Biopharmaceutical production technology
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| adam_text | IMAGE 1
CONTENTS
PREFACE X X I I I
LIST O F CONTRIBUTORS XXV
VOLUME 1
PART O N E UPSTREAM TECHNOLOGIES 1
1 STRATEGIES FOR PLASMID DNA PRODUCTION IN ESCHERICHIA COLI 3
EVA BRAND, KATHRIN RALLA, AND PETER NEUBAUER 1.1 I N T R O D U C T I O N
3
1.2 R E Q U I R E M E N T S FOR A P L A S M I D D N A P R O D U C T I O
N PROCESS 4
1.3 STRUCTURE O F A D N A VACCINE P R O D U C T I O N PROCESS 6
1.4 CHOICE O F A N T I G E N 7
1.5 VECTOR D N A C O N S T R U C T 8
1.5.1 P O P U L A R AMPLIFICATION SYSTEMS 8
1.5.2 INTRINSIC FACTORS 9
1.6 H O S T STRAINS 11
1.6.1 ENDA A N D RECA 12
1.6.2 RELA 12
1.6.3 NUCLEOSIDE PATHWAY 14
1.6.4 GYRA 15
1.6.5 STRAINS FOR P R O D U C T I O N PROCESSES 15
1.7 CULTIVATION M E D I U M A N D PROCESS C O N D I T I O N S 16
1.8 LYSIS/EXTRACTION O F P L A S M I D D N A 19
1.9 PURIFICATION 2 0
1.9.1 CLARIFICATION O F T H E LYSATE A N D I N T E R M E D I A T E
PURIFICATION 21
1.9.2 PURIFICATION B Y C H R O M A T O G R A P H Y 23
1.9.2.1 ANION-EXCHANGE C H R O M A T O G R A P H Y 23 1.9.2.2 H Y D R O
P H O B I C INTERACTION C H R O M A T O G R A P H Y 24
1.9.2.3 GEL FILTRATION 2 4
1.9.2.4 M E M B R A N E C H R O M A T O G R A P H Y 2 4
1.9.2.5 C H R O M A T O G R A P H Y O N P O R O U S MONOLITHIC SUPPORTS
2 5
HTTP://D-NB.INFO/1017775001
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VI | CONTENTS
1.10 F O R M U L A T I O N 2 6
1.10.1 LIPOPLEXES 2 7
1.10.2 POLYPLEXES 2 7
1.10.3 INORGANIC NANOPARTICLES 28
1.11 CONCLUSIONS 2 8
REFERENCES 28
2 ADVANCES IN PROTEIN PRODUCTION TECHNOLOGIES 43
LINDA H.L. LUA AND YAP PANG CHUAN 2.1 I N T R O D U C T I O N 43
2.2 GLYCOENGINEERING FOR H O M O G E N O U S H U M A N - L I K E
GLYCOPROTEINS 4 5
2.3 BACTERIA AS PROTEIN FACTORIES 4 7
2.4 M A M M A L I A N CELL TECHNOLOGY 5 0
2.5 YEAST P R O T E I N P R O D U C T I O N 5 3
2.6 BACULOVIRUS-INSECT CELL TECHNOLOGY 5 5
2.7 T R A N S G E N I C A N I M A L PROTEIN P R O D U C T I O N 5 7
2.8 PLANT MOLECULAR F A R M I N G 5 9
2.9 CELL-FREE PROTEIN P R O D U C T I O N 6 2
2.10 F U T U R E PROSPECTS 6 5
REFERENCES 66
PART TWO PROTEIN RECOVERY 79
3 RELEASING BIOPHARMACEUTICAL PRODUCTS FROM CELLS 81
ANTON P.J. MIDDELBERG 3.1 I N T R O D U C T I O N 81
3.2 CELL STRUCTURE A N D STRATEGIES FOR D I S R U P T I O N 83
3.3 CELL MECHANICAL S T R E N G T H 8 5
3.4 H O M O G E N I Z A T I O N 89
3.4.1 M E C H A N I S M S 90
3.4.2 MODELING 91
3.5 BEAD MILLING 95
3.5.1 MODELING 96
3.6 C H E M I C A L T R E A T M E N T 9 8
3.7 CELLULAR DEBRIS 100
3.7.1 MODELING 102
3.8 CONCLUSIONS 103
REFERENCES 104
4 CONTINUOUS CHROMATOGRAPHY (MULTICOLUMN COUNTERCURRENT SOLVENT GRADIENT
PURIFICATION) FOR PROTEIN PURIFICATION 107 CUIDO STROHLEIN, THOMAS
MULLER-SPATH, AND LARS A U M A N N 4.1 I N T R O D U C T I O N 107
4.1.1 OVERVIEW O F T H E BIOPHARMACEUTICAL M A R K E T 107
4.1.2 OVERVIEW O F PURIFICATION O F BIOPHARMACEUTICALS 108 4.1.3 I N T R
O D U C T I O N TO C O N T I N U O U S C H R O M A T O G R A P H I C
PROCESSES 108
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CONTENTS | VII
4.2 OVERVIEW O F C O N T I N U O U S C H R O M A T O G R A P H I C
PROCESSES 110
4.2.1 SMB A N D ITS DERIVATIVES 110
4.2.1.1 APPLICATIONS O F SMB I N T H E PHARMACEUTICAL INDUSTRY: SMALL
MOLECULES 111 4.2.1.2 LIMITATIONS O F SMB 112
4.2.2 M C S G P GOES BEYOND SMB A N D MAKES C O N T I N U O U S C H R O
M A T O G R A P H Y POSSIBLE FOR BIOSEPARATIONS 112
4.3 PRINCIPLES O F M C S G P 113
4.3.1 TASKS I N BATCH C H R O M A T O G R A M 113
4.3.1.1 G E N E R I C PURIFICATION P R O B L E M 114 4.3.2 SIX-COLUMN M
C S G P PRINCIPLE 115
4.3.3 T H R E E - C O L U M N M C S G P PRINCIPLE 115
4.3.4 F O U R - C O L U M N M C S G P W I T H SEPARATE C I P POSITION
116
4.3.5 F O U R - C O L U M N M C S G P W I T H A SEPARATE POSITION FOR C
O N T I N U O U S
F E E D 118
4.3.6 M C S G P PROCESS FOR SEPARATIONS W I T H M O R E T H A N T H R E
E FRACTIONS 119
4.4 APPLICATION EXAMPLES O F M C S G P 120
4.4.1 POLYPEPTIDE PURIFICATION W I T H REVERSED-PHASE C H R O M A T O G
R A P H Y 120 4.4.2 M A B C H A R G E VARIANT SEPARATION 125
4.4.3 M A B C A P T U R E A N D POLISH F R O M S U P E R N A T A N T 127
4.4.4 SIZE-EXCLUSION C H R O M A T O G R A P H I C PURIFICATION W I T H
M C S G P 129 4.5 ENABLING FEATURES A N D E C O N O M I C I M P A C T O
F M C S G P 134
4.6 A N N E X 1: C H R O M A T O G R A P H I C PROCESS DECISION T R E E
135
REFERENCES 136
5 VIRUS-LIKE PARTICLE BIOPROCESSING 139
YAP PANG CHUAN, LINDA H.L. LUA, AND ANTON P.J. MIDDELBERG 5.1 I N T R O
D U C T I O N 139
5.2 U P S T R E A M PROCESSING 143
5.2.1 INTRACELLULAR EXPRESSION A N D A S S E M B L Y 143
5.2.2 CELL-FREE APPROACHES 147
5.3 D O W N S T R E A M PROCESSING 147
5.3.1 GARDASIL D O W N S T R E A M PROCESSING 148
5.3.2 VLP AGGREGATION 149
5.3.3 PURIFICATION O F CELL-ASSEMBLED VLPS 150
5.3.4 PURIFICATION FOR IN VITRO A S S E M B L Y 152
5.4 ANALYSIS 154
5.5 C O N C L U S I O N S 157
5.6 N O M E N C L A T U R E 158
A C K N O W L E D G M E N T S 158 REFERENCES 158
6 THERAPEUTIC PROTEIN STABILITY A N D FORMULATION 165
ROBERT FALCONAR
6.1 I N T R O D U C T I O N 165
6.2 PROTEIN STABILITY 167 -
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VIII | CONTENTS
6.2.1 STRUCTURAL STABILITY 167
6.2.2 T H E R M A L STABILITY 168
6.2.3 CHAOTROPES, SOLVENTS, A N D P H 168
6.2.4 SHEAR 169
6.2.5 FREEZING 169
6.2.6 DRYING 170
6.2.7 AIR-LIQUID A N D SOLID-LIQUID INTERFACES 170
6.2.8 CHEMICAL STABILITY 171
6.2.9 PRECIPITATION, AGGREGATION, A N D FIBRIL F O R M A T I O N 173
6.2.10 LEACHABLES 174
6.3 F O R M U L A T I O N A N D MATERIALS 175
6.3.1 LIQUID F O R M U L A T I O N S 175
6.3.2 P H 176
6.3.3 A M I N O ACIDS A N D O T H E R O R G A N I C BUFFERS 177
6.3.4 SUGARS A N D POLYOLS 177
6.3.5 SALTS 177
6.3.6 SURFACTANTS 178
6.3.7 SPECIFIC B I N D I N G 178
6.3.8 CHELATING AGENTS 178
6.3.9 REDOX POTENTIAL 179
6.3.10 CONTAINERS A N D CLOSURES 179
6.3.11 F R O Z E N F O R M U L A T I O N S 179
6.3.12 FREEZE-DRIED F O R M U L A T I O N S 180
6.4 SCREENING M E T H O D S 185
6.4.1 DSC 185
6.4.2 T H E R M A L S C A N N I N G W I T H SPECTROSCOPIC DETECTION O F
PROTEIN U N F O L D I N G 187
6.5 ACCELERATED A N D LONG-TERM STABILITY T E S T I N G 188
6.5.1 REGULATORY PERSPECTIVE 188
6.5.2 ACCELERATED STABILITY T E S T I N G 189
6.6 ANALYTICAL T E C H N I Q U E S FOR STABILITY T E S T I N G 189
6.6.1 CELL-BASED BIOASSAYS A N D I N VITRO BINDING ASSAYS 190
6.6.2 H I G H - P E R F O R M A N C E LIQUID C H R O M A T O G R A P H Y
A N D CAPILLARY Z O N E ELECTROPHORESIS 191 6.6.3 M A S S
SPECTROMETRY-BASED ANALYSIS 192
6.6.4 DETECTION O F PROTEIN AGGREGATES 192
6.6.5 C R U D E ANALYTICAL ASSAYS: PAGE, IEF, BLOTTING, FTIR, CD, A N D
U V FLUORESCENCE 193 6.7 CONCLUSIONS 194
REFERENCES 195
7 PRODUCTION O F PECYLATED PROTEINS 199
CONAN J. FEE AND VINOD B. DAMODARAN 7.1 INTRODUCTION 199
7.2 G E N E R A L CONSIDERATIONS 2 0 0
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CONTENTS
7.2.1 EFFICIENCY O F PEG C O N J U G A T I O N 2 0 0
7.2.2 CONTROL O F POSITIONAL I S O M E R I S M 201
7 . 2 3 CONTROL O F T H E N U M B E R O F PEG ADDUCTS 2 0 2
1 .2.4 PURIFICATION O F T A R G E T PRODUCTS 203
7.3 PEGYLATION C H E M I S T R Y 204
7.3.1 A M I N E C O N J U G A T I O N 204
7.3.2 THIOL C O N J U G A T I O N 206
7.3.3 OXIDIZED CARBOHYDRATE O R N-TERMINAL C O N J U G A T I O N 208
7.3.4 T R A N S G L U T A M I N A S E - M E D I A T E D ENZYMATIC C O N
J U G A T I O N 208 7.3.5 MISCELLANEOUS C O N J U G A T I O N C H E M I
S T R I E S 209
7.3.6 REVERSIBLE PEGYLATION 2 0 9
7.4 PEGYLATED PROTEIN PURIFICATION 2 1 0
7.4.1 REMOVAL O F LOW-MOLECULAR-WEIGHT C O N T A M I N A N T S 2 1 0
7.4.2 REMOVAL O F FREE PEG 2 1 2
7.4.3 SEPARATION O F PEGYLATED A N D NATIVE PROTEIN F O R M S 213
7.4.4 SEPARATION O F PEGYLATED SPECIES 215
7.5 CONCLUSIONS 217
REFERENCES 218
PART THREE ADVANCES IN PROCESS DEVELOPMENT 223
8 AFFINITY CHROMATOGRAPHY: HISTORICAL A N D PROSPECTIVE OVERVIEW 225
LAURA ROWE, GRAZIELLA EL KHOUIY, AND CHRISTOPHER R. LOWE 8.1 HISTORY A N
D ROLE O F AFFINITY C H R O M A T O G R A P H Y I N T H E SEPARATION
SCIENCES 2 2 5
8.1.1 I N T R O D U C T I O N 2 2 5
8.1.2 EARLY HISTORY 226
8.1.3 BIOLOGICAL LIGANDS 226
8.1.4 SYNTHETIC A N D D E S I G N E D LIGANDS 228
8.1.5 ALTERNATIVE LIGANDS 229
8.1.6 ROLE O F AFFINITY C H R O M A T O G R A P H Y I N T H E SEPARATION
SCIENCES 2 2 9
8.2 OVERVIEW O F AFFINITY CHROMATOGRAPHY: T H E O R Y A N D M E T H O D
S 2 3 0
8.2.1 BASIC C H R O M A T O G R A P H I C THEORY 230
8.2.2 MATRIX SELECTION A N D I M M O B I L I Z A T I O N O F A N
AFFINITY LIGAND 2 3 2
8.2.3 O T H E R CONSIDERATIONS 2 3 7
8.3 AFFINITY LIGANDS 239
8.3.1 BIOLOGICAL LIGANDS 239
8.3.1.1 I M M U N O A F F I N I T Y A D S O R B E N T S 239 8.3.1.2
BACTERIAL PROTEINS 242
8.3.1.3 LECTINS 246
8.3.1.4 H E P A R I N 247
8.3.1.5 G L U T A T H I O N E 248
8.3.1.6 AVIDIN A N D STREPTAVIDIN 248
8.3.1.7 V I T A M I N S A N D H O R M O N E S 249
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X CONTENTS
8.3.1.8 NUCLEIC ACIDS 249
8.3.1.9 ALTERNATIVE AFFINITY M E T H O D S 250 8.3.2 SYNTHETIC A N D D E
S I G N E D LIGANDS 251
8.3.2.1 I M M O B I L I Z E D METALS 252
8.3.2.2 H Y D R O P H O B I C LIGANDS 253
8.3.2.3 THIOPHILIC LIGANDS 253
8.3.2.4 H I S T I D I N E 2 5 4
8.3.2.5 MIXED-MODE ADSORBENTS 255 8.3.2.6 BORONATE 256
8.3.2.7 BENZHYDROXAMIC ACID 256 8.3.2.8 DYE LIGANDS 2 5 7
8.3.2.9 BIOMIMETICS 2 5 8
8.4 AFFINITY LIGANDS I N PRACTICE: BIOPHARMACEUTICAL P R O D U C T I O N
269
8.5 CONCLUSIONS A N D F U T U R E PERSPECTIVES 271
REFERENCES 272
9 HYDROXYAPATITE IN BIOPROCESSING 283
FRANK HILBRIG AND RUTH FREITAG 9.1 INTRODUCTION 283
9.2 MATERIALS A N D INTERACTION M E C H A N I S M S 285
9.2.1 APATITES FOR C H R O M A T O G R A P H Y 285
9.2.2 S T R U C T U R E - F U N C T I O N RELATIONSHIP 289
9.2.3 RETENTION M E C H A N I S M S I N APATITE C H R O M A T O G R A P
H Y 2 9 4
9.3 SETTING U P A SEPARATION 301
9.3.1 G E N E R A L CONSIDERATIONS 301
9.3.2 ELUTION M O D E 3 0 5
9.3.3 D I S P L A C E M E N T M O D E 3 0 9
9.4 SEPARATION EXAMPLES 313
9.4.1 PROTEINS I N G E N E R A L 313
9.4.2 ANTIBODIES 313
9.4.3 POLYNUCLEOTIDES 3 2 2
9.4.4 O T H E R S 323
9.5 C O N C L U S I O N S 323
REFERENCES 3 2 4
10 MONOLITHS IN BIOPROCESSING 333
ALES PODGORNIK, MILOS BARUT, MATJAZ PETERKA, AND ALEI STRANCAR
10.1 I N T R O D U C T I O N 3 3 3
10.2 PROPERTIES O F C H R O M A T O G R A P H I C M O N O L I T H S 3 3
3
10.3 MONOLITHIC ANALYTICAL C O L U M N S FOR PROCESS ANALYTICAL
TECHNOLOGY APPLICATIONS 3 3 8
10.3.1 U P S T R E A M APPLICATIONS 3 3 9
10.3.2 D O W N S T R E A M APPLICATIONS 3 4 0
10.3.2.1 H P L C ANALYSIS O F IGG PROTEINS 3 4 0 10.3.2.2 H P L C
ANALYSIS O F T H E IGM S A M P L E S 341_
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CONTENTS XI
10.3.2.3 H P L C ANION-EXCHANGE ANALYSIS O F T H E PEGYLATED PROTEINS 3
4 2
10.3.2.4 VIRUSES 344
10.4 MONOLITHS FOR PREPARATIVE C H R O M A T O G R A P H Y 348
10.4.1 PROTEIN PURIFICATION 349
10.4.2 PURIFICATION O F VIRUSES 351
10.4.3 P L A S M I D D N A PURIFICATION 354
10.4.4 NEGATIVE C H R O M A T O G R A P H Y 357
10.5 E N Z Y M E REACTORS 3 5 8
10.5.1 P R O T E O M E ANALYSIS 3 5 8
10.5.2 BIOSENSORS 3 6 0
10.5.3 BIOCONVERSION O F T A R G E T MOLECULES 3 6 0 10.5.4 STUDY O F
ENZYME-INTRINSIC PROPERTIES 3 6 2
10.6 CONCLUSIONS 364
REFERENCES 3 6 4
11 M E M B R A N E CHROMATOGRAPHY FOR BIOPHARMACEUTICAL MANUFACTURING 3
7 7 O M A R M. WAHAB 11.1 M E M B R A N E A D S O R B E R S - I N T R O
D U C T I O N A N D TECHNICAL
SPECIFICATIONS 3 7 7 11.1.1 I N T R O D U C T I O N 3 7 7
11.1.2 M E M B R A N E A D S O R B E R CONSTRUCTION 3 8 0
11.1.3 TYPES O F AVAILABLE LIGANDS 3 8 2
11.1.4 U S E A N D SCALING-UP W I T H M E M B R A N E ADSORBERS 384
11.2 C O M P A R I N G RESINS A N D M E M B R A N E ADSORBERS 3 8 7
11.2.1 FLOW-THROUGH POLISHING APPLICATIONS 3 8 9 11.2.2 BIND-AND-ELUTE
APPLICATIONS 3 9 0 11.2.3 ECONOMICAL MODELING A N D C A S E STUDIES 391
11.3 M E M B R A N E C H R O M A T O G R A P H Y APPLICATIONS A N D CASE
STUDIES 3 9 3
11.3.1 VALIDATION O F M E M B R A N E S INTO A PURIFICATION PROCESS 3 9
3 11.3.2 VIRUS PURIFICATION A N D VACCINE M A N U F A C T U R E 3 9 5
11.3.3 VIRUS REMOVAL 3 9 6
11.3.4 ENDOTOXIN REMOVAL 3 9 9
11.3.5 H C P REMOVAL 4 0 2
11.3.6 D N A REMOVAL 4 0 4
11.3.7 AGGREGATE REDUCTION 4 0 4
11.4 CONCLUSIONS 406
REFERENCES 4 0 7
12 MODELING A N D EXPERIMENTAL MODEL PARAMETER DETERMINATION WITH
QUALITY BY DESIGN FOR BIOPROCESSES 409 CHRISTOPH HELLING AND JOCHEN
STRUBE 12.1 I N T R O D U C T I O N 4 0 9
12.2 Q B D F U N D A M E N T A L S 4 1 0
12.3 PROCESS MODELING A N D EXPERIMENTAL MODEL P A R A M E T E R D E T E
R M I N A T I O N 411
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XII J CONTENTS
12.3.1 M O D E L I N G 413
12.3.2 EXPERIMENTAL MODEL P A R A M E T E R D E T E R M I N A T I O N 4
1 4 12.3.2.1 I S O T H E R M P A R A M E T E R S 414 12.3.2.2 FLUID
DYNAMICS 416 12.3.2.3 M A S S T R A N S F E R KINETICS 417
12.4 PROCESS ROBUSTNESS STUDY 4 2 5
12.4.1 MODEL ERROR 425
12.4.2 MODEL P A R A M E T E R D E T E R M I N A T I O N ERROR 426
12.4.3 VARIATION O F PROCESS CONDITIONS 431
12.5 CONCLUSIONS 439
12.6 N O M E N C L A T U R E 4 4 0
A C K N O W L E D G M E N T S 441 REFERENCES 4 4 2
VOLUME 2
PART FOUR ANALYTICAL TECHNOLOGIES 445
13 BIOSENSORS IN T H E PROCESSING A N D ANALYSIS O F
BIOPHARMACEUTICALS 4 4 7 SRIRAM KUMARASWAMY 13.1 I N T R O D U C T I O N
447
13.2 PRINCIPLES A N D C O M M E R C I A L APPLICATIONS O F BIOSENSORS
448
13.2.1 LABELED V E R S U S LABEL-FREE BIOSENSORS 4 4 9 13.2.2 LABEL-FREE
BIOSENSORS 451
13.2.2.1 LABEL-FREE BIOSENSORS I N C O M M E R C I A L U S E 451
13.2.2.2 I N T R O D U C T I O N TO BLI 453
13.2.2.3 I N T R O D U C T I O N TO SPR 453
13.2.2.4 I N T R O D U C T I O N TO R W G 455 13.2.3 S A M P L E H A N D
L I N G CONSIDERATIONS 4 5 5
13.2.3.1 S A M P L E H A N D L I N G BY BLI 456 13.2.3.2 S A M P L E H A
N D L I N G BY S P R 456 13.2.3.3 S A M P L E H A N D L I N G BY R W G
458 13.2.4 C O M P A R I S O N O F BIOSENSOR C H I P S 458
13.2.4.1 OCTET D I P A N D READ BIOSENSORS 459
13.2.4.2 BIACORE C H I P S 4 5 9
13.2.4.3 EPIC MICROPLATES 4 6 2 13.2.5 C O M P A R I S O N O F T H R O U
G H P U T 4 6 2
13.3 U S E O F BIOSENSORS I N BIOPHARMACEUTICAL P R O D U C T I O N A N
D
PROCESSING 4 6 4
13.3.1 QUANTIFICATION O F THERAPEUTICS A N D O T H E R M I N O R I M P U
R I T I E S 464 13.3.2 PURIFICATION O N C H R O M A T O G R A P H Y C O
L U M N S I N D O W N S T R E A M P R O C E S S D E V E L O P M E N T 4
6 5
13.3.3 KINETIC ANALYSIS FOR CHARACTERIZATION O F BIOPHARMACEUTICALS 466
IMAGE 9
13.3.4
13.4
VACCINE D E S I G N A N D EFFICACY 468 CONCLUSIONS 4 6 9
REFERENCES 4 7 0
CONTENTS XIII
14 PROTEOMICS TOOLKIT: APPLICATIONS IN PROTEIN BIOLOGICAL PRODUCTION A N
D
METHOD DEVELOPMENT 473 G/EMVYN KEMP AND ACHIM TREUMANN 14.1 I N T R O D
U C T I O N 473
14.1.1 P R O B L E M O F AVAILABILITY 4 7 4
14.1.2 W H A T IS PROTEOMICS? 4 7 4
14.2 APPLICATIONS O F PROTEOMICS 475
14.2.1 PROTEIN IDENTIFICATION A N D CHARACTERIZATION 475 14.2.2 PROTEIN
MODIFICATIONS 4 7 6
14.2.3 PROTEIN INTERACTIONS 4 7 6
14.2.4 P R O T E I N Q U A N T I T A T I O N 4 7 7
14.3 MYTHS A N D M I S C O N C E P T I O N S - P E R C E I V E D
DRAWBACKS O F PROTEOMICS 4 7 7 14.3.1 H I G H SET-UP COST 4 7 7
14.3.2 T I M E - C O N S U M I N G / L O W T H R O U G H P U T 478
14.3.3 EXPERTISE A N D T R A I N I N G 4 7 8
14.3.4 REPRODUCIBILITY 4 7 9
14.4 CRITICAL FACTORS FOR INDUSTRIALIZATION O F PROTEOMICS 4 8 0
14.4.1 QUALITY CONTROL 4 8 0
14.4.2 R O B U S T N E S S A N D RELIABILITY 4 8 1
14.5 C A S E STUDIES 481
14.5.1 T W O - D I M E N S I O N A L PAGE 481 14.5.2 M A S S
SPECTROMETRY AS A PROCESS D E V E L O P M E N T TOOL 4 8 2 14.5.2.1
MATRIX-ASSISTED LASER D E S O R P T I O N IONIZATION BIOTYPING 483
14.5.3 QUANTITATIVE PROTEOMICS 4 8 4
14.5.3.1 STABLE ISOTOPE LABELING 4 8 4 14.5.3.2 ISOBARIC LABELING 485
14.6 C O N C L U S I O N S 4 8 6
REFERENCES 4 8 7
15 SCIENCE O F PROTEOMICS: HISTORICAL PERSPECTIVES A N D POSSIBLE ROLE
IN H U M A N HEALTHCARE 4 8 9
NAWIN MISHRA
15.1 SCIENCE O F OMICS 4 8 9
15.2 M A J O R ADVANCES I N BIOLOGY T H A T LED T O T H E SCIENCES O F
OMICS 489
15.3 M E N D E L S PRINCIPLES O F I N H E R I T A N C E 4 9 0
15.4 O N E G E N E / O N E E N Z Y M E C O N C E P T O F BEADLE A N D T
A T U M 4 9 0
15.5 W A T S O N - C R I C K STRUCTURE O F D N A 4 9 0
15.6 D E V E L O P M E N T O F DIFFERENT TECHNOLOGIES RESPONSIBLE FOR T
H E E M E R G E N C E O F G E N O M I C S A N D PROTEOMICS 491 15.6.1
GENOMICS-SPECIFIC TECHNOLOGIES 491
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XIV | CONTENTS
15.6.2 PROTEIN SEPARATION, PROTEIN SEQUENCING, A N D T H E I R T H R O U
G H P U T
TECHNOLOGIES 4 9 2
15.7 G E N O M I C S 4 9 2
15.8 PROTEOMICS 493
15.8.1 START O F PROTEOMICS 4 9 6
15.8.2 D E V E L O P M E N T O F PROTEOMICS 498
15.8.2.1 TWO-DIMENSIONAL GEL ELECTROPHORESIS 498 15.8.2.2 MASS
SPECTROMETRY 4 9 9 15.8.2.3 X-RAY CRYSTALLOGRAPHY A N D NUCLEAR MAGNETIC
R E S O N A N C E SPECTROSCOPY 501
15.8.3 PROTEOMICS AS A BASIS FOR DIFFERENTIATION 501
15.9 INTERACTOMICS: COMPLEXITY O F A N O R G A N I S M BASED O N T H E
INTERACTIONS O F
PROTEINS 501
15.10 RELATION B E T W E E N DISEASES, G E N E S , A N D PROTEINS: D I S
E A S O M E CONCEPT 503
15.11 PROTEINS AS BIOMARKERS O F H U M A N DISEASES 503
15.11.1 MODIFICATION O F PROTEINS 503 15.12 METABOLOMICS 505
15.13 PROTEOMICS A N D D R U G DISCOVERY 506
15.14 C U R R E N T A N D F U T U R E BENEFITS O F PROTEOMICS I N
H U M A N HEALTHCARE 5 0 6
15.14.1 U N D E R S T A N D I N G COMPLEX DISEASES A N D POSSIBILITY O F
PERSONALIZED MEDICINE 506
15.14.2 BETTER D R U G S FOR H U M A N DISEASES 5 0 7
15.14.3 IDENTIFICATION O F PROTEIN BIOMARKERS 5 0 7 15.14.4 D R U G D E
V E L O P M E N T 5 0 7
15.14.5 DISCOVERY O F N E W PROTEINS AS D R U G S 5 0 7
15.14.6 PROTEINS LINKED TO BRAIN DISEASES 5 0 8
REFERENCES 5 0 8
PART FIVE QUALITY CONTROL 511
16 CONSISTENCY O F SCALE-UP FROM BIOPROCESS DEVELOPMENT T O
PRODUCTION 513
STEFAN JUNNE, ARNE KLINGNER, DIRK ITZECK, EVA BRAND, A N D PETER
NEUBAUER 16.1 I N H O M O G E N E I T I E S I N INDUSTRIAL FED-BATCH
PROCESSES 513
16.2 EFFECTS O F CONDITIONS I N INDUSTRIAL-SCALE FED-BATCH PROCESSES O N
T H E
M A I N C A R B O N METABOLISM 515 16.3 EFFECTS O F CONDITIONS I N
INDUSTRIAL-SCALE FED-BATCH PROCESSES O N A M I N O ACID SYNTHESIS 518
16.4 SCALE-DOWN REACTORS FOR IMITATING LARGE-SCALE FED-BATCH PROCESS
CONDITIONS A T T H E LABORATORY SCALE 5 2 0 16.5 I M P R O V E D T W O -
C O M P A R T M E N T REACTOR SYSTEM TO I M I T A T E LARGE-SCALE
CONDITIONS A T T H E LABORATORY SCALE 523
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CONTENTS
16.6 DESCRIPTION O F T H E H Y D R O D Y N A M I C CONDITIONS I N T H E
P F R P A R T O F T H E
P R E S E N T E D T W O - C O M P A R T M E N T REACTOR 526 16.7
DESCRIPTION O F OXYGEN T R A N S F E R I N T H E PFR P A R T O F T H E
T W O - C O M P A R T M E N T REACTOR 5 2 9 16.8 E. COLI FED-BATCH
CULTIVATIONS I N T H E T W O - C O M P A R T M E N T REACTOR SYSTEM 531
16.9 F U T U R E PERSPECTIVES FOR T H E APPLICATION O F A T W O - C O M
P A R T M E N T REACTOR 5 3 7
REFERENCES 538
17 SYSTEMATIC APPROACH T O OPTIMIZATION A N D COMPARABILITY O F
BIOPHARMACEUTICAL CLYCOSYLATION T H R O U G H O U T T H E DRUG LIFE
CYCLE 545 DARYL L. FERNANDES 17.1 COSTS O F INCONSISTENT, U N O P T I M
I Z E D D R U G GLYCOSYLATION 545
17.2 S C H E M E 1: TRADITIONAL A P P R O A C H TO COMPARABILITY O F D R
U G GLYCOSYLATION 5 47
17.2.1 I N C O M P A R A B L E GLYCOSYLATION D U R I N G SCALE-UP O F
MYOZYME 548 17.2.2 W H Y I N C O M P A R A B L E GLYCOSYLATION OCCURS W
I T H TRADITIONAL D R U G SCALE-UP 549
17.3 S C H E M E 2: COMPARABILITY O F D R U G GLYCOSYLATION U S I N G Q
B D DS 551
17.3.1 Q B D A P P R O A C H TO GLYCOSYLATION I N T H E A-MAB CASE STUDY
5 5 2 17.4 S C H E M E 3: E N H A N C E D Q B D A P P R O A C H TO
COMPARABILITY O F D R U G
GLYCOSYLATION 554 17.4.1 INFORMATICS TOOLS FOR E N H A N C I N G Q B D
FOR GLYCOPROTEIN D R U G S 554 17.4.2 CASE FOR A POPULATION MODEL FOR
COMPARABILITY O F GLYCOPROTEIN T H E R A P E U T I C S 5 5 5
17.4.3 D O M A I N ONTOLOGY MODEL FOR D R U G REALIZATION 5 5 7 17.4.4
ONTOLOGY M A P 5 5 7
17.4.5 ELEMENTS VIEW O F T H E ONTOLOGY M A P 5 6 0
17.4.6 BUILDING A P O P U L A T I O N COMPARABILITY MODEL F O R D R U G
GLYCOSYLATION 561 17.4.6.1 SE BOARD 5 6 2
17.4.6.2 STEP 1: CATEGORIZE T H E BIOLOGICAL BEHAVIORS O F T H E D R U G
I N T E R M S O F SAFETY A N D EFFICACY 563 17.4.6.3 STEP 2: D E T E R M
I N E A N D PRIORITIZE T H E GLYCOSYLATION CRITICAL QUALITY ATTRIBUTES
563
17.4.6.4 STEP 3: DEVELOP A T U N E D GLYCOPROFILING S Y S T E M TO M E A
S U R E T H E
G C Q A S 571
17.4.6.5 STEP 4: DESCRIBING A N D O P T I M I Z I N G T H E
GLYCOSYLATION Q T P P B Y GLYCOFORM ACTIVITY MODELING 573 17.4.6.6 U S I
N G GLYCAN ACTIVITY MODELING I N GLYCOSYLATION O P T I M I Z A T I O N A
N D COMPARABILITY STUDIES 5 7 7 17.5 CONCLUSIONS 5 8 0
A C K N O W L E D G M E N T S 581 REFERENCES 581
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XVI CONTENTS
18 QUALITY A N D RISK M A N A G E M E N T IN ENSURING T H E VIRUS SAFETY
O F
BIOPHARMACEUTICALS 5 8 5 ANDY BAILEY 18.1 I N T R O D U C T I O N 5 8 5
18.2 Q R M A N D VIRUS SAFETY 5 8 6
18.2.1 P R O D U C T COMPLEXITY A N D RISK 5 8 7
18.3 PILLARS O F SAFETY 5 9 0
18.3.1 S O U R C I N G - D E F I N I N G T H E BASELINE RISK 5 9 0
18.3.1.1 E P I D E M I O L O G Y - A POWERFUL TOOL FOR R E D U C I N G
RISK FOR H U M A N - A N D ANIMAL-DERIVED C O M P O N E N T S 5 9 2
18.3.1.2 ADDITIONAL M E A S U R E S FOR CONTROLLING ANIMAL-DERIVED
MATERIALS 5 9 6 18.3.2 T E S T I N G - R E D U C I N G F U R T H E R T H
E BASELINE RISK 5 9 6
18.3.2.1 IN VITRO A N D I N VIVO ADVENTITIOUS A G E N T T E S T S - A D
V A N T A G E S A N D DISADVANTAGES 5 9 7 18.3.2.2 INFECTIVITY TESTS FOR
E N D O G E N O U S RETROVIRUSES 5 9 7
18.3.2.3 ELECTRON MICROSCOPY TESTS F O R RETROVIRUSES 5 9 8 18.3.2.4
REVERSE TRANSCRIPTASE ASSAYS 5 9 8 18.3.2.5 P C R T E S T I N G - A D V
A N T A G E S A N D DISADVANTAGES 5 9 9
18.3.3 S O U R C I N G A N D T E S T I N G - I S I T E N O U G H ? 5 9 9
18.3.4 P A T H O G E N C L E A R A N C E - C O N T R O L L I N G T H E
RESIDUAL RISK 6 0 0 18.3.5 CONTROLLING SUPPLIERS O F MEDIA A N D O T H E
R ACTIVE P H A R M A C E U T I C A L
INGREDIENTS 601
18.4 C O M M I T T E E FOR PROPRIETARY MEDICINAL PRODUCTS GUIDELINES FOR
INVESTIGATIONAL MEDICINAL P R O D U C T S - R I S K M A N A G E M E N T
I N PRACTICE 602 18.4.1 U S I N G G E N E R I C DATA TO R E D U C E
VIRUS SAFETY T E S T I N G 603
18.4.2 EXPERIENCE WITH WELL-CHARACTERIZED CELL LINES 603 18.4.3 REDUCING
VIRUS VALIDATION R E Q U I R E M E N T S FOR I M P S 6 0 4 18.4.4
PLATFORM PURIFICATION PROCESSES 605
18.5 DEVELOPING A R O B U S T RISK M I N I M I Z A T I O N S T R A T E G
Y - W H A T IS T H E CORRECT PARADIGM? 6 0 7
REFERENCES 609
19 ENSURING QUALITY A N D EFFICIENCY O F BIOPROCESSES BY T H E
TAILORED APPLICATION O F PROCESS ANALYTICAL TECHNOLOGY A N D QUALITY BY
DESIGN 613 HELMUT TRAUTMANN 19.1 I N T R O D U C T I O N 613
19.2 PAT A N D Q B D I N B I O P R O C E S S I N G - E N G I N E E R I N
G MEETS BIOLOGY 614
19.2.1 PAT A N D Q B D 614
19.2.2 E N G I N E E R I N G MEETS BIOLOGY 616
19.3 ASPECTS O F BIOLOGICAL D E M A N D S - S E L E C T E D EXAMPLES 617
19.3.1 BASIC PATTERNS O F N U T R I E N T METABOLISM: GLUCOSE A N D G L
U T A M I N E A S C O M P L E M E N T A R Y MAJOR C A R B O N A N D
ENERGY SOURCES 618
19.3.1.1 GLUCOSE UTILIZATION 619 19.3.1.2 G L U T A M I N E M E T A B O
L I S M 625 19.3.1.3 GLUCOSE A N D G L U T A M I N E CONCENTRATIONS I N
BATCH C U L T U R E S 625
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CONTENTS XVII
19.3.2 EFFECT O F CULTURE STATES O N GLYCOSYLATION 626
19.3.2.1 DISSOLVED OXYGEN PARTIAL P R E S S U R E A N D P H 6 2 7
19.3.2.2 CONCENTRATIONS O F N U T R I E N T S 629 19.3.2.3
CONCENTRATIONS O F METABOLIC BYPRODUCTS: LACTATE A N D A M M O N I A 629
19.3.2.4 S U P P L E M E N T I N G SUITABLE P R E C U R S O R S 632
19.3.2.5 EFFECTS O N SECRETED GLYCOPROTEINS I N T H E M E D I U M 632
19.3.3 CELL-CELL A D H E S I O N A N D AGGREGATION: INFLUENCE O N T H E
G R O W T H
BEHAVIOR O F C H O CELLS 632
19.3.3.1 CONCLUSIONS 637 19.4 TECHNICAL A N D E N G I N E E R I N G
SOLUTIONS 6 3 8
19.4.1 PAT A N D Q B D C O M P L I A N T PROCESS U N D E R S T A N D I N
G A N D PROCESS CONTROL: F R O M DATA TO I N F O R M A T I O N A N D
KNOWLEDGE, A N D ITS T R A N S F E R F R O M BIOPROCESS D E V E L O P M
E N T TO M A N U F A C T U R I N G 639
19.4.1.1 ACQUISITION O F P R I M A R Y DATA 640 19.4.1.2 G A I N I N G /
D E R I V I N G I N F O R M A T I O N F R O M DATA 644 19.4.1.3 PROCESS
U N D E R S T A N D I N G BASED O N KNOWLEDGE 646 19.4.1.4 D E M O N S T
R A T I O N O F PROCESS U N D E R S T A N D I N G A N D PROOF-OF-CONCEPT
647
19.4.1.5 PROCESS CONTROL 648 19.4.2 CHALLENGE O F S P E E D A N D
QUALITY I N BIOPROCESS D E V E L O P M E N T 649 19.5 CONCLUSIONS 653
A C K N O W L E D G M E N T S 653 REFERENCES 654
PART SIX PROCESS DESIGN A N D M A N A G E M E N T 6 5 7
2 0 BIOPROCESS DESIGN A N D PRODUCTION TECHNOLOGY FOR T H E FUTURE 659
JOCHEN STRUBE, FLORIAN CROTE, AND REINHARD DITZ 20.1 I N T R O D U C T I
O N 659
20.2 ANALYSIS O F B I O M A N U F A C T U R I N G TECHNOLOGIES 662
20.2.1 PROCESS CONCEPTS I N B I O M A N U F A C T U R I N G 663 20.2.2
TOTAL PROCESS ANALYSIS 666
20.2.2.1 M A B S 6 6 7
20.2.3 BATCH TO C O N T I N U O U S M A N U F A C T U R I N G 672
20.2.3.1 DISCUSSION 6 7 7
20.3 AAC: A N Y T H I N G A N D C H R O M A T O G R A P H Y 679
20.3.1 EXPANDED-BED C H R O M A T O G R A P H Y 679
20.3.2 M E M B R A N E C H R O M A T O G R A P H Y 681 20.3.3
LIQUID-LIQUID EXTRACTION 682
20.3.4 CRYSTALLIZATION/PRECIPITATION 684 20.4 PROCESS INTEGRATION 685
20.5 PROCESS D E S I G N A N D Q B D 689
20.6 PACKAGE U N I T E N G I N E E R I N G A N D STANDARDIZATION 691
20.7 D O W N S T R E A M O F D O W N S T R E A M PROCESSING 694
20.7.1 H U M A N I N S U L I N 695 - -
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XVIII | CONTENTS
20.7.2 ANTIBIOTICS (PENICILLIN) 696
20.8 CONCLUSIONS 699
A C K N O W L E D G M E N T S 699 REFERENCES 700
21 INTEGRATED PROCESS DESIGN: CHARACTERIZATION O F PROCESS A N D PRODUCT
DEFINITION O F DESIGN SPACES 707 RICHARD FRANCIS 21.1 INTRODUCTORY
PRINCIPLES 707
21.2 ORIGINAL PROCESS D E V E L O P M E N T P A R A D I G M 707
21.3 T H E ESSENTIAL Q B D CONCEPTS 710
21.4 C O N C L U S I O N 715
REFERENCES 715
22 EVALUATING A N D VISUALIZING T H E COST-EFFECTIVENESS A N D
ROBUSTNESS O F
BIOPHARMACEUTICAL MANUFACTURING STRATEGIES 717 SUZANNE S. FARID
22.1 I N T R O D U C T I O N 717
22.2 SCOPE O F RESEARCH O N DECISION-SUPPORT TOOLS FOR T H E BIOTECH
SECTOR 71 9
22.2.1 CHALLENGES 720
22.2.2 TYPICAL STAGES O F ANALYSIS A N D A P P R O A C H E S 722 22.3 C
A P T U R I N G PROCESS R O B U S T N E S S U N D E R UNCERTAINTY 723
22.3.1 FED-BATCH V E R S U S P E R F U S I O N C U L T U R E STRATEGIES
723 22.3.2 ROBUSTNESS O F LEGACY PURIFICATION FACILITIES TO H I G H E R
TITER PROCESSES 725
22.4 RECONCILING MULTIPLE CONFLICTING O U T P U T S U N D E R
UNCERTAINTY 7 2 8
22.4.1 STAINLESS STEEL VERSUS SINGLE-USE FACILITIES FOR CLINICAL TRIALS
728 22.5 SEARCHING LARGE DECISION SPACES EFFICIENTLY 731
22.5.1 PORTFOLIO M A N A G E M E N T : PORTFOLIO SELECTION A N D
CAPACITY SOURCING 731 22.5.2 C H R O M A T O G R A P H Y SIZING O P T I
M I Z A T I O N FOR F U T U R E FACILITIES 735 22.6 INTEGRATING
STOCHASTIC S I M U L A T I O N W I T H MULTIVARIATE ANALYSIS 736 22.6.1
PREDICTING SHORT-TERM FACILITY FIT U P O N T E C H T R A N S F E R TO
LARGER
FACILITIES 7 3 7
22.7 CONCLUSIONS 7 3 7
A C K N O W L E D G M E N T S 739
REFERENCES 740
PART SEVEN CHANGING FACE O F PROCESSING 743
23 FULL PLASTICS: C O N S E Q U E N T EVOLUTION IN PHARMACEUTICAL
BIOMANUFACTURING FROM VIAL T O W A R E H O U S E 745 ROLAND WAGNER AND
DETHARDT MULLER 23.1 INCREASED D E M A N D , REDUCED V O L U M E S , A N
D M A X I M U M
FLEXIBILITY-DRIVING FORCE TO PLASTIC DEVICES 745
IMAGE 15
CONTENTS
23.2 P L A S T I C - T H E FLEXIBLE ALL-ROUND REPLACER: F R O M MATERIAL
T O
F U N C T I O N 7 4 7
23.3 POLLUTION W I T H PLASTICS: LEACHABLES A N D EXTRACTABLES 753
23.4 PLASTICS FOR STORAGE: VIAL A N D BAG 755
23.4.1 VIAL 755
23.4.2 BAG 755
23.5 PLASTICS FOR CULTIVATION: FLASK, TUBE, A N D U N S T I R R E D A N
D STIRRED
BIOREACTOR 7 5 7
23.5.1 FLASKS 7 5 7
23.5.2 T U B E S 7 5 7
23.5.3 BIOREACTORS 7 5 7
23.6 PLASTICS FOR PURIFICATION: C O L U M N A N D M E M B R A N E 760
23.6.1 C O L U M N 760
23.6.2 M E M B R A N E 761
23.7 CASE STUDY: COMPARABILITY O F PLASTIC BAG-BASED BIOREACTORS I N
CULTIVATION PROCESSES 761 23.8 CONCLUSIONS A N D PROSPECTS 763
REFERENCES 765
24 BIOSMB* TECHNOLOGY: C O N T I N U O U S COUNTERCURRENT CHROMATOGRAPHY
ENABLING A FULLY DISPOSABLE PROCESS 769 MARC BISSCHOPS 24.1 I N T R O D
U C T I O N 769
24.1.1 EVOLUTION O F C O N T I N U O U S C O U N T E R C U R R E N T C H
R O M A T O G R A P H Y 769 24.1.2 C O N T I N U O U S C H R O M A T O G
R A P H Y SYSTEMS 773 24.1.3 INDUSTRIAL APPLICATIONS O F C O N T I N U O
U S C H R O M A T O G R A P H Y 774 24.1.3.1 FRACTIONATION C H R O M A T
O G R A P H Y 774 24.1.3.2 C O N T I N U O U S ION-EXCHANGE C H R O M A
T O G R A P H Y 775 24.2 C O N T I N U O U S C H R O M A T O G R A P H Y
I N BIOPHARMACEUTICAL I N D U S T R I E S 776
24.2.1 I N D U S T R Y DRIVERS 776
24.2.2 POTENTIAL APPLICATION AREAS 778
24.2.3 KEY CHALLENGES 779
24.2.4 BIOSMB* TECHNOLOGY 780
24.2.4.1 DISPOSABLE F O R M A T 780 24.2.4.2 PREPACKED C O L U M N S 780
24.2.4.3 ALTERNATIVE C H R O M A T O G R A P H Y F O R M A T S 781 24.3
PROCESS D E S I G N PRINCIPLES 781
24.3.1 PROCESS DESIGN F U N D A M E N T A L S 781
24.3.1.1 T H E R M O D Y N A M I C E Q U I L I B R I U M 781 24.3.1.2
MASS T R A N S F E R KINETICS 782 24.3.1.3 O T H E R P H E N O M E N A
783 24.3.1.4 P E R F O R M A N C E PREDICTION 783 24.3.2 PROCESS D E S I
G N FEATURES 783
24.3.2.1 FRACTIONATION C H R O M A T O G R A P H Y 784
24.3.2.2 C A P T U R E C H R O M A T O G R A P H Y 785
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XX I CONTENTS
24.4 CASE STUDIES 786
24.4.1 PROTEIN A C H R O M A T O G R A P H Y 786
24.4.2 AGGREGATE REMOVAL U S I N G H Y D R O P H O B I C INTERACTION C H
R O M A T O G R A P H Y 7 8 7 24.4.3 VACCINE PURIFICATION U S I N G
SIZE-EXCLUSION C H R O M A T O G R A P H Y 7 8 8
24.5 CONCLUSIONS 789
REFERENCES 790
25 SINGLE-USE TECHNOLOGY: OPPORTUNITIES IN BIOPHARMACEUTICAL PROCESSES
793
MAIK W. JORNITZ, DETLEV SZARAFINSKI, AND THORSTEN PEUKER 25.1 C U R R E
N T SINGLE-USE TECHNOLOGIES 793
25.1.1 LIQUID H O L D BAGS 7 9 4
25.1.2 MIXING 795
25.1.3 P R O D U C T A N D C O M P O N E N T T R A N S F E R 7 9 7
25.1.4 PURIFICATION 7 9 8
25.1.5 FILTRATION 8 0 0
25.1.6 STERILE C O N N E C T I O N S 801
25.1.7 FILLING 8 0 2
25.2 F U T U R E SINGLE-USE OPERATIONS 8 0 2
25.2.1 U P S T R E A M O P P O R T U N I T I E S 8 0 3
25.2.2 D O W N S T R E A M O P P O R T U N I T I E S 804
25.2.3 SINGLE-USE PROCESS E N G I N E E R I N G 804
25.3 A U T O M A T I O N R E Q U I R E M E N T S I N SINGLE-USE M A N U
F A C T U R I N G 8 0 6
25.3.1 DATA ACQUISITION 8 0 8
25.3.2 M O N I T O R I N G A N D CONTROL 8 0 8
25.3.3 FACILITY-WIDE A U T O M A T I O N STRUCTURE 8 0 8 25.4
QUALIFICATION A N D VALIDATION EXPECTATIONS 8 0 9
25.4.1 E Q U I P M E N T QUALIFICATION 8 0 9
25.4.2 PROCESS VALIDATION 811
25.5 O P E R A T O R T R A I N I N G 8 1 5
REFERENCES 815
2 6 SINGLE-USE BIOTECHNOLOGIES A N D MODULAR MANUFACTURING ENVIRONMENTS
INVITE PARADIGM SHIFTS IN BIOPROCESS DEVELOPMENT A N D
BIOPHARMACEUTICAL MANUFACTURING 817 ALFRED LUITJENS, JOHN LEWIS, AND
ALAIN PROLONG 26.1 I N T R O D U C T I O N 8 1 7
26.2 P A R A D I G M SHIFT A T CRUCELL 819
26.2.1 I N T R O D U C T I O N TO CRUCELL 819
26.2.2 EVOLUTION O F SINGLE-USE BIOTECHNOLOGY 821 26.2.2.1 P H A S E I:
SINGLE-USE TECHNOLOGY D E V E L O P M E N T - S U C C E S S W I T H
SMALL-SCALE PLASTIC CELL C U L T U R E U N I T S 821
26.2.2.2 P H A S E II: SINGLE-USE BIOTECHNOLOGIES D E V E L O P M E N T
- S C A L E - U P ,
CAPSULES, A N D C O U P L I N G 8 2 4
IMAGE 17
CONTENTS
26.2.2.3 P H A S E III: SINGLE-USE BIOTECHNOLOGIES D E V E L O P M E N T
- I N D U S T R I A L I Z A T I O N
A N D SIMPLIFICATION 829 26.2.2.4 CRUCELL M A N U F A C T U R I N G O F
M A B S W I T H T H E P E R . C 6 CELL LINE: A COMPLETELY SINGLE-USE
FED-BATCH PROCESS 835 26.2.2.5 MISSING E L E M E N T S A N D OUTLOOK 839
26.2.3 ADAPTATION O F FACILITY LAYOUT TO SINGLE-USE TECHNOLOGY 8 4 2
26.2.4 PROCESS D E V E L O P M E N T VALUE S T R E A M 849 26.2.5 A S S
E S S M E N T O F T H E CRUCELL P A R A D I G M SHIFT 854
26.3 CONCLUSIONS A N D G E N E R A L OUTLOOK 856
REFERENCES 857
INDEX 859
|
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| illustrated | Not Illustrated |
| indexdate | 2025-02-03T17:28:01Z |
| institution | BVB |
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| language | English |
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| spellingShingle | Biopharmaceutical production technology Biotechnologie (DE-588)4069491-4 gnd Pharmazeutische Technologie (DE-588)4045699-7 gnd |
| subject_GND | (DE-588)4069491-4 (DE-588)4045699-7 |
| title | Biopharmaceutical production technology |
| title_auth | Biopharmaceutical production technology |
| title_exact_search | Biopharmaceutical production technology |
| title_full | Biopharmaceutical production technology ed. by Ganapathy Subramanian |
| title_fullStr | Biopharmaceutical production technology ed. by Ganapathy Subramanian |
| title_full_unstemmed | Biopharmaceutical production technology ed. by Ganapathy Subramanian |
| title_short | Biopharmaceutical production technology |
| title_sort | biopharmaceutical production technology |
| topic | Biotechnologie (DE-588)4069491-4 gnd Pharmazeutische Technologie (DE-588)4045699-7 gnd |
| topic_facet | Biotechnologie Pharmazeutische Technologie |
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