Ion Exchange Chromatography……Page 209
6.4.1.5 Choice of Salts forWash and Elution……Page 210
6.4.1.7 Methodology for IEX Process Development……Page 211
6.4.2 HYDROPHOBIC INTERACTION CHROMATOGRAPHY……Page 213
6.4.2.1 Physicochemical Basis for HIC……Page 215
6.4.2.2 Resins for HIC……Page 216
6.4.2.3 Selection of Loading Conditions……Page 218
6.4.2.5 Selection of Elution Conditions……Page 220
6.4.2.6 Methodologies for Process Development……Page 221
6.4.3 REVERSED- PHASE CHROMATOGRAPHY……Page 223
6.4.4 HYDROXYAPATITE CHROMATOGRAPHY……Page 225
6.4.5 IMMOBILIZED METAL AFFINITY CHROMATOGRAPHY……Page 226
6.4.5.1 IMAC Resins and Metal Ions……Page 227
6.4.5.2 Buffers for IMAC……Page 230
6.4.5.4 Process Development on IMAC……Page 231
6.4.6.1 Thiophilic Interaction Chromatography……Page 232
6.4.6.3 Mixed Mode Ion Exchangers and Silica……Page 233
6.5 CONCLUSIONS……Page 234
REFERENCES……Page 235
7.1 INTRODUCTION……Page 241
7.2.1 SELECTION OF RESINS……Page 242
7.2.2 HIGH THROUGHPUT SCREENING TECHNIQUES……Page 245
7.2.3 OTHER POINTS TO CONSIDER WHILE SELECTING A RESIN……Page 249
7.3 CASE STUDY: DEVELOPMENT OF A CATION EXCHANGE PURIFICATION STEP FOR AN FC FUSION PROTEIN……Page 250
7.3.2 STEP 2 — BATCH CAPACITY MEASUREMENTS……Page 251
7.3.4 STEP 4 — PEAK SPLITTING SCREENING……Page 252
7.3.5 STEP 5 — SELECTIVITY FOR HIGH MOLECULAR WEIGHT AGGREGATE CLEARANCE……Page 254
7.3.6 STEP 6 — SELECTIVITY FOR LEACHED PROTEIN A AND HOST CELL PROTEIN REMOVAL……Page 255
REFERENCES……Page 257
CONTENTS……Page 259
8.2 QUANTITATIVE STRUCTURE– PROPERTY RELATIONSHIPS……Page 260
8.3.1 MOLECULAR DESCRIPTORS……Page 262
8.3.2 FEATURE SELECTION……Page 263
8.3.3 MODELING TECHNIQUES……Page 264
8.4.1 MOE DESCRIPTORS……Page 265
8.4.2 TAE/ RECON DESCRIPTORS……Page 266
8.5 SVM MODELING ALGORITHM……Page 267
8.6 MULTISCALE MODELING FOR THE PREDICTION OF COLUMN CHROMATOGRAPHIC PERFORMANCE FROM PROTEIN STRUCTURE DATA: A CASE STUDY……Page 270
8.6.1 STERIC MASS ACTION FORMALISM……Page 271
8.6.2 CHROMATOGRAPHIC TRANSPORT MODELS……Page 272
8.6.3 PROTEIN DATASET……Page 273
8.6.5 THE MULTISCALE MODEL……Page 274
8.6.6 SUMMARY OF CASE STUDY……Page 276
8.7 QSPR AS A BIOPROCESS DEVELOPMENT TOOL……Page 277
8.8.1 PHYSICALLY INTERPRETABLE DESCRIPTORS……Page 279
8.8.2 QSPR MODELS FROM PRIMARY SEQUENCE INFORMATION……Page 281
ACKNOWLEDGMENTS……Page 282
REFERENCES……Page 283
CONTENTS……Page 290
9.2 PRINCIPLES OF MEMBRANE CHROMATOGRAPHY……Page 291
9.2.1 ADSORPTION KINETICS……Page 292
9.2.3 MIXING IN THE FLOW SYSTEM……Page 294
9.3 EXPERIMENTAL DESIGN AND DATA ANALYSIS……Page 295
9.3.2 MIXING IN THE FLOW SYSTEM……Page 296
9.3.3 MASS TRANSFER……Page 297
9.3.4 ADSORPTION KINETICS AND THE BREAKTHROUGH CURVE……Page 298
9.3.5 SCALE-DOWN AND SCALE-UP……Page 300
9.4.1.1 Irreversible Adsorption Case……Page 301
9.4.1.2 Linear Adsorption Case……Page 302
9.4.2 USE OF THE MODEL FOR DESIGN……Page 304
9.4.3 COMPARISON TOTHE LITERATURE……Page 305
9.5 CONCLUSIONS……Page 307
REFERENCES……Page 308
CONTENTS……Page 310
10.1 ULTRAFILTRATION PROCESS REQUIREMENTS……Page 311
10.2 ULTRAFILTRATION TECHNOLOGY FUNDAMENTALS……Page 312
10.2.1 SURFACE POLARIZATION……Page 313
10.2.2 SIEVING AND RETENTION……Page 314
10.2.3 FLUX……Page 315
10.2.4 PROCESSING……Page 317
10.3.1 ULTRAFILTRATION MEMBRANES……Page 320
10.3.2 ULTRAFILTRATION MODULES……Page 322
10.4.1 OBJECTIVES AND METHODS……Page 323
10.4.2 DATA ANALYSIS……Page 325
10.5.1 SIZING……Page 329
10.5.2 OPERATING PROCEDURE……Page 334
10.5.3 SYSTEM CONSIDERATIONS……Page 335
10.6.1 EQUIPMENT SELECTION……Page 336
10.6.2 SKID LAYOUT……Page 339
10.7 ULTRAFILTRATION PROCESS VALIDATION AND COMMISSIONING……Page 340
10.8 TROUBLESHOOTING……Page 342
REFERENCES……Page 343
CONTENTS……Page 346
11.1 BACKGROUND……Page 347
11.2 VIRUS FILTER SELECTION……Page 348
11.3 PROCESS DESIGN AND OPTIMIZATION……Page 349
11.3.1 NORMAL FLOW OPERATION……Page 350
11.3.1.2 NFF Test Equipment and Protocol……Page 352
11.3.1.3.2 Impact ofF eed Concentration……Page 355
11.3.1.3.4 Impact ofPrefiltr ation……Page 358
11.3.2.1 TFF Virus Filters……Page 360
11.3.2.2 TFF Test Equipment and Protocol……Page 361
11.3.2.3 TFF Process Optimization……Page 363
11.3.2.3.2 Impact ofF eed Cross- Flow Rate and Permeate Flux……Page 364
11.4.1 NORMAL FLOW FILTRATION……Page 365
11.4.2 TANGENTIAL FLOW FILTRATION……Page 366
11.5 VIRUS VALIDATION STUDIES……Page 367
11.6.1 HARDWARE CONSIDERATIONS……Page 369
11.6.2.3 Measurement of NormalizedWater Permeability……Page 370
11.6.2.4.1 Steam- In- Place……Page 371
11.6.2.4.3 Hot Water Sanitization……Page 372
11.6.2.5 Pre- and Post- Use Integrity Testing……Page 373
11.6.2.5.2 Pre and Post- Use Integrity Testing……Page 374
11.6.2.5.4 Integrity Testing Multifilter Assemblies……Page 375
11.6.2.6 Protein Processing and Product Recovery……Page 376
REFERENCES……Page 377
12.1 INTRODUCTION……Page 379
12.2 INITIAL RECOVERY AND SEPARATION OF RECOMBINANT PROTEIN FROM TRANSGENIC LEAFY CROP……Page 384
12.2.1.1 Background and Practical Considerations……Page 385
12.2.1.2 Experiment Protocol for Developing an Optimized ATPE System for Protein Recovery from Transgenic Tobacco……Page 388
12.2.1.2.2 ATPE Experimentsand Determination of the Optimal Conditionsfor Lysozyme Recovery by DOE Methods……Page 390
12.2.2.1 Background and Practical Considerations……Page 393
12.2.2.2 Experimental Protocol for Lysozyme Precipitation by PAA from Tobacco Extract……Page 395
12.3 RECOMBINANT PROTEIN PURIFICATION FROM TRANSGENIC ANIMAL MILK……Page 396
12.4 CONCLUSIONS……Page 400
REFERENCES……Page 401
CONTENTS……Page 407
13.2 REGULATORY GUIDANCE……Page 408
13.3 OVERVIEW……Page 410
13.4 SETTING SPECIFICATIONS……Page 413
13.5 ANALYTICAL TESTING STRATEGIES……Page 414
13.6.1 POTENCY……Page 415
13.6.2 QUANTITY……Page 417
13.6.3 PRODUCT IDENTITY……Page 418
13.7.1 HOST CELL PROTEINS……Page 419
13.7.2 HOST CELL DNA……Page 422
13.8 PRODUCT- RELATED IMPURITIES……Page 423
13.9 MASS/ SIZE DISTRIBUTION……Page 424
13.10 CHARGE VARIANTS……Page 425
13.12 SAFETY TESTING……Page 426
13.14 BIOPHYSICAL ANALYSIS……Page 427
13.15 PROCESS ANALYTICAL TECHNOLOGIES……Page 428
REFERENCES……Page 429
CONTENTS……Page 431
14.1 INTRODUCTION……Page 432
14.2 HEALTH RISK FROM VIRUS CONTAMINATION……Page 433
14.3 RATIONALE AND ACTION PLAN FOR VIRAL CLEARANCE STUDIES……Page 434
14.4 CHOICE OF VIRUSES IN THE VIRAL CLEARANCE STUDIES……Page 435
14.5 SELECTION OF STEPS TO BE EVALUATED IN VIRAL CLEARANCE STUDIES……Page 438
14.6 SCALE DOWN OF MANUFACTURING PROCESS STEPS……Page 439
14.7 ESTIMATION OF VIRUS TITERS……Page 441
14.8 CYTOTOXICITY AND VIRAL INTERFERENCE TESTING……Page 442
14.9 DESIGN OF VIRUS- SPIKING STUDIES……Page 444
14.10 CALCULATION OF LOG REDUCTION FACTORS IN A VIRAL CLEARANCE STUDY……Page 445
14.11 ASSESSMENT OF THE SAFETY FACTOR IN THE FINAL DRUG PRODUCT……Page 446
14.12 QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY FOR VIRUS QUANTITATION……Page 447
14.13 IDENTIFICATION OFWORST- CASE SITUATIONS……Page 449
14.14 COLUMN SANITIZATION AND REUSE OF CHROMATOGRAPHY RESINS……Page 450
14.15 LIMITATIONS OF VIRAL CLEARANCE STUDIES……Page 451
14.17 BRACKETED GENERIC APPROACH TOVIRUS CLEARANCE STUDIES……Page 452
14.19 VIRUS CLEARANCE ACROSS MEMBRANE ADSORBERS……Page 454
APPENDIX: USE OF THE POISSON DISTRIBUTION TO DETERMINE VIRUS TITERS……Page 456
REFERENCES……Page 458
15.1 INTRODUCTION……Page 461
15.1.1 THE CRITICAL PATH INITIATIVE……Page 462
15.1.2 CRITICAL VS. NONCRITICAL OPERATING PARAMETERS……Page 463
15.1.4 STREAMLINED APPROACHES……Page 464
15.1.5 VIRUS SPIKE QUALITY……Page 465
15.2.1 FILTER CLASSES……Page 466
15.3.1 SOLVENT/ DETERGENT TREATMENT……Page 467
15.3.3 HEAT TREATMENT……Page 468
15.4.2 ION EXCHANGE CHROMATOGRAPHY……Page 469
15.4.3 MEDIA AGE……Page 470
15.6 NEWVIRUS DETECTION METHODS — Q- PCR……Page 471
REFERENCES……Page 472
CONTENTS……Page 475
16.2 MONOCLONAL ANTIBODIES AND FC- FUSION PROTEINS……Page 476
16.3 PURIFICATION OF MONOCLONAL ANTIBODIES AND FC- FUSION PROTEINS……Page 480
16.4 PROTEIN A AFFINITY CHROMATOGRAPHY……Page 481
16.4.1 Protein A Chromatographic Stationary Phases……Page 483
16.4.2.1 Binding Capacity and Process Throughput……Page 486
16.4.2.2 Elution Conditions……Page 490
16.4.2.3 Wash for Impurity Removal……Page 491
16.4.2.4 Protein A Leaching……Page 492
16.4.2.5 Resin Lifetime……Page 493
16.5 CONCLUSIONS……Page 494
REFERENCES……Page 496
17.1 INTRODUCTION……Page 502
17.2 ANION EXCHANGE CHROMATOGRAPHY……Page 503
17.3 CATION EXCHANGE CHROMATOGRAPHY……Page 504
17.4 HYDROPHOBIC INTERACTION CHROMATOGRAPHY……Page 506
17.5 CERAMIC HYDROXYAPATITE……Page 507
17.6 INTEGRATED PURIFICATION SCHEMES……Page 509
17.7 VIRUS INACTIVATION AND FILTRATION……Page 511
17.8 FUTURE TRENDS……Page 513
REFERENCES……Page 515
CONTENTS……Page 517
18.2 INFLIXIMAB STRUCTURE, FUNCTION, AND FORMULATION……Page 518
18.3 INFLIXIMAB MANUFACTURING PROCESS OVERVIEW……Page 519
18.4 PROCESS CHANGES AND PRODUCT COMPARABILITY DURING DEVELOPMENT……Page 521
18.5 PROCESS CHANGES AND PRODUCT COMPARABILITY FOR COMMERCIAL MANUFACTURING……Page 525
18.5.1 SCALE- UP AND POST-APPROVAL CHANGES……Page 527
18.6 REGULATORY STRATEGIES TO SUPPORT PROCESS CHANGES……Page 529
19.1 SUMMARY……Page 533
19.2 ULTRAFILTRATION OF POLYSACCHARIDE PROCESS STREAMS AND LINEAR SCALE- UP……Page 534
19.3 MATERIALS AND METHODS……Page 538
19.4 RESULTS AND DISCUSSION……Page 539
19.4.1 CONTRIBUTION TO PRESSURE DUE TO DIFFERENCES IN SYSTEM HARDWARE……Page 542
19.4.2 CONTRIBUTION TO PRESSURE DUE TO MEMBRANE CASSETTE CONSTRUCTION……Page 544
19.5 CONCLUSIONS……Page 547
ACKNOWLEDGMENTS……Page 548
REFERENCES……Page 549
CONTENTS……Page 550
20.1.1 ADENOVIRAL VECTORS……Page 551
20.1.4 PLASMID DNA……Page 552
20.2.1 PURIFICATION OF AD VECTORS……Page 553
20.2.3 PURIFICATION OF LENTIVIRAL VECTORS……Page 555
20.2.4 PURIFICATION OF LENTIVIRAL VECTORS……Page 556
20.3 MEMBRANE- BASED CHROMATOGRAPHY APPROACHES……Page 558
20.4 AD CAPTURE BY ANION EXCHANGE MEMBRANE CHROMATOGRAPHY……Page 559
20.6 LENTIVIRAL VECTOR CAPTURE BY ANION EXCHANGE MEMBRANE CHROMATOGRAPHY……Page 564
20.7.1 VIRAL VECTOR CAPTURE……Page 565
20.7.2 DYNAMIC BINDING CAPACITY……Page 566
20.9 CONCLUSIONS……Page 567
ABBREVIATIONS……Page 568
REFERENCES……Page 569
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