413

Index

aabsorption (of an active substance) 146absorption spectrum 125accelerated stability study 113acceptance (econ.) 317acceptance criteria– analytical 104– contractual 385access control 199, 209accuracy 114acetic acid 119action of a drug 144active pharmaceutical ingredient 37activity assay 109actual account 330addiction 150additional services 315adenosine-triphosphate 20administration 255adsorbent 76adsorption-desorption mechanism 81adsorption process 29, 76adverse drug event 165adverse drug reaction 165aeration 56, 285aerobic respiration 20aerosol 96affinity chromatography 85, 107, 123affinity gel 92agarose-dextrane material 92aggregation 29, 109air changes 295air duct 295air filter 295airlock 19, 292air shower 292alanine 98alarm threshold 306

algae 17allocation key 331allowance factor 309aluminum-oxide 94ambient air 291ambient temperature 283ppamino acid 25– analysis 108, 115amphoteric behavior 30amplification steps 48ampoule 97anabolism 20analogue data 152analysis of primary structure 107analytical artifact 182analytical chromatography 123analytical report 210analytical transfer 385analyzer 126animal experiment 154animal husbandry 46, 61animal model 130anion exchanger 85annuity 369antibiotics 16, 72antibody 28, 122anticounterfeiting 100anti-foaming agent 72, 137antigen 121antigen-antibody reaction 122API-plant 256API production 37apoptosis 22appearance 98application patent 325aqua purification 279aqueous phase 89archae bacteria 17

Manufacturing of Pharmaceutical Proteins: From Technology to Economy, Second Edition. Stefan Behme.© 2015 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2015 by Wiley-VCH Verlag GmbH & Co. KGaA.

414 Index

area under the curve (AUC) 149Aspergillus niger 44assessment matrix 361association 29asymmetrical membrane 94attenuation 12audit trail 186, 209automation of water systems 284availability of oxygen 49

bbaby-hamster kidney (BHK) 45bacteria 17, 110, 129balance of interests 312base 31baseline separation 124basic engineering 303basis of design 205batch adsorption 76batch culture 50batch documentation 211batch mode 50batch number 209batch-record review 209, 212batch-to-batch cleaning 202bed height 93beta elimination 29Betaferon® 45beta-sheet structure 125bidding process 312bid-proposal preparation 338binding affinity 73binding offer 349bioavailability 146bioburden 53bioburden controlled 71bioburden reduction 66biogenerics 138biological activity 27, 109biological barrier 146biological clock 47biological effect 109biological hazard 288biological license application 242biological membrane 146biological safety class 269biological variability 154biomass 49bioreactor 56biosuspension 71biotech working party 232blinded study 162blood-brain barrier 146blood cells 56

blood circulation 146blood fractionation 13blood serum 62boiler 291book value 337bottleneck analysis 374bovine serum 62bovine spongiform encephalopathy (BSE) 137break-even point 325bridging study 376bridging trial 160budget request 309buffer exchange 69buffer-preparation area 88, 254buffer solution 39building automation-system (BAS) 297building drawings 304building laws 318building regulations 317building shell 294build-or-buy 361bulk filling 39Bundesinstitut für Arzneimittel undMedizinprodukte (BfArM) 233

butanol 89byproduct 49

ccalculation surcharge 316calibration 114campaign mode 273cap 99capacity usage 372capillary electrophoresis 118capital commitment 261capital costs 335capital demand 353capital interest 366capital investment 273capital value 368carbohydrates 31carbohydrate structure 127carbon dioxide 62carbon source 61carcinogenicity 165cardiovascular system 156carry-over 198cartridge filter 79cascade concept 268case report form 160catabolism 20cation exchanger 92ceiling-air inlet 295ceiling diffusor 295

Index 415

cell– activity 49– debris 70– density 49, 41– dry weight 26– expansion 47– growth 49– growth-rate 372– lifetime 48– nucleus 19– retention system 51, 52– substrate 38pp, 47– viability 132cell bank 46cell culture 130cell-culture medium 62cell division 22cell line 45cell mass 50cell separation 73cell therapy 13cellulose 31center effects 161Center for Biologics Evaluation and Research(CBER) 230

Center for Devices and Radiological Health(CDRH) 230

Center for Drug Evaluation and Research(CDER) 230

central compartment 146central nervous system (CNS) 156centrifugation 73certificate of analysis 183, 212certificate of compliance 183, 212chain-termination method 128chamber filter-press 74change control 185change management (engineering) 316change management (quality) 210change-over investment 357change request 215change requiring regulatoryapproval 214

change of scope 316charge/mass ratio 117, 126chemical compatibility 277chemical inactivation 90chemical ionization (CI) 126chicken eggs 46China Food and Drug Administration(CFDA) 236–237

Chinese hamster ovary (CHO) 45chlorination 281chromatogram 124, 133

chromatography 81– gel 91– skid 88chromosome 21, 25cleaning in place (CIP) 275, 290, 283cleaning out of place (COP) 290CIP-return line 64circular dichroism 130claims management 315clarity 112classified environment 199clean room 289clean steam 285clean utilities 278cleaning agent 57cleaning area 266cleaning procedure 289cleaning protocol 289cleaning validation 207cleanliness class 290ppcleanliness requirements 257clean-room cascade 199clean-room class 197, 258– clothing 197– concept 263– finishing 291– monitoring 32clearance 148client-manufacturer relation 184ppclimate chamber 207ppclinical endpoint 154clinical trials 105, 154– application 242– directive 194, 217closed process 199comedication 165Code of Federal Regulations (CFR) 230codon 24codon usage 25cold chain 207cold processing 42cold spot 282cold storage 260cold withdrawal 283colony-forming unit 129color 112color particle 136column-packing station 89combined production 348commercial supply 374ppcommissioning 305Committee for Medicinal Products for Human Use(CHMP) 232

416 Index

Committee for Medicinal Products for VeterinaryUse (CVMP) 232

Committee for Orphan Medicinal Products(COMP) 232

common technical document 238comparability 215ppcomparability protocol 215comparability study 160, 384comparative trial 159comparison of profitability 367compartment (body) 146compartment (environment) 318compendial water quality 279complaint 184complex media 62computer validation 208concept engineering 303conceptual design 260concomitant administration 150conductivity measurement 136confidentiality 312, 315confidentiality agreement 312conflict resolution 380conformance runs 206, 308consideration 312construction costs 310construction time 308consumable 266contact inhibition 22, 56contact switches 277contamination 198ppcontent 106contingency 310continuous cell line 22continuous mode 50contract design 312contract manufacturer 377contract negotiation 378contract partner 188ppcontract review 188ppcontractor 311contractual risk 313contraindication 150contribution margin 351control group 167controlled environment 199cooling loop 286cooling media 286cooling tower 286Coomassie blue 119cooperation structure 378core process 253corn 46corrective action 182, 186, 212

corrective action–preventive action(CAPA) 212

cost– accounting 329– allocation 330– comparison 367– control 379– estimate 304, 309– function 349– risk 325cost center accounting 333cost-distribution sheet 348cost inertia 331cost model 338cost of piping 309costs-by-cause principle 331costs of labor 310cost structure analysis 349cost type accounting 333cost unit accounting 334counter ion 85Creutzfeldt–Jacob disease 137critical observations 186critical parameter studies 42critical path 308critical system 306cross contamination 198crossover study 162cryoconservation 47cryoprotectant 98crystallization 89cumulation 149currency risk 298current GMP 191cytoplasm membrane 19, 32

d2D matrix code 1006-D rule 282data accessibility 209data-archiving system 208data safety 209dead volume 282dead-end filtration 73deamidation 29Dear Doctor letter 169death kinetics 54decanter 73dedicated plant 273deep-freeze system 278degradation product 49, 70, 113degree of automation 270dehumidification 295deionization 62

Index 417

deionized water 280demand peak 392denaturation 108Department of Health and Human Services 229depreciation 335depth filtration 79desalting 62design control 177design qualification 204design validation 189design verification 189desorption 76desoxy-nucleotide-triphosphate 128destruction 184detail engineering 303development agreement 380development report 210deviation 210deviation investigation 210deviation management 211deviation report 210ppdextrane 94diabetes 14diafiltration 39, 72dictiosomes 20differential scanning calorimetry 131DIN 227DIN ISO 9000 176direct-capture chromatography 78direct costs 329direct-impact system 306discoloration 112displacement flow 292disposable bag technology 277dissolved oxygen 132distillation 281distribution 146disulfide bridge 26, 106, 118dithiothreitol 118DNA sequencing 128document control 211document transfer 385documentation 209documentation for regulatory permits 318donor anamnesis 137dose-finding study 159dose recommendation 154dose-response relationship 144dossier 242double blinding 162double peak 124doubling time 22, 45downstream 39drinking water 62

drug– allergy 165– approval 242– interaction 150– product 37– safety 164, 184– study 154

eEcherischia coli (E. coli) 44Edman degradation 116effect of investment 357effective dose (ED50) 151efficacy 144electrical power supply 287electronic batch record (EBR) 208, 297electronic signature 209electrospray ionization (ESI) 126electrophoresis 118elimination 147eluate 82elution buffer 82elution step 82EMA 231emergency-power generator 288endoplasmic reticulum 19endotoxin 129endotoxin load 70energy balance 304engineering run 307enhanced design review 306environmental legislation 318environmental monitoring 135environmental protection 318enzymatic reaction 121enzyme-linked immunosorbent assay (ELISA) 122episomal plasmid DNA 44Epogen® 46equilibration 82equipment cleaning 289, 373equipment layout 304Erythropoietin 14escape door 258ethical responsibility 324ethics committee 160Eudralex 233eukaryotic cell 19European Directorate for the Quality of Medicines(EDQM) 232

European Pharmacopoeia (PhEur) 233European Union 231evaluation software 124excipient 195exclusion criterion 161

418 Index

excretion capacity 147excretion organ 147executed batch record 209exhaust-air scrubber 289expandability 262expanded bed adsorption 77expansion areas 274expansion investment 357exponential growth 49expression strength 49expression system 43external service 335extinction 125extinction coefficient 108extracellular expression 44extracellular fluid 146extraction 89

ffacade area 274Factor VIII 14, 52factory acceptance-test (FAT) 307failure costs 175failure mode and effect analysis (FMEA)-analysis184

failure prevention 181– costs 175failure root-cause 181fast-atom bombardment (FAB) 126fast-track review 242fast-track status 327fatty acids 32feasibility study 304fed batch mode 52Federal Register 226fee-for-service contract 313fermentation 48– analytics 132– area 260– capacity 372– conditions 35– course 57– debris 289– titer 41– volume 67fetal bovine serum 137fields of activity of ISO 9000 176Filgrastim 153filling 96filling level 57filter– cake 74– cassette 74– cloth 74

– residue 74– test 63filtration 73filtration membrane 94final container 98final formulation 280final purification 80final rinse 207, 289final treatment step 280financial planning 353finished product 101fire code 317fixed costs 331fixed investment 356fixed unit costs 332flexibility 269flexible hose 275flexible piping 275flocculation 71floor plan 259flow rate 92flow resistance 92flow visualization, smoke study 295fluidization 78fluidized bed reactor 60foam control 58foaming 57folding 26, 107folding box 97follow-up investment 273, 357follow-up product 113follow-up stability study 113food and drug administration (FDA) 299form of administration 96formulation buffer 97formulation 96, 134fouling 79fractal plant 274fraction 82fraction collection tank 82fractionation 125Freedom of Information Act 230functional description 205

ggastrointestinal tract 153gel electrophoresis 118gel-filtration chromatography 85gel-permeation chromatography 72gel staining 118gene expression 19gene sequence 108gene therapy 13gene vector 24

Index 419

general contractor 312generic drug 138genetic code 24genetic instability 48genetic stability 22genetically modified organisms 288genome 44, 129genotype characterization 17Gerstmann–Straeussler syndrome 137glass ampoule 97glycine 98glycoanalytics 127glycogen 31glycolipid 31glycolysis 20glycoprotein 31, 127glycosylation 26, 14glycosilation pattern 127genetically modified organisms (GMO)-free 266,288

GMP flows/diagram 263go/no-go criterion 358gold standard 327golgiapparatus 78, 200, 360good automated manufacturing practice 174good clinical practice 174good engineering practice 174good laboratory practice 174good manufacturing practice (GMP) review 189,191

good storage practice 174good tissue practice 174gowning 197gowning area 293gradient elution 88gram staining 17, 130grant of a patent 325granulocyte colony-stimulating factor(G-CSF) 153

granulocyte macrophage colony-stimulating factor(GM-CSF) 14

gross investment 357growth factor 62growth limitation 49

hhalf-life 148Hansenula polymorpha 44hard piping 275head of manufacturing 196head of quality control 196healthy volunteer, test person 158heat sterilization 54heat supply 285

heating jacket 57heating-circuit (-media,-steam) 285ppheat-transfer system 285heat, ventilation and air-conditioning (HVAC)installation 294

heavy metals 279helical structure 108Herbal Medicinal Products Committee(HMPC) 232

high-efficiency particulate air (HEPA)-filter 295high-pressure homogenization 75high-pressure liquid chromatography (HPLC) 87,95, 127, 374

holding point (in the process) 39homogenizer 75horizontal design 260hormone 62horse-shoe crab 129host cell 43host cell protein 69pphost cell protein ELISA 122hot storage 282human growth-hormone 14human immunodeficiency virus (HIV) 24human insulin 27human serum albumin 137humidity 294Humulin® 45hurricane 300hybridization 127hydrogen bonding 118hydrolysis 29, 115hydrophobic interaction chromatography 86hydrophobicity 86hydroxy propyl methyl cellulose (HPMC) 98hygiene policy 197hypersensitivity reaction 165

iidentity test 107idiosyncratic side effect 150immune system 156immunoelectroblot 121Immunologicals Working Party 232improvement process 196impurity 68impurity profile 109immunogenicity 26, 138inclusion body 18, 44inclusion criterion 161indirect impact system 306infectivity 130informed consent 161infrared spectroscopy 125

420 Index

initial application 150injection site 153, 156inoculation 48, 256, 268inorganic salts 69in-process control (IPC) 132, 211installation qualification 205instrument air 285insulin 27integrated plant 274integrator 124interest rate for calculation 364interface management 378International Conference on Harmonization (ICH)237

International Society of Pharmaceutical Engineering(ISPE) 238

interferon 14interleukins (ILs) 14intermediate 195intermediate precision 114intermediate release 106internal rate of return 368intracellular expression 44intravenous injection 146inventory management 392investigational drug 216investigational medicinal product dossier 242Investigational New Drug (IND) application 242investigations operations manual 241investment– appraisal 365– calculation 365– costs 309– decision 357– planning 362in-vivo stability 153ion concentration 70ion-exchange chromatography 85ion exchanger 85ion-exchanger gel 91ppionization 126ion source 126IPC analytics 254IPC lab 132IP safety 300irrelevant costs 333Ishikawa diagram 184ISO 238isoelectric point 119isoelectrical focusing 119isolation 80isolator technology 292isometric drawing 304

jJapan Pharmaceutical Manufacturers Organization235

kkey performance indicators (KPIs) 397kidney 147KIKO 235Kjeldahl 118know-how safety 300Kogenate® 46

llabeling 40pplabor legislation 235laboratory information management system(LIMS) 208

lag phase 50laminar air flow 292Lantus® 153large-scale process 385launch 324pp, 374ppleachable 69leaching 93lead time 308Lepirudin 14lethal dose (LD50) 151Letter of Intent 312Leukine® 45liability 313liberation 146liberation–absorption–distribution–metabolism–excretion (LADME) 146

license payment (royalty) 328life cycle 324life cycle of investment 354ligand 85, 92limit of detection 114limit of quantification 114limulus amebocyte lysate (LAL) -test 129LIMS 208linearity 114lipid 109lipo-polysaccharide 31, 44, 70, 109liquid nitrogen 286liquidation value 364liver 147living cell mass 49loading capacity 372loading step 83local tolerance 156long-term side effect 165lower price-limit 329lymphatic system 146

Index 421

lump-sum contract 316lyophilisate 135lyophilization 98pp– cake 98, 153

mmachine hour-rate accounting 347mad cow disease 137main drying 98main equipment list 310main peak 124main service 314maintenance costs 335major change 213major observation 187major variation 213make-or-buy 387make-up 41mammalian cell 45mammalian cell-culture 55manufacturing and supply agreement 380manufacturing costs 41, 160manufacturing documentation 209manufacturing license 233pp, 240ppmarginal costing 346marker 121market exclusivity 326market release 211market saturation 324market share 323marketing authorization 234, 380mass spectrometry 125master batch record (MBR) 201, 210master cell bank (MCB) 47material airlock 200material balance 254material costs 335material flow 258material of construction 69, 94, 291matrix-assisted laser-desorption ionization (MALDI)126

maturation phase 324maturity of application 270Maxam–Gilbert method 128maximum tolerable dose (MTD) 151mechanical completion 303media– component 61– hold tank 62pp– prep tank 64– preparation 256– supply 63medical investigator 160medication error 166

medium (fermentation) 61membrane bioreactor 60membrane module 60, 185mercaptoethanol 118metabolic system 35metabolism 20, 147method validation 114microbial contamination 129, 267, 280microbial count 54microfiltration 79microorganisms 17, 278, 301microparticle 153microtiter plate 123milk 46mill 75minimal therapeutic concentration 149minimal toxic concentration 149Ministry of Health, Labor and Welfare (MHLW)(Kosei-roudou-sho) 235

minor change 214minor observation 187minor variation 214mitochondria 20mobile CIP-skid 276mock run 122mode of action 138model process 273model virus 91moderate change 214modular construction 275molecular weight 108molecular weight cutoff (MWCO) 80, 94monocellular layer 55monocentric 161monoclonal antibody 13, 29, 45mortality rate 154moss cell 46mouse-myeloma 45movable tank 276multicentric trial 161multiple application 149multi-purpose plant 202ppmunicipal sewer system 288municipal water 281mutagenicity 156mutation 22, 48mycoplasma 110

nnasal administration 152nasal mucosa 152National Health Surveillance Agency(ANVISA) 237

natural disaster 300

422 Index

net cash flow 368net charge 120net costs 329net investment 357net present value (NPV) 365, 368net profit 351Neulasta® 153neutralizing antibodies 156new drug application 242nitrocellulose matrix 120noise protection 318nominal accounting 330nominal capacity 332non-binding orientation bid 349Northern blot 120Note for Guidance 227NovoSeven® 46Novolin®45NPH-insulin 153NS0 45nuclear magnetic resonance 108nucleic acids 30nucleotide building-block 128nutrient medium 61

oobligation to co-operate 313occupational health 318Office of the Commissioner 230Office of Regulatory Affairs (ORA) 230Official Journal of the European Communities 226Official Medicines Control Laboratories (OMCL)233

off-label use 327oil-free compressor 285olfactory nuisance 288–289once-through cleaning 290OOS resultopen process 199open study 162operating assets 337operating costs 270operating time 372ppoperational qualification 205operational readiness 331oral mucosa 153organelle 19organic phase 89organic solvent 42, 89organics 277, 288organization schedule 308orphan drug 242orphan drug status 326outer appearance 112

overall yield 67overfill 372overhead calculation 329overhead costs 328oxygen supply 62–63ozonization 281

ppackage units 297packaging 99, 134packing homogeneity 89paper-based documentation 296parallel study 162Parenteral Drug Association (PDA) 240Pareto-analysis 184parking-lot effect 164particle 134, 295particle filtration 79, 281past pollution 318patent protection 325patient compliance 164patient-information leaflet 97, 151Paul-Ehrlich Institute (PEI) 233payback time (static/dynamic) 367pppeak area 124peak height 124peak profit 324peak sales 324peak symmetry 124poly(ethylene glycol) (PEG) 153peptide mapping 116peptide pattern 116peptide 26perforated ceiling 295performance management 396–398performance qualification 206periplasmic space 44permit procedure 318permit situation 299personnel airlock 292personnel flow 263personnel hygiene 267personnel investment 356pH-adjustment 57, 281phages 110Pharmaceutical Affairs Bureau 235Pharmaceutical and Food Safety Bureau(PFSB) 235

Pharmaceutical Inspection Convention/Scheme(PIC/S) 238

pharmaceutical legislation 225pharmaceutical manufacturing 38Pharmaceutical and Medical Devices Agency(PMDA) 235

Index 423

pharmacodynamics 149pharmacokinetics 146pharmacokinetics (PK)-profile 144pharmacopoeia 227, 233, 237pharmacopoeial quality 62pharmacovigilance 167Pharmacovigilance Agreement 380Phase IV 167phase of clinical trial 157phenomenon of acquired tolerance 156pH-gradient 119phosphoric acid 289ppphotosensitivity 125photosynthesis 60pH-swing 90phylogenetic tree 18Pichia pastoris 44pilot plant 375pppiping and instrumentation diagram(P and ID) 304

pivotal study 159placebo-controlled study 161placenta 146plant maintenance 258plant usage 331plaque test 130plasma 13plasma concentration 148plasma desorption 126plasmid 18plasmid DNA 44plastic tube 277platform technology 262, 273, 377point-of-use heat exchanger 282points to consider 227polarity 73pollen dispersal 61poly(ethylene glycol) (PEG) 89, 153polymer membrane 94polymerase 128polymerase chain reaction (PCR) 127polysaccharides 31pooling 374pore size 79, 93posttranslational modification 26, 107potatoe 46precipitation 29, 89precision 114preclinical study 156pre-fermenter 63ppprefilled syringe 97pregnancy 156preparation area 266preparative chromatography 81

present value 368pressure– drop 92– gradient 267pp– test 63– vessel 57pressurized-air system 278prevalidation study 385price regulation 226pricing 327primary cell 15primary container 96, 112primary structure 26, 116primer 127prion 137priority review 242procedural segregation 257process– air 285– analytics 132– change 213– consistency 296– control 208, 296– control system 296– description 210, 254, 306– documentation 296– flow-diagram 259– optimization 389– patent 325– piping 276– support 254– validation 206processing time 63, 91process-related impurity 104procurement 176product– change-over 273– comparability 137– concentration 67– flow 263– instability 112– life-cycle 326– loss 66– patent 325– release 211– safety 257– stability 42– testing 105– yield 66production facility 253production fermenter 56product-related impurity 69ppproduct-related substances 69ppprofit 324

424 Index

profit and loss account 330profit comparison analysis 365profit margin 378programmable logic control 296project organization 311project time-plan 308prokaryotic cell 18Proleukin® 45promoter 19promotion 324proof of concept 376proof of principle (concept) 159prospective validation 208protease inactivation 76protease inhibitor 76protease 110protein-A chromatography 86protein aggregate 70, 75protein expression 43proteins 26protein-sequence analysis 116protein structure 27, 107proteolytic degradation 50Protropin® 45psychogenic effects 161pulmonary administration 152purchasing documents 302purification 39purification area 260purified water 62purity 109pyrogen 129

qQuadrupol MS 126qualification 189, 203pp, 284pp, 305ppqualification protocol 204qualification report 204qualified person 197qualitative method 114quality assurance (QA) 211ppquality assurance agreement 187, 380quality– control 212pp– deficiency 183– of life 154– management system 178– policy 185– system 176quality control (QC) 211ppquality control lab (QC-lab) 297quality working party 232quantitative method 114quartiary structure 27

rrapid-alert system 169rapporteur 232rationalization investment 357raw material 61, 195raw-material testing 136recall 169, 184receptor 17recombinant protein 10Recombinate® 46recommittal rate 154re-examination 175reduction factor 91reference project 377reference sample 125reference standard 110reference substance 207Refludan® 45refolding 74regulatory affairs 210ppregulatory approval 376regulatory dossier 188regulatory inspection 238regulatory procedures manual 241release behavior 153release certificate 209release specification 104release status 255relevant costs 333reliability 254repeatability 114replacement problem 360reprocessing 183reproducibility 114reservation fee 387residence time 145residual moisture 110residual solvent 110resolution 91respiratory tract 152restriction enzyme 128retention capacity 94retention time 124retrospective validation 208retrovirus 71reverse osmosis 280reverse transcriptase 128reversed phase chromatography85pp

review phase 359rhizosecretion 60ribosome 19right of continuance 273right to use 358

Index 425

risk– analysis 138– assessment 288– communication 184– control 185– of flooding 300– identification 184risk-based approach 184risk-benefit assessment 143risk-management process 184robustness of the manufacturing process 42rodent 156roller bottle 59room air 291pproom book 304room-in-room concept 294root-cause analysis 212route of administration 96routine audit 186routine operation 295

sSaccharomyces cerevisiae 44saccharose 98safety interlock 206safety stock 43safety working party 232salt content 82sample port 132sample-size calculation 161sampling 284ppsandwich ELISA 123Sanger–Coulson method 128sanitization 56saturation phase 325scalability 277scale-up 384scale-up step 39scale-up study 384scaling method 362scientific advice 243scope of work 313ppsearch phase 358second supplier 393secondary drying 98secondary packaging 98secondary structure 27sector field 126seed train 47segregation steps 257selection problem 360self sanitizing 282self-draining system 282semi-finished goods 101

sensitivity analysis 365separation principles 64separation zone 83sequence ladder 128serum 62pp, 137shake flask 39shear stress 55side effect 150sight glass 132silica gel 92silver-nitrate solution 119singular event 184site acceptance-test (SAT) 307site location factor 298size-exclusion chromatography 87small-scale model 385smoke study 295sodium dodecylsulfate 116sodium dodecylsulfate–polyacrylamide gelelectrophoresis (SDS–PAGE) 118

sodium hydroxide 57, 291solid-liquid extraction 89solid waste 288solubility of proteins 29ppsolubilization 74solubilizing agent 75solvency 354source of contamination 282southern blot 120special permit 299specifications– analytical 104– devices 42specificity 114spectrophotometer 125spectroscopy 125spectrum 125spectrum of byproducts 35ppspine, backbone 274sponsor 160spray ball 57sprinkler system 258stability 112stability of the expression system 48stability data 376stability profile 112stability test 255stabilization 75stainless steel technology 54standard costing 346standard operating procedure 179standard technology 377standard therapy 162

426 Index

starting culture 192starting material 195state of the art 226statistical methods 178, 185statistical relevance 161steam– condensate 285– distribution 285– sterilizability 282– sterilization 54– trap 291steering committeestem cells 16step yield 67sterile filter 64sterile filtration 90, 199sterile gases 285sterile manufacturing 268sterile technology 53sterility 53sterilization in place (SIP) 57, 290sterilization method 53sterilization time 54stirred bioreactor 55stirrer rotational speed 132stopper 98ppstorage buffer 97storage conditions 113strategic investment 353street clothing 266structural data 107study design 155study protocol 160subcontractor 311subcutaneous injection 153subloops 282success of cleaning 289sugar chain 108sugar molecule 127supernatant 39supplementary protection certificate 325supplier qualification 187supply chain 391supply-chain management 392supply safety 393surface filtration 78suspension culture 56symmetrical membrane 94symmetry test 89synthetic medium 62syringe 97system wall 294systemic application 147

ttactical investment 357tangential flow filtration 78target location 144target profile 154, 327tax incentives 298technical complexity 270technical risks 313technical specification 302technology transfer 384temperature logger 207tender vetting 330teratogenty 156term sheet 312terminal sterile filtration 268termination of a contract 315termination fee 387tertiary structure 35testing costs 175testing status 177therapeutic dose 151therapeutic window 149thermal bridge 55thermal inactivation 76, 90throughput 91time-concentration curve 148time of flight (TOF) 127time point of investment 375pptime-point of market approval 112time-to-market 113tissue culture 57tissue engineering 15tissue-plasminogen activator 14titer 41tobacco plant 46tolerable impurity 138tolerance formation 156tooth-brush effect 164topical application 147total body water 146total organic carbon (TOC) method 136total protein content 107total spectrum of activity 150toxicity of metabolites 49toxicity 156toxicology 156traceability 99training 185, 197transcription 25transfection 24transfer panel 275transformed cell line 15transgenic systems 46translation 25

Index 427

trans-membrane flow 79pptrans-membrane pressure 133transmissible spongiform encephalopathie(TSE) 137

transmission electron microscopy (TEM) 130transport conditions 113transport protein 26transport validation 207trehalose 98trend analysis 185triplet 24ppturbulent flow 295two phase extraction 89type A, B, C, D-reactions 165

uultra/diafiltration 79unidirectional personnel flow 266unit costs 333unit profit 350United States Pharmacopoeia 237upfront investment 262upstream 39use point 283useful economic life 364user requirements 301user requirements specification 204utilities 278ppUV-detection 84UV/Vis spectroscopy 125

vvaccination 11vaccines 11validation 206– batch 377– master plan 208– protocol 208– report 208– run 307value engineering 310value-benefit analysis 361variable costs 331

vendor-managed inventory 394verum 161vial 97ppvirus 22– contamination 23– inactivation 90– load 90– production 11– reduction 90– testing 130– validation 91visual inspection 134V-model 204

wwage level 299warehouse-management system 208warning letter 230warranty 315washing step 82waste flow 266waste incineration 266waste management 288waste treatment 288water 278ppwater for injection (WFI) 62water solubility 73western blot 118wholesaler 163wipe test 136working cell bank (WCB) 48World Health Organization (WHO) 238

yyeast extract 61yeast 44yield 41, 66, 373yield loss 68

zZentralstelle für Gesundheitsschutz beiArzneimitteln und Medizinprodukten (ZLG) 233

zoning concept 266