Index

Page numbers appearing in italics refer to tables and page numbers appearing in bold refer to figures.

Acceptability limits 596 Action levels 596 Adsorbent preparation 70-7 Affinity adsorption 70-87

adsorbent preparation 70-7 affinity ligands 73

antibodies 73 antigen 73 Protein A 73 Protein G 73

azlactone 76 cyano-transfer agents 74 cyanogen bromide activation 74 glutaraldehyde 76 N-hydroxy succinimide 76

adsorbent stability 77 CNBr-activated Sepharose 79 cyclic 3',5' -adenosine monophosphate 78 denaturation 77 E-DNP-lysine 78 equilibrium constant 80 Freundlich isotherm 81-2 immobilizes antibodies 79 Langmuir isotherm 80 leakage 77 matrix degradation 77 proteolysis 77 Sips isotherm 81

agarose 71, 72 bead structure 84 cellulose 71 electrophoretic-based transport 85 elution

immunoadsorbents 86 metal chela tors 85 recombinant proteins 86 standard molar heat of reaction 86 thermal and pressure 85-6 thermally stable structural motifs 86 Van't Hoff equation 86

hydroxyethyl methacrylate 71, 72 irreversible 84 ligand distribution 84

in porous media 84 membranes 86

non-specific 72 operation 82-7

dilute feed streams 85 elution 85-6

chaotropic salts 85 denaturants 85 organic solvents 85

fixed beds 82 stirred tank 82 transport properties 82

polyacrylamide 71, 72 silica 71, 72 support materials 70-3

controlled pore glass 72 polyviny1chloride 73 regenerated cellulose 73

Agitators 357-416 and fermenters 357-71

aseptic equipment 358 axial flow turbine 359 bioreactors 357 blend time 364 circulation times 403 dispersion volume 406 Escherichia coli 358 fluid dynamics 402 fluid momentum 359 fractional gas holdup 406 frequency controllers 380 gas dispersion 359, 366

intimate 366 minimum 366 retention time 368 uniform 366

gas hold-up and flooding 381-3 antifoam agents 381 bubble diameter 383 gas retention 381 surface tension 381

gas-liquid dispersions 364-8 physical dispersion 365-8

'geysering' 365 horsepower 365

solidity 364 genetic engineering 358

706 HANDBOOK OF DOWNSTREAM PROCESSING

heat transfer 358, 388-97 area 389 coefficient 389 conduction 388 convection 388

forced 388 fluid properties 391 fouling characteristics 389 geometrical properties 390--1 helical coils 392 jacket surface 392 kinematic viscosity 396 Nusselt number 390 Prandtl number 390 propeller use 388 Reynolds number 390 specific gravity of fluids 389 specific heat 389, 390 tank dimensions 389 temperature difference driving force

389 thermal conductivity 390 vertical plate or panel coil 394-7 vertical tubes 393

hydraulic motors 380 hydrofoils 359, 364, 372

solidity ratios 372 impeller

-type mixers 358, 360 power consumption 358 pumping capacity 358 velocity 358

diameter 360 K factor 378 rotation speed 360 tip speed 363, 364

laminar flow 362 shear rate

average 362 macroscale 362 maximum 362 Reynolds number 362

laser velocity measurement 409 low viscosity 372 mammalian cell 358, 371 mass transfer 358, 359, 369

coefficient 369 Henry's law 369

microcarrier 357 microscale mixing 363 mycelial fermentation 359 oxygen transfer rate 359 penicillin 358 pneumatically agitated 397 -407

airlift 398 airlifts 397 applications 398 bubble columns 397

friction factor 400 kinetic energy 400 monoseptic 398 Newton-Raphson iteration 401 Pachuca tank 399 potential energy 400 slip velocity 400 terminal velocity 400

primary pumping capacity 363 pseudoplastic fermentation 404 residence time 406 root mean square velocity gradient 409 shear rate 357 shear stress 357 solka floc (SF) cellulose fibers 406 sparging devices 384-8

sparge plate 385, 387 sparge ring 384

tank shape 380 superficial gas velocity 380

torque 361 velocity gradients 363 viscosity 359 yeasts 358

Air pollution 653, 654-5 Air and stream stripping 698-701 Airborne particle counts 544-5 Airflow parallelism 547-9 Albumin 158 Alert levels 596 American Society of Heating, Air Conditioning

and Refrigeration Engineers (ASHRAE) 532 American Society for Testing and Materials

(ASTM) 532 Amicon Corporation 94 Angiotensin 158 Application software 596 Arrhenius constant 265, 272 Aseptic processing 241 ASH RAE 532 ASHRAE standards 592 Autoclaving 278-9

,II-galactosidase production 661-8 Bacillus stearothermophilus 266, 268, 269,

270, 272, 273, 293 Bacillus subtilis 266, 269, 293 Bead mills 1,5-10,11,13,14,17,17 Biocontainment 611-12 Biological safety cabinets 514, 532, 593 Biological water treatment 688-95 Biopharmaceuticals

plant design 623, 627, 628-9, 646-7 safety 655-6

Bioproducts, non-living 251 Biosafety 18 Biosafety levels 1-4, 517-19 Biotechnology 127 - 35

batch concentration 129 diafiltration 129, 130

fouling 131 fractionation 131 protein purity 130 retention 130 yield 129

enzymes 132 shear sensitivity 132

membrane reactors 131-2 bioconversions 132 bioreactors 131

nanofiltration 135 antibiotic purification 135

process micro filtration 133 cassettes 134 clarification 133 cross-flow 133 dead-end flow 133 lysed cel1s 134 plate and frame devices 134 shear rate 134-5 solids recovery 133

protein fractionation 127 sterile filtration 132

Pseudomonas diminuta 133 Biotechnology of electrodialysis 157-61 Biotechnology facility 601-21

biocontainment, biosafety levels 611 biocontainment 611-12 construction 620 coordination 613

maintenance access 613 cost of 619 design 613-19

architectural layout 614 HVAC system 614

air pressure differential 615 noise level 615

utility systems 615-16 deionized water 616 USP purified water 616 WFI water 616

example of 617-19 fermentation facility 617-19

FDA regulations 620 instrumentation and control 619 passivation 610 process design 604- 10

bioreactors 606 cell culture 605 high purity tubing systems 607 -8, 609 piping system design 608-9

deionized water 609 sampling point 609 water for injection 609

project management 601-3 GMP 603

INDEX

sampling points 603 sterilization requirements 610-11

clean-in-place 610 validation 621

707

Bipolar membranes 153-5, 154, 155, 159, 160 Bisoxiranes 75 Building interiors 626 Bulk fluid velocity 413 Bulk manufacturing 626, 627 Bulk pharmaceuticals 340-3

plant design 623, 645-6 safety 655 steam 648-9

1, 3-butanediol diglycidyl ether 75

Calibration 595, 596 Carbon-bed adsorption 254, 257-9 1, l-carbonyldiimidazole 76 Cartridge filtration 39, 42 Ceramic monoliths 118, 123 Certification 530-1, 554-6, 596

contractor 551-4 Change control 596 Chemical decontamination 654 Chemical sterilization 241, 302-5 Chromatography 167-84

GMP purification 167 large-scale 167-84

bioburden level 168 construction materials 176 contamination 176

DNA evaluation 167 equipment selection 177-9 facility requirements 179 fraction col1cction 171 gradient elution 171 production documentation 182 protein purification 167 resin lot constituency 170 sanitization agents 168 scale-up 172-6

depyrogenation 175 documentation 172 Food and Drug Administration 172 isocratic elution 175 process 173, 174, 175 regeneration 175

system design 180-1 system qualifications 181

installation 181 operational 181 process 181

Clean room 509 Clean room testing 530-56

airborne particle counts 544-5 at rest 545 laminar flow equipment 544 operational 545

708 HANDBOOK OF DOWNSTREAM PROCESSING

static 545 upper confidence limit (UCL) 544

airflow parallelism 547-9 dispersion of particulate 547

certification 530-1, 554-6 as-built 530 at-rest 531 heating, ventilation and air conditioning

(HVAC) 530 static 530

certification contractor 551-4 bid documents 553

certification tests ceiling assembly shroud test 538-9 HEPA filters 535

polystyrene latex spheres 535 silica dust 535

HEPA leak testing 534-40 aerosol challenges 534

DOP 534 DOS 534

overall efficiency test 539-40 scan test 538

HEPA filters 538 installed filter 538 isokinetic probe 536, 538

scanning instruments 536-8 particle counters 536, 539 photometers 536, 537, 539 sample dilution device 537, 539

HEPA filter pressure drop 547 manometer 547

induction leak test 549 light level tests 551

photometer 551 noise level testing 550-1

airborne sound pressure levels 550 octave band analysis 551

room differential pressure 543-4 room recovery 549 standards 531-2

American Society for Testing and Materials (ASTM) 532

ASH RAE 532 biological safety cabinets 532 Federal Standard 531-2

airborne cleanliness 531 Good Manufacturing Practices 532 Institute of Environmental Sciences (IBS)

531, 532 National Environmental Balancing

Bureau 532, 533 National Sanitation Foundation 532 Scientific Apparatus Makers Association

(SAMA) 532 total air flow 542-3

air balancing standards 542 balometer 542

sensing grid 543 turbulent flow 542

velocity and uniformity 540-2 'K' factor 541-2 test instruments 540-1

electromanometer 541 hot wire anemometer 540 incline manometer 541, 543 rotating vane anemometer 540

vibration testing 551 equipment 551

Clean steam generation 484-5 Clean-in-place 318-34

cleaning process 331-2 control system 332-4

electronic sequencers 332 microprocessors 332 PC-based controllers 332 PLCs 332

disinfection 319 key pieces 324 monitoring 333-4

chemical composition 333 flow rate 333 pressure 333 return temperature 333 rinse conductivity 334 supply temperature 333

procedures 320 sterilization 319 systems 327-31

re-use 327, 328-9 single-use 327, 329 solution recovery 327, 329-31

using detergents 318 biodegradable 319 containing alkalis 319 surfactants 319

Clostrium botulinum 266, 269 Clostrium sporogens 293 CNBr-activated Sepharose 79 Code of Federal Regulations 570 Column sizing, distillation 449-52 Commercial extractors 57 -65 Computer systems 596 Computer-aided protein recovery 658-60 Concentration polarization 116-18

cross-flow 116, 117 fouling 117 lysed cells 117 mass transfer 116

Concurrent process validation 595 Consolutes 59 Continuous sterilization 279-92 Control parameters 597 Controls and automation 335-56

bulk pharmaceuticals 340-43 process controls 338-40, 339, 342-3

process equipment 337, 340 process operations 337 -8, 341

Controls hardware and software 343-56 data-highway 354

token-passing bus 355 token-passing ring 355-6

dedicated control (DC) 352-3, 353 direct digital control (DDC) 351-2 engineering workstation 348-9 historical trend unit 351 keyboard 345 memory 345-6 monitor 345 operating system 346-7 operator station 344, 345, 347-8 periphery 346 programmable logic controller (PLC) 352 programming 349, 350

Craig extractor 59 Critical parameter 597 Cross-flow filtration 109, 110 Crystal-size distribution 197 Crystallization 412 l-cyano-4-(dimethyl) pyridinium

tetrafluoroborate (CTEA) 74 Cyclic 3' 5' -adenosine mono phosphate 78

Dairy industry 107-8 diafiltration 108 polarization 107 reverse osmosis 107 spiral wound modules 108 ultrafiltration 107 whey 107

Damkiihler number 287 Data-highway 354 De Danske Sukkerfabriker 120 Debye-Huckel theory 187 Dedicated control (DC) 352-3, 353 Degradation of media 264-5 Depth filters 295-7, 298 Design criteria, distillation 443-52 Diafiltration 129, 130 Differential extractors 60-2

Liquid-liquid extraction 61 Dioctyl phthalate (DOP) 534 Dioctyl sebecate (DOS) 534 Direct digital control (DDC) 351-2 Direct type dryers 240 Disks 9 Displacement washing 25-6 Distillation 417-52, 464-6

design criteria 443-52 packing 448-9

column sizing 449-52 random 448 structured 448-9

thermodynamic equilibria 443

INDEX

tray types 446-7 baffle 447 bubble cap 447 dual-flow 447 sieve 446-7 valve 447

methods 426-42 azeotropic 428-32

heterogeneous 429 homogeneous 429

batch 436-8 extractive 428, 432-3 molecular 438-40 pressure swing 433 short path 440 simple 426-8

709

stripping section 428 supercritical fluid extraction 440-2

molecular interactions 417-18 phase equilibria 418-19

ideal gas 419 negative deviation 420 positive deviation 420

intermolecular forces 422-6 chameleonic 424 dipoles 422 dispersion forces 422 interactions

Bronstead acid-base 423 Debye 422 electron donor-acceptor 423 hydrogen bonding 423 Keesom 422 Lewis acid-base 423

London forces 422 miscibility 424

local composition model 425 Divinylbenzene crosslink 142 DNA evaluation 167 Documentation 597 Donnan exclusion 143 DOP test 592 DOff-Oliver 94, 120 Dryers

agitated-pan 242 anabiosis 236 band 240, 242 batch 240 batch mode 236 for bioproducts 236

changes in 237 capillary transport 238 conduction 237 convection 237 critical moisture content 238 crystallization 240

dispersion 240 cyclone 242

710 HANDBOOK OF DOWNSTREAM PROCESSING

dielectric heating 237 direct type 240

continuous-tray 240 fluid-bed 240 tray 240

drum 240, 242, 246 evaporation/condensation 238 and explosion/fire 235 fermentation broths 236 flash 242, 245-6, 246

for penicillin 245 for tetracycline 245

fluid-bed 242, 243, 246-8, 247 freeze 242, 243, 250-2 for granular solids 240 as granulators 235 indirect type 240

vacuum contact 240 liquid diffusion 238 mixer 244, 245, 248 and moisture content 236 Nutsch filter-dryers 240, 243, 244

Krauss-Maffei 244 ovens 242 and oxidative damage 235 paddle 248-9, 249 for paste-like solids 240 plate 244, 245 radiation 237 removal of solvent vapor 254

biofiltration 254 carbon-bed adsorption 254, 257-9 condensation 254-7 incineration 254

sorption isotherm 239 spin-flash 240 spray 240, 242,252-3,253 spray dryers 236 thermal sensitivity 236 for thermolabile products 235 thermostability 236 turbo-shelf 242

vacuum band 249-50, 250 vacuum-tumbler 242, 243, 248 vapor diffusion 238 vibrated beds 242 xerostability 236

Drying 235-59 Dynamometer 414

E-DNP-Iysine 78 Economics of protein recovery 667-80 ED stacks 147-9 Electrodialysis 140-65,466

biotechnology applications 157-61 Albumin 158 amino acid recovery 158 Angiotensin 158

cellulose 159 desalting

arginine 159 histidine 159 lysine 159 soy sauce 159

fermentation 158 interferon 158 lysine recovery 158 organic acids 159-61

citric acid 159 lactic 161 succinic 161

Polypeptide 158 protein desalting 158 reverse osmosis 158 semipermeable membrane 158 Vasopressin 158

bipolar membranes 153-5, 154, 155,159,160 ion-exchange 153

cation-exchange membrane 142 co-ion concentration 143 design of equipment 162

limiting current density (LCD) 162, 165 polarization 162

divinylbenzene crosslink 142 Donnan exclusion 143 ED stacks 147-9

anion-exchange membrane 148 applications of 150-3

citrus juices 151, 152 dairy processing 150 desalination 150 food processing 150 metal finishing 151 Ni-electroplating bath 152

cation-exchange membrane 148 gasket-spacers 147 sheet -flow type 148 tortuous-path 148, 149 Vexar 148

equipment manufacturers 165 ion-exchange membranes 141-7 membrane fouling 155-7

c1eaning-in-place 156, 157 electrodialysis reversal (EDR) 155, 157 problems 156

membrane properties 145-6 membrane types 143-5

anion-exchange functionality 144 heterogeneous 143 homogeneous 143 ion-exchange 144

paste method 144 polystyrene chain 142 special membranes 146-7

Nafion 146 univalent cation-selective membranes 147

water transport 146 Electrodialysis reversal (EDR) 155, 157 Engineering workstation 348-9 Environmental factors 597 Equipment for lyophilization 210-17 Equipment and piping systems 634-45

reactors 634-6 Escherichia coli 266, 269, 358, 661 Eukaryotes 251 Extended aeration 691-2

Facility design 509-29 biological hazards 517-21

laboratory design 517-19 biosafety levels 1-4, 517-19

National Institute of Health 517 biosafety cabinet 514 bubble diagrams 511 building codes 515 clean room 509 firewalls 516 high efficiency particulate air filtration

(HEPA) 520, 521 room classifications 511, 521-2 room finishes 522-6

airtight separation 526-8 interlocking doors 527-8 service chases 528 vision panels 528 wall and ceiling closures 528

ceilings 525 HEPA filters 525

flush vision panel frames 522 seamless vinyl floor 523 trowelled epoxy floor 522 walls 524-5

epoxy paint 524 space containment 514 space separation 514 sterile corridor 515-16

FDA 172 FDA inspections 565-6 FDA regulations 620 FDA regulations for validation 594 Federal Food, Drug and Cosmetic Act 557 Federal Standard 531-2 Federal Standard 209E 591 Feedwaters 458-62 Fermentation media 272, 663-5 Fick's law 53 Filter aids 29-30 Filter bacterial removal 46 Filter ratings 44-5 Filter sterilization procedures 46 Filtration 20-47, 115-16

batch-pressure filters 20 cake resistance 115 centrifugation 20

INDEX

compressible cake 115 continuous-pressure filters 20 decantation 20 drying technology 30 effect of pressure 26-8

filtrate 26 porous support 26 pressure filter 26 suspension 26

filter aids 29-30 precoating 29

filter area 23 filter design 21

cake resistance 21, 22 gra vi ty filters 20

711

hydrophilic and hydrophobic filters 45 - 7 performance 24-6

cake-squeezing 24 cake-washing 24

displacement washing 25-6 Nutsche filters 25, 32-6, 33

reslurry washing 25 pressing 20 pressure filters 20, 21 reverse osmosis 39

metabolites 39 separators 23-4

cake filtration 23 centrifugal sedimentation 23 corrosive properties 24 deep-bed filtration 23 density of fluid 24 filter/dryers 24 flotation 23 gravity sedimentation 23 screening 23 solid -liq uid 23, 24 viscosity of fluid 24

small-scale 31-2 bomb filters 32 continuous rotary pressure filter 36, 37, 38 Nutsche-type filter/dryer 35-6

solid separation 21 theory of 21-3

filtration rate 22 ultra-fine 39

compressed fiber filters 43 filter ratings 44-5 fixed pore media depth filters 44 mechanisms 40-2

cartridge filtration 40, 43 diffusional in terception 41

pore filters 43 pressure pulsation 43

ultrafiltration 39 vacuum filters 20 validation 47

Fishkin conversion chart 457

712 HANDBOOK OF DOWNSTREAM PROCESSING

Floors 522, 523 Flow chart 597 Fluid management 109-14

concentration polarization 111 cross-flow filtration 109, 110 dead-end flow 110

guard filter 110 laminar flow 113 Taylor vortex flow 114 turbulent flow 112

fouling 113 suspensions 113

vibratory flow 114 Fluid-bed dryers 242, 243, 246-8, 247 Food and Drug Administration, see FDA Freeze-dryers for lyophilization 217-23 Freeze-drying, see Lyophilization Freezing methods 207-8 Freundlich isotherm 61-2 Functional testing 597

Gas dispersion 359, 366 Gas hold-up and flooding 381-2 Gas-liquid dispersions 364-8 Genetic engineering 358 GMP purification 167 GMP regulations 569 Good Manufacturing Practice (GMP) 224-8,

485-91, 511, 532, 561, 603 Guideline on General Principles Process

Validation 570, 571

Hardware 597 Heat exchangers 282-3 Heat transfer 358, 388-97 Heating, ventilation and air conditioning, see

HVAC Heavy metals removal 702-4 Hemodialysis 106 Henry's Law 369, 699 HEP A, see High Efficiency Particulate Air

Filtration High Efficiency Particulate Air Filtration

(HEPA) 299, 301, 520, 521 High purity water 456-508

clean steam generation 484-5 distillation 464-6 electrodialysis 466 feedwaters 458-62

organic matter in 459 toxicity of 460

Fishkin con version chart 457 GMP

field execution 488-9, instrument libration 488

protocols 488 validation 486-7

ion exchange 465-6

major treatment 468-81 sterility barriers 474

dead legs 475 sanitary fittings 475

water for injection (WFI) 468, 483-4 reverse osmosis 464 reverse osmosis deionization (RODI),

preparation 478, 479 ROm

pretreatment 477 storage 481-3

treatment methods aeration 458 chlorination 458 demineralization 458 disinfection 458 distillation 458 filtration 458 softening 458 sterilization 458

ultrafiltration 466 UV radiation 466

HI PO chart 597 Hofmeister series 187 Hollow-fiber membranes 122, 125 Homogenization 1-5, 18 HVAC systems 647-8 HVAC validation 579, 591-3 Hydrofoils 359, 364, 372 Hydrophilic filters 45-7 Hydrophobic filters 45-7 Hydroxyethyl methacrylate 71, 72

Immobilized Protein A 70 Impellers 358, 360, 363, 378 Installation qualification (IQ) 571, 595, 597 Institute of Environmental Sciences (IES)

531, 532 Interferon purification 70 Intermolecular forces 422-6 Ion-exchange membranes 141-7

Juice filtration 108 diafiltration 108 tubular membranes 108 ultrafiltration 108

Karl Fischer t~ration 229 Karr columns 65 Kefauver-Harris Drug Amendments 557 Kuhni columns 64

Laboratory design 517 -19 Langmuir isotherm 80 Large-scale chromatography 167-84 Lexsol222 Life cycle 597 Limiting current density (LCD) 162, 165

Liquid wastes 652, 653-4 Liquid-liquid extraction 48-68

agitated columns 64-5 Karr columns 65 Kuhni columns 64 Oldshue-Rushton columns 64 rotating-disc contactors 65

asymmetrical 65 centrifugal extractors

residence time 62 solvent extraction 63

commercial extractors 57-65 Craig extractor 59 crossflow 58 extraction factor 58 multi-stage extraction 58 stagewise extractors 57

differential extractors 60-2 centrifugal extractors 60, 62-4 reciprocating extractors 60 rotary agitator extractors 60 transfer unit 61

height of 61 number of 61

equilibrium 49-53 acetates 51 alcohols 51 distribution 51

penicillin 51 ketones 51 partition coefficient 49, 52

greasy salts 53 ionized species 52 organic counterions 52

solvents 49, 51 fractional extraction 49 hydrodynamic factors 55-7

centrifugal extractors 55 coalescence rates 55 coalescence time 55 extraction efficiency 55 flooding velocity 56 hold-up 55 'rag' layer 55 slip velocity 56 superficial velocity 56

mass transfer 53-5 axial mixing 56 back mixing 56

channeling flow 57 pulsation 57

diffusional mass-transfer resistance 53 dispersed droplets 53 droplet coalescence 54 mass flux 53 redispersion phenomena 54

mass transfer coefficients 54 diffusivity 54

JNDEX

film thickness 54 interfacial surface area 54 interfacial surface tensions 54 interfacial turbulence 54 viscosities 54

Podbielniak extractor 48 process design 66 protein extraction 49 protein purifications 66-7 reverse micellar-extraction 49

Loeb-Sourirjan 94, 118 London forces 422 Lyophilization 203-33

application 228 control systems 223 cost of 232-3 end point determination 229 equipment 210-17 freeze-dryers 217 - 23

ice-condenser capacity 218 overall concept 218 presence of solvents 218 refrigeration systems 221

circulating fluid 222 sizing 217 steam sterilization 220 stoppering mechanism 221 vial bungs 220

future of 233 good manufacturing practices 224-8 history of 204 leakage 230-2 principles of 204-10

freezing 206 collapse temperature 206 eutectic point 206

freezing methods 207-8 secondary drying 209-10

bound moisture 209 residual moisture 209

sublimation 208-9

Mechanical disruption of cells 1-19 age of cell 18 algal cells 1 autolysis 1 bacterial cells 1 bead mills 1, 5-10, 11

agitator speed 5, 7 bead size 5, 7-8

bead volume 8 cell disintegration 8 cytoplasmic enzymes 8 peri plasmic enzymes 8 proteins 8

cavitation 5 collision 5 euipment design 9-10

713

714 HANDBOOK OF DOWNSTREAM PROCESSING

disks 9 cone-shaped 9 notched 9 slotted 9

separators 9-10 dynamic 9-10 microslit 9-10

sieve plates 10 blinding 10

flow rate 8 backmixing 8 continuous stirred tank reactors

(CSTRs) 8 lysis 8 residence time 8

glass beads 5 grinding media 5, 7 kinetics 5-7 shear forces 5

centrifugation 2 chemical lysis 1 denaturation of biological materials 2 economics of 11-15

bead mills 13, 17 homogenizer capacities 11 homogenizers 13, 14 labor 13 replacement parts 14

bead mills 14, 17 grinding media 14

utilities 13-14 enzymatic lysis 1 equipment 1, 15-18, 16

aerosol generation 17 biosafety of mills 17 cleaned in place 1 lysis monitoring 15-17 manufacturers 15 recombinant organisms 17 sterilizable 1 validated 1

eukaryotic cells 1 fungal cells 1 high mechanical shear 1 homogenization 1-2,3 homogenizers 2-5, 17

cell concentration 5 centrifugation 5 harvesting 5 lysis 5 ultrafiltration 5

cell disruption 2-3 cell lysis 3 cell physiology 3

age of cells 3 growth rate 3 media 3

hydrodynamic shear 2

organelles 3 positive-displacement pump 2

cell slurry 2 orifice valve 2 restricted nozzle 2

protein release 3 rate of disruption 4 shear force 2 temperature 4-5

adiabatic compression 5 external cooling 5 multiple-pass treatments 5

valve design 4 ball valve 4 flat valve 4 impingement 4 knife-edge valve 4, 11 shear 4 two-stage valve 4

valve piston 2 lytic systems 2 lytic techniques 1, 2 microorganisms 1, 10-11

bacteria 10, 11 lysis in bead mill 11

filamentous organisms 10 homogenization 10 milling 10 yeast 10, 11

lysis in bead mill 11 milling 1 proteolysis 1 ultrafiltration 2 yeast cells 1

Membrane components 118-27 capillaries 118, 122 cassettes 120

ultrafilters 120-1 ceramic monoliths 118, 123 hollow-fiber membranes 122, 125 Loeb-Sourirjan 118 modules 118 parallel-plate designs 120

De Danske Sukkerfabriker 120 DOIT-Oliver 120 Millipore Corporation 120 Rhone Poulenc 120

rotary modules 127 shake stacks 125

vibration 125 spirals 121-2, 122 tubular membranes 118

Membrane filters 295-7, 298 Membrane fouling 155 - 7 Membrane history 92-5

Amicon Corporation 94 Dorr-Oliver 94 Loeb-Sourirajan 94

Michaels, Alan 94 microfiitration 92 Millipore Corporation 93 Reid 94 reverse osmosis 93 Sartorious 92 ultrafiltration 93

Membrane ratings 99-106 Membrane reactors 131-2 Membrane separations 90-137

asymmetric membrane 94, 97 flux 93 manufacturers 136-7 pore size 94, 98

Membrane taxonomy 95-106 asymmetric composites 98 dynamic membranes 98 liquid membranes 99 membrane ratings 99-106

conductivity 99 microfiltration 100-1

ASTM standard methods 101 bubble test 100 markers 100 Pseudomonas diminuta 100

reflection 99 rejection 99 retention 99 ultrafiltration 101-6

fouling 103 fouling and flux 105 globular proteins 101 molecular-weight cut-off 101

self-assembled membranes 98 sintered membranes 95 'skinned' membranes 98 thermal phase inversion 97 thin composite membranes 98 zirconium oxide 96

Membrane types 143-5 Millipore Corporation 93, 120 Modular construction 682, 687 Module 597 Modules 118, 127 Molecular interactions 417-18

N -cyanotriethyl ammonium tetrafluoroborate (CTEA) 74

N-hydroxy succinimide 76 Nanofiltration 109 National Environmental Balancing Bureau

532, 533 National Institute of Health 517 National Sanitation Foundation 532 Newton-Raphson iteration 401 NIST (formerly National Bureau of Standards)

579 Noise level testing 550-1

INDEX

Nucleation 190-1 Nusselt number 390 Nutsche filter-dryers 240, 243, 244 Nutsche filters 25, 32-6, 33

Off-site construction 682-7 conceptual arrangement 684 containment facilities 682 containment requirements 683 modular 682, 687 module arrangement 684 shipping and installation 687 transportation by rail 687 transportation by road 687

Oldshue-Rushton columns 64 On-going evaluation 597 Operating system 597 Operating variables 598

715

Operational qualification (OQ) 571, 595, 598

Pachuca tank 399 Packaging operations 309-17

liquids 310 bottle unscrambler 310-11 bundling 312 cartoning 311 case palletizing 312 case-packing 312 filler/capper 311 labeler 311 tamper-evident seal 311

package-line clearance 313-14 completion 315-16 set-up 314

solids 312-13 bundling 313 cartoning 313 checkweigher 313 thermoformer 312

trends 316-17 bar-coding 317 computer control 317

Peclet number 287 Performance qualification 579 Peripheral 598 Pharmaceutical applications of extraction

48-68 Pharmaceutical plant design 623-57

air and other gases 650-1 biopharmaceuticals 623, 646-7

WFl systems 647 bulk pharmaceuticals 623, 645-6 equipment 642-5

autoclaves 643-4 centrifuges 642 control system 642 diafiiters/ultrafilters 643

716 HANDBOOK OF DOWNSTREAM PROCESSING

packaged system 642 piping systems 644

plastic 644 WFI645

facility layout 624-9 batch processing 624 biopharmaceutical 627, 628-9

building finishes 629 cross-contamination 628 floors 629 low temperature storage 629

building interior finishes 626 bulk manufacturing 626, 627 c1ean-in-place 625 cross-contamination 625 finished pharmaceutical 627 flammables 625-6 isolation areas 625 modular construction 627-8

installation time 628 multipurpose continuous reactor 625

HVAC systems 647-8 regulation 656-7

Center for Biological Evaluation and Research (CBER) 657

Center for Drug Evaluation and Research (CDER) 657

establishment license applications (ELAs) 657

Food and Drug Administration 656 Good Manufacturing Practices 656 new drug applications (NDAs) 657 Pharmaceutical Manufacturers

Association 656 product license applications (PLAs) 657 validation of bulk facilities 656-7

safety 655-6 biopharmaceuticals 655-6

National Institute of Health 655-6 bulk pharmaceuticals 655

steam 648-9 biopharmaceuticals 648-9 bulk pharmaceuticals 648

unit operations 630 absorption 637-8 biopharmaceuticals 633-4

cell recovery 633-4 fermentation 633 purification 634 seed generation 633

bulk pharmaceuticals 630 bulk packaging 630 crude filtration 630, 631 crude isolation 630, 631-2 crystallization 630, 631 drying 630, 632 pure bulk isolation 630 reaction 630

recrystallization 630 size reduction 630 solution preparation 630

centrifugation 638 distillation 637 equipment and piping systems 634-45

reactors 634-6 extraction 636-7 phase separation 636 piping systems 641-2 separations

centrifugation 640 perforate-basket 641 solid bowl 640-1

evaporation 638 filtration 638

belt 639 centrifuge 638 horizontal plate 640 Nutsche 639 plate and frame 639 pressure 638 recessed plate 640 rotary vacuum 639 vacuum 638 vertical plate 640

settling 638 waste disposal 651-5

biopharmaceuticals air pollution 654-5 chemical decontamination 654 liquid wastes 653-4 solid wastes 654

bulk pharmaceuticals 651-2 air pollution 653 liquid wastes 652 solid wastes 652-3

water 649-50 pretreatment of 650 ultra pure water for injection 649

Phase equilibria 418-19 Physical treatment of waste water 695-704 Pneumatic agitators 397-407 Podbielniak extractor 48 Polyacrylamide 71, 72 Polypeptide 158 Polyvinylchloride 73 Positively cooperative system 81 Prandtl number 390 Precipitation 185-201

antibiotics 185 crystallization 185, 186, 190-7

nucleation 190-1 homogeneous 191-3

supersaturation 192 induction period 193

secondary nucleation 196-7 crystallization 196

kinetics 197 surface nucleation

growth 193-7 crystallization 194, 195 Reynolds number 195 Schmidt number 195 Sherwood number 195 supersaturation 193-5

equipment 197-201 controlled cooling 199-200

crystal growth 200, 201 metastable zone 200 nucleation 200 supersaturation 200

crystal-size distribution (CSD) 197 growth kinetics 197 nucleation rate 199 population balances 197, 198

moment analysis 198 population density 198

proteins 185, 186, 187, 188 solid-liquid equilibria 185-90

effect of electrolyte 186 Debye-Huckel theory 187 Hofmeister series 187 salting-in 187 salting-out 187, 188, 189 solventing-out 189

special considerations 201 crystallization 201 solid-liquid separation 201

Preventive maintenance procedure 595 Process controls 338-40, 339, 342-3 Process (performance) qualifications 595 Process qualification (PQ) 571, 573-4, 579 Process validation 593-4, 598 Programmable logic controller (PLC) 352 Prospective validation 595 Protein purification 66-7 Protein recovery 658-80

computer-aided 658-60 environmental issues 659 process simulation 658 project selection 659 R&D 659

material balances 666 process scheduling 666 process simulation

f3-galactosidase production 661-8 absolute filter 665 anion exchange 665 axial compressor 665 cell debris removal 663 cell harvesting 663, 665 disk-stack centrifuge 663 Escherichia coli 661 eukaryotes 661 fermentation 663

INDEX

fermentation media 663-5 final purification 663 gel filter 665

717

high pressure homogenizer 663, 665 media preparation 663 protein solution 663

economics 667-80 capital cost 667 cell harvesting 674-8 economy of scale 679-80 operating cost 667 process scheduling 678 profitability analysis 670 protein solution concentration 678

Protocol 598 Pseudocode 598 Pseudomonas diminuta 100, 133

Quality assurance 598

Regulations 557-67 FDA inspections 565-6 Federal Food, Drug and Cosmetic Act

(FDC) 557 finishing requirements 562

labeling 562 packaging 562

Kefauver-Harris Drug Amendments 557 plant design 656-7 process requirements 559-60 the recipe 560-1

batch production record 561 master production record 560

reports and records 563-4 complaint file 564 equipment cleaning 563 inventories 563 laboratory 563 production reviews 563 returned products 564

validation requirements 561 GMP 561

Retrospective validation 596 Revalidation 598 Reverse osmosis 39

water filtration 108 Reverse osmosis deionization, see RODI Reverse osmosis of waste water 703-4 Reynolds number 195, 285, 323, 362,

390 Rhone Poulenc 120 ROm 478-83, 479 Room classifications 511, 521-2 Room differential pressure 543-4 Room finishes 522-6

Scanning instruments 536-8 Schmidt number 195

718 HANDBOOK OF DOWNSTREAM PROCESSING

Scientific Apparatus Makers Association (SAMA) 532 Secondary drying 209-10 Secondary nucleation 196-7 Separators 9-10, 23-4 Sequencing batch reactor 693-5 Sherwood number 195 Sieve plates \0 Silica 71, 72 Silicon oil 222 Sintered ceramic membranes 297 Software 598

development standards 598 diagnostic procedures 598

Solid wastes 652-3, 654 Solka floc (SF) cellulose fibers 406 Solvent extraction, see Liquid-liquid

extraction Sorption isotherm 239 Source code 598 Sparging devices 384-8 Specific gravity of fluids 389 Standards, clean room 531-2 Sterile corridor 515 -16 Sterilization 241, 261-306

in antibiotic fermentation 261 autoclaving 278-9

air-purging cycle 279 batch 274, 275

of solids 276-8 chemical 241, 302-5

agents 303 alcohols 303 aldehydes 303 chlorine 304 ethylene oxide 304 ozone 304 peracetic acid 305 peroxides 304 quaternary ammonium salts 305

disinfection 303 chemical inactivation 263 continuous 279-92

heat exchangers 282-3 Damkohler number 287 dOUble-pipe 282 Peclet number 287 plate-and-frame 282, 285 Reynolds number 285 shell 282 spiral 283 tube 282

nutrient degradation 280 suspended solids 287 -8, 290, 291, 292

definition 261 disinfection 261 dry-heat 292-4

Bacillus stearothermophilus 293

Bacillus subtilis 293 Clostrium sporogens 293

effectiveness 279 biological indicators 279 chemical indicators 279

filtration 262, 295-302 high efficiency particulate-arresting

(HEPA) 299, 301 membrane filters 295-7, 298

sintered ceramic membranes 297 viruses 295

gas 262 of parental drugs 261 pasteurization 261, 306 radiation 305-6 radioactive 241 thermal 241, 263-94

autoclaves 264 Bacillus stearothermophilus 266, 266, 268,

269, 270 Bacillus subtilis 266, 269 batch 266 Clostridium botulinum 266, 269 decimal reduction time (D value) 269, 270 degradation of media 264-5 dry heat 264 Escherichia coli 266, 269 microbial death rate 265

activation energy 265 Arrhenius constant 265

moist heat 264 oxidation 264 protein denaturation 264 spore death 267 temperature effects (Z value) 269, 270-1 thermal death time (F value) 269-72 using steam 264 of vials 263

thermal degradation 272-3 Arrhenius constant 272 B. stearothermophilus 272, 273 fermentation media 272

activation energies 272 protein denaturation 272 of thiamine 272

ultraviolet 241, 305-6 UV radiation 263

via filtration air filtration 297 bacteriophages 295 depth filters 295-7, 298

aerosol tests 298-9, 301 microbial challenge 298, 301, 302 retention capacity 298-9

validation 294, 300 Food and Drug Administration 294 United States Pharmacopeia 294 viral challenge test 302

Sterilization process validation 594 Sterilization requirements 610-11 Sterilize in place 320

system design 320, 325-7 condensates 325 fittings and valves 323 pressure drop 322 Reynolds number 323 standards 320-1 steam quality 327

clean 327 pyrogen-free 327

steam sterilization 325 storage and process tanks 323 thermostatic traps 325 velocities 322

Stirred tanks 86-7 Sublimation 208-9 Supercritical fluid extraction 440-2 Suspended solids, sterilization 287-8, 290,

291,292 System design 320, 325 - 7

Taylor vortex flow 114 Thermal decomposition 241 Thermal sterilization 241, 263 -94 Total air flow 542-3 Tray types, distillation 446-7 Trichloroethylene (TCE) 222 2,2, 2-trifluoroethanesulfonyl (tresyl) chloride

74

Ultrafiltration 101-6 Ultraviolet 241, 305-6 Utility programs 598 UV radiation 466

Vacuum-tumbler 242, 243, 248 Validation 294, 300,486-7, 569-99

acceptance criteria 574-5, 586 ASHRAE standards 592 biosafety cabinets 593 change control 589-90 COOe of Federal Regulations (CFR) 570 concurrent process 580 critical instruments 579 DOP test 592 fume hoods 593 GMP regulations 569 Guideline on General Principles Process

Validation 570, 571 HEPA filter 592 of HVAC systems 579, 591-3

background count 591-2 Class 100 environment 591 Federal Standard 209E 591

lexicon 593 master plan 570, 582-3

INDEX

computer control 582 schedule of activities 583

NIST (formerly National Bureau of

719

Standards (NBS)) 579 prequalification phase 583-5 preventive maintenance 579, 580, 590 product characteristics 570 product recall 591 prospective 580, 581 protocols 571

installation qualification (IQ) 571 operational qualification (OQ) 571 performance qualification 579 process qualification (PQ) 571, 573-4, 579

c1eanability 576 filling and packing 575-6

qualification phase 585-6 proper hazard/operation (HAZOP) 585 systems description 505

regulations biological 571 medical 571

retrospective 580 standard operating procedures (SOP) 586 sterilization

autoclave 578 dry 578 inplace 577 or sanitation 579 temperature 577-8, 590

trend analysis 590 validation phase 587-9

as-built drawings 587 autoclaves 588 filling machine 588 freeze-dryer 588 instrument calibration 587 select validation committee 589 tableting machine 588

Validation phase 587-9 Validation protocol 594, 599 Validation requirements 561 Valve design 4 Van't Hoff equation 86 Vapor-separation membranes 258-9 Vasopressin 158 Velocity and uniformity 540-2

Walls 524-5 Waste disposal 651-5 Waste water treatment 688-704

biological 688-95 activated sludge 690 biotower/trickling filter 692-3 complete mix 690 contact stabilization 691 contaminated biowaste 695 equalization 689

720 HANDBOOK OF DOWNSTREAM PROCESSING

extended aeration 691-2 neutralization 689 sequencing batch reactor 693-5 step aeration 692 tapered aeration 692

physical treatment 695-704 activated carbon 695-8

adsorption 695-8 air and stream stripping 698-701 Henry's Law 699

heavy metals removal 702-4 hydroxide precipitation 702

ion exchange 703 iron coprecipitation 703 reverse osmosis 703-4 sulfide precipitation 703

Water filtration 198 electronic chips 108 Orange County Water District 108 reverse osmosis 108 sewage 108

Water for injection (WFI) 468, 483-4 Wine microfiltration 107