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389

Index

Note: Page locators in bold and italics represent tables and gures, respectively.

absolute neutrophil count (ANC) 8– 9, 27, 119 absolute and relative errors 333 absorption barriers, administration routes 287, 287 acceptance criteria 91 accountability of lots 92 accuracy, and precision 334, 334 activities, evaluation of 323 activity assays 122 adalimumab 123 additives 70 adenovirus vector 174 administration routes 114, 117

absorption barriers 287, 287

see also drug delivery aeration 218– 220 aerobic culture, Komagataella phafi 212 afnity chromatography (AC) 230, 238, 243, 250 Affordable Care Act (ACA) 349 African green monkey kidney (CDS) cells 171, 174 aggregates 87 aggregation 266– 268

protein 267, 267 agitation 214– 218 air lter

inlet 214, 216

outlet 214, 216 air sensors 259 airlift bioreactor 171, 204– 206, 205 airlift reactor (ALR), internal- loop 204, 205 aldehyde- activated membranes 66 algae 175 alteplase 286, 299, 344 American Association of Pharmaceutical Scientists (AAPS)

138 amplication 160, 164, 173, 178, 184 analysis

methods 256– 257, 326– 327 proles 39– 40 tools 201– 202

analytical assessment 82– 110

critical quality attribute (CQA) 82, 84, 106

methodologies 82, 83 analytical ultracentrifugation (AUC) 93, 97– 99 ancillary equipment 225– 226 animal component- free (ACF) culture media 183 animals

immunogenicity testing 110

pharmacodynamics measures 110

pharmacokinetics measures 110

toxicology 25, 41

transgenic expression systems 178 annuity fees 371 anti- drug antibodies (ADA)

assay 136– 137, 142– 143, 147– 148 clinical relevance 137 development 123, 127, 134– 135, 139, 146– 147 efcacy 147 immunogenicity testing 126 incidence 137 neutralization 142 and pharmacokinetics 137, 146– 147 production 8, 86, 125– 130, 140 response 117, 130, 146– 147 specicity 142 testing 138, 146

antibody dependent cell mediated cytotoxicity (ADCC) 10

and rituximab 124 testing 21, 39, 96, 98– 99, 107

and trastuzumab 124 antibody products, patent claims 369, 369 antibody subtypes, purication media 245, 245 antigen- presenting cells (APC) 126, 132, 137 antisense technology 367– 368 area under the curve (AUC) 8– 9, 26, 104, 115– 116, 119 articial media 183 Aspergillus sp. 175

expression systems 178 assays

considerations 121

specic 121– 122

variability 106 ATF bioreactor, perfusion 212, 213 audit trail 332

B- cell epitope 142 B- cell lines 137 B- cell lymphoma 3 B- cell receptor (BCR) 127– 128, 367 B- cells

activation 136

maturation 126 baby hamster kidney (BHK) cells 161– 162, 171, 174, 217 background 43– 44 bacterial cells 164– 168

expression systems 165, 166, 177 baculovirus vector 178

expression systems 178 bafed pivot bioreactors 208 bafes 214, 216 Basic Local Alignment Search Tool (BLAST) 375 batch culture 207– 208 batch operation mode 214, 215 batch- to- batch variation 74 batch- to- lot variability 107 batches

cell growth kinetics 210

389

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390

number 21, 39 size 34– 35

see also fed- batch best mode requirement 362 bias, unbiased samples 104 binding, protein- A chromatography media 246, 247 biobetters 11, 87 biological patents 366– 369 Biological Price Competition and Innovation Act (BPCIA)

19, 41, 82, 348– 350, 353, 368, 376 Biologicals Licensing Application (BLA) 16, 35, 150, 368 biomass sensors 58 biopharmaceuticals

deamidation effects 270, 271 manufacturing processes 53, 54 nasal 290– 292, 292 ocular 293– 294, 293 oral 290, 290 patents protecting 344, 344– 345 protein stability 265, 265 subcutaneous 288– 290, 289

bioreactors

airlift 204– 206, 205 bafed pivot 208 components 214– 224, 215 cycles 48 exhaust- free 209 fed- batch prole 210 uidized bed 206, 206 parts 214, 216 perfusion in ATF system 212, 213 rocking 206, 207 single- use (SUB) 53– 56, 55, 60, 225 stirred- tank 201, 204, 205 systems 204 types 204– 206

see also reactors biosimilar biopharmaceuticals, development of 1– 12 biosimilar products, development of 33– 35 biosimilarity 11

statistical concepts 99, 100– 104 biosimilars

candidates 7– 8

clinical efcacy exemption 10

clinical endpoints testing 154, 154, 157

European Union approval 5– 7

FDA approvals 4– 5

FDA testing 36, 36, 37

International Council for Harmonisation (ICH)

guidelines 96, 97 pharmacodynamics markers 9, 10 terminology 11, 11– 12

biotechnology 263

medications 367 procedures 179 products 21, 67, 251

biotechnology- derived proteins 23, 108– 109, 125 biotherapeutic products, host cells 161, 162– 163, 165 BLAST (Basic Local Alignment Search Tool) 375 blinding 104

blood- borne infections 171 blood– brain barrier 291, 295 blood– retinal barrier 293 bone morphogenetic protein (BMP) 79 bottlenecks, decision matrix 45, 46 bovine spongiform encephalopathy (BSE) 171, 181– 182 bubble column reactor (BCR) 204, 205 business methods patents 358– 359

capillary electrophoresis 45, 75, 91, 96 capture 240

protein- A chromatography 242– 247

carboxyuorescein diacetate succinimidyl ester (CFSE)

133– 134

cell culture

Chinese hamster ovary (CHO) cells 188– 190, 194, 196,

209– 210, 221 fermentation 186– 187, 202 operational parameters 189, 190 operations 47– 48

cell culture media 44– 45, 180– 186, 185

articial 183 components 181, 181, 182, 183, 184 natural 183 osmolality 181, 202, 210

cell death 189 cell disruption 164, 177, 232– 236, 240

and recovery analysis (CDRA) 256

cell growth 188– 189

batch kinetics 210 and glucose consumption 190, 191 phases 188, 189 temperature effect 221, 221

cell harvest 65, 202 cell lines

common 183, 185 development 44 non- human 171– 174 oxygen uptake 218, 219

cell separation and harvesting 195– 201 cell- based bioassay, neutralizing antibodies 145 cell- specic perfusion rate (CSPR) 214 Center for Biologics Evaluation and Research (CBER) 370 Center for Drug Evaluation and Research (CDER) 370, 372 centrifugation 196– 198

continuous ow centrifuge 196– 197 see also ultracentrifugation

Certicate of Analysis (COA) 320, 329, 340 Certicate of Suitability (CEP) compliance 309, 309, 324 certication, laboratory facilities 329 certied samples, clinical pharmacology testing 38 change control 316 chaperones 293 chemical reference standards (CRS) 310 chemically dened (CD) culture media 182– 183 chemically sensitive eld- effect transistors (ChemFET) 58 chemicals

degradation 268– 276

Index

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391

Index

methods 234– 235

protein modications 269, 270 Chemistry, Manufacturing, and Controls (CMC) 96 chimeric antigen receptor (CAR) 79 chimeric monoclonal antibodies 367 Chinese hamster ovary (CHO) cells 79, 180, 183, 185, 217,

219 biotherapeutic products 161, 162– 163 cell culture 189– 190, 194– 196, 209– 210, 221 critical quality attribute (CQA) 173, 173 expression systems 163, 174, 177, 201 growth 187– 190 non- human cell lines 171– 174 perfusion 212 production 228 purication 241 tangential ow ltration (TFF) 253

chromatofocusing 230 chromatography 229, 230, 250

protein properties 229, 230

ciliary neurotrophic factor (CNTF) 79, 276 circular dichroism (CD) 96, 98– 99 claims 355– 356 clean- in- place (CIP) 47, 49, 52, 61, 69, 203 cleaning- in- place 225– 226, 259 clinical data, extrapolation of 157– 158 clinical efcacy 35, 41– 42

assessment 149– 159 exemption 10 patients 28– 29

clinical endpoints 154, 154, 156– 157, 157 clinical immunogenicity 25– 29, 125– 148 clinical pharmacology 25, 41, 111 clinical relevance

anti- drug antibodies (ADA) 137 immunogenicity 140, 140

clinical safety 29, 154– 159

and efcacy 35

clinically meaningful differences 11 cloning vectors 165, 177– 178

pBR322 plasmid 163, 165

closed- system lling transfer 69, 69 Clostridium tenani 302, 345 Code of Federal Regulations (CFR) cGMP regulations

evaluation activities 322, 323 management 316, 317 manufacturing 322, 322 resources 318, 319

commercial membranes 253, 254 commercial online les 373 comparability testing 11 comparative testing 89– 90 competition 33 competitive ligand binding assay 145 complement dependent cytotoxicity (CDC) 10, 21, 39, 96,

98– 99, 107

complementarity determining region (CDR) 107, 134, 369 compliance 307– 313 components, bioreactors 214– 224, 215 concentration assays 122

conductivity monitoring 259 condence interval (CI) 94, 100– 101, 115, 120 connectors 60– 62 containers and mixing systems 50 continuous chromatography systems 76– 77 continuous ow centrifuge 196– 197 continuous manufacturing (CM) 43, 64, 73– 77

therapeutic proteins 78, 78, 79 continuous operation mode 214, 215 continuous reactor process 211– 212 continuous stirred- tank reactor (CSTR) 211, 211, 212 contract research organizations (CRO) 137, 311, 313 control outsourced operations 318– 320 controller system 222– 224 conventional culture process 191, 191 cooling jacket 214, 216 corrective action 324 corrective and preventive action (CAPA) 307, 316 cost of goods 33 costs, treatment 2– 4 coverage, broad 369 critical micelle concentration (CMC) 83, 268 critical quality attribute (CQA) 11, 74, 92– 93, 93

analytical assessment 82, 84, 106

Chinese hamster ovary (CHO) cells 173

drug candidates 133

equivalence level 101– 102

functional attributes 86

monitoring 74

osmolality 92– 93

Quality- by- Design initiative 126

reference product 17, 38, 105 cross- reference, applications 355 culture media 44– 45, 180– 186, 185

animal component- free (ACF) 183

articial media 183

chemically dened (CD) 182– 183

components 181, 181, 182, 183, 184

microbial cells 180– 181

natural media 183

optimization 185– 186

preparation 183– 185

protein- free 183 culture process, conventional 191, 191 culture production process 190– 195 cytopathic assays 252 cytopathic effects (CPE) 252

danger- associated molecular patterns (DAMP) 128 data

errors 333

evaluation 21, 39

handling 330– 331

management 316

records 331 deamidation 269– 270, 271 decision matrix, bottlenecks 45, 46 degradation, protein sequence hotspots 268, 268

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deimmunization 135 delivery devices 374 dendritic cell assays 133 depth ltration

and membrane ltration 198, 198 refolded protein 239

setup 199, 199 design and development, product and processes 319 design of experiments (DoE) 185– 186, 237, 277 detergent 250 developing freedom- to- operate 375– 376 development, of personnel 317– 318 diabetic macular edema (DME) 293 diabetic retinopathy (DR) 293 dialtration 67– 73 diagnostics 306, 358 dialysis 238– 239, 239 diatomaceous earth (DE) 199 diethylamine 66 digital- to- analog connectors (DAC) 61 diketopiperazine 269, 269 dilution 238– 239, 239 disclosure 356

non- disclosure agreement (NDA) 351, 361, 368 disulde bond 272– 273 disulde bridges 166 Division of Applied Regulatory Science (DARS) 8– 9 documentation 31– 32, 327

and records 329– 330 dosage form 14 dose selection 114 downstream processing

equipment 257

monitoring 73, 74– 75, 258, 258

recombinant proteins 231, 232 downstream unit operations, recombinant proteins 228, 229 drawings 355– 356 drug candidates, critical quality attribute (CQA) 133 drug delivery 277

device 15

effectiveness 263

invasive 287

long- term 290

nanoparticles 298

ocular 293, 296

oral 297

protein 286– 287, 294, 296, 298

pulmonary 290– 292

rectal 294, 296

skin 293

systems 72, 116, 287

see also administration routes drug product (DP) 11, 72

analytics 142, 325

dosage form 14

exclusivity 368

ll- nish operations 68, 228

nished 94– 108

formulation 43, 255

microparticles 125– 126

performance 91 plastics 70– 71 polishing 241 preparation 255, 255, 263 purity 72 quality 93 regulation 30 safety 70 specication 140 testing 337 see also product

drug substance (DS) 11, 82, 228, 242– 243, 255

analysis 325 analytical software 325 batches 79 characterization 94– 95 ll- nish 228 ltration 68 formulation 262 manufacturing 37, 40 post- translational modications 22 quality control 337 reference standard 17 strength 14– 15

testing 337 drug targets 129 drugs

immunogenicity determinant 129

over- the- counter (OTC) 312 drum containers 50– 52 dynamic binding capacity (DBC) 229, 246, 246

efcacy

anti- drug antibodies (ADA) 147

endpoints 153– 154 electrochemical sensors 58– 59 electrochemiluminescence 144 electronic data

handling 330– 331

records 331 elution, protein- A chromatography media 246, 247 endoplasmic reticulum (ER) 86, 140, 160 endpoints 146

efcacy 153– 154 environmental factors, protein degradation 264, 264 enzyme- linked immunosorbent assay (ELISA) 10, 98– 99,

144, 202, 257, 340– 341 epidermal growth factor (EGF) 80, 124, 169, 184, 271, 292 episomal vectors 169 epoxy- activated membranes 66 equivalence

critical quality attribute (CQA) 101– 102 interval model 101

testing 150– 151 erythropoietin (EPO) 80, 125, 127 Escherichia coli 193– 194

expression strains 167, 167

expression systems 177

Index

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393

Index

ltration products 281 growth and temperature 221, 221 recombinant proteins 231, 232 recovery and purication 231– 235 soluble protein purication 241, 242

therapeutic proteins 79, 79– 81 Establishment Inspection Report (EIR) 312 etanercept 148 ethics and practicality 152 European Directorate for the Quality of Medicines and

Healthcare (EDQM) 309– 311, 309, 324

European Medicines Agency (EMA) 16, 37, 42, 125, 156,

311– 313 European Medicines Evaluation Agency (EMEA) 50, 73, 324 European Patent Convention (EPC) 363 European Patent Ofce (EPO) 358, 362– 364, 372 European Public Agency Reports (EPAR) 150 European Union approval 5– 7 evaluation, CFR cGMP regulations 322, 323 excipients 95, 272, 277– 280 exclusivities, biological products 368– 369 exhaust- free bioreactor 209 expanded bed adsorption 236, 247 expression strains, Escherichia coli 167, 167 expression systems 21– 22, 34, 39, 84– 85, 163– 164

bacterial cells 165, 166 Chinese hamster ovary (CHO) cells 163, 174, 177, 201 comparison of 176, 177– 178 industrial attributes 168, 168 recombinant proteins 163, 164 Saccharomyces cerevisiae 169, 170

yeast protein 169, 170 expression vectors 44, 161, 164, 169, 176, 369 extrapolation 29– 30

justication of 152

and substitution 15– 16

facilities and equipment 318 Fc fusion proteins 246, 246

see also immunoglobulins fed- batch 208– 211

bioreactor 210

operation mode 214, 215

process 193– 195

see also batch federal regulations 21 federally sponsored research 355 feedback control loop 223, 223 fermenter setup 193 ll- nish operations 68– 69, 69 ltration

applications 68

depth 198, 198

E. coli products 281

in- line 77, 77, 261– 262

membrane 198, 198

sterile 261– 262 ngerprint- like similarity 12 nished drug product 94– 108

rst- to- le rule 361– 362 rst- to- invent rule 361 ve- year view 139– 141 xed margin approach 102 ow cytometry 133– 134 ow meters 259 ow path 260 uidized bed bioreactor 206, 206 foam control 222 follicle- stimulating hormone (FSH) 80 Food and Drug Administration (FDA) 8, 14, 307– 309

approvals 4– 5, 9

testing 36, 36, 37 format 143 formulation 15, 24, 40, 263, 283– 286

components 278, 279

composition 276– 286, 374

compound ranges 277, 278

factors 264, 264

higher- concentration 282– 283

lifecycles 374

liquid 281

lyophilized 281– 282

technologies 294– 298 freedom- to- operate (FTO) 373– 376 function- based tests 21, 39 functional assessments 107 functional attributes 86 fungi, expression systems 178

gel ltration 230 gene amplication 160, 164, 173, 184 general arrangements 317 generally accepted scientic knowledge (GASK) 17 generally regarded as safe (GRAS) 177– 178 genetically modied Komagataella phafi, aerobic culture 212 Global Medicines Agency (GMA) 38 glucose consumption, and cell growth 190, 191 glutamine synthetase (GS) 44, 172, 174, 184, 187 glutathione S- transferase 80 glycation 273 glycine, hypoxanthine, and thymidine (GHT) 172– 173 glycosylation 98– 99 Good Clinical Practice (GCP) 311– 312 Good Laboratory Practice (GLP) 328– 337 Good Manufacturing Practice (GMP)

compliance 15, 307– 312, 330, 341

criteria 326

standards 185, 224

training 310

see also quality assurance graphical data, and raw data 102 growth hormone 125, 165, 269, 271, 276, 281, 338 growth hormone receptor (GHR) 80

harmonization 311– 313 harvest and clarication systems 224– 225

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heat treatment 250 heterogeneity 90 high- cell density cryopreservation 45– 46 high- performance liquid chromatography (HPLC) 45, 63,

75, 91, 193, 202, 261 CEX- HPLC 96, 98 RP- HPLC 99, 239, 243, 256 SE- HPLC 93

high- performance tangential ow ltration (HPTFF) 254 high- pressure homogenizer 233, 234 higher- concentration formulations 282– 283 higher- order structures (HOS) 19, 21, 39, 82– 83, 89, 91,

99, 108

homogenizer, high- pressure 233, 234 host cell protein (HCP) 22, 65, 74

and residual DNA 88

host cells, biotherapeutic products 161, 162– 163, 165 human cells 174 human factors studies 31, 42 human leukocyte antigen (HLA)

alleles 131 binding 131– 132, 138 peptide assays 134 and T- cells 137 type 139

hybridomas 171, 174, 219, 251– 252, 267 hydrogels 294– 295 hydrolysis 272 hydrophobic interaction chromatography (HIC) 66, 230,

240, 248

iminodiacetic acid (IDA) 66 immobilized metal- afnity chromatography (IMAC) 230 immune complexes (IC) 86, 125, 140 immunochemical properties 20 immunogenicity 41

anti- drug antibodies (ADA) 126 assay 142 clinically relevant effects 140, 140 investigation 141– 148 testing 126, 145– 147 therapeutic biologics 141, 142

immunogenicity- associated factors 141, 141 immunogenicity- focused organizations 137– 138 immunoglobulins

protein- A binding 244, 244 protein- A chromatography media 246, 247 see also Fc fusion proteins; monoclonal antibodies

(mAb)

impellers 214, 216– 217, 216, 216– 217 improvement, promoting 324 impurities 39, 87 in silico screening 130 in situ forming gels 294– 295 in vitro methods, immunogenicity risk 131– 134 in vivo assessment 108– 110 in vivo studies

animals 109– 110 need for 108– 109

in- line ltration 261– 262 in- process control 338– 340 inclusion body (IB) 199

recovery 200– 201, 232, 243, 258 renaturation 237– 239 separation 202 solubilization 199, 201, 232, 235– 238, 237

indications

and dosage 374

extrapolation across 158– 159 industrial attributes, expression systems 168, 168 iniximab 148 innate immune response 128– 129 inoculation, production vessel and sampling 193 inputs, examining 320 insect cells 175– 176

expression systems 176, 178 instrumentation validation 328– 329 insulin- like growth factor- 1 274 insulin- like growth factor- binding protein (IGFBP) 80 Integrated Inspection Report (IIR) 313 integration, risk assessments 138– 139 intellectual property 343, 343 interchangeability, and substitution 30– 31 interferons 285, 289, 292, 303– 304, 338, 344– 345, 373

peginterferon 10, 304, 344– 345 interleukins 80, 128, 165, 184, 283, 283, 291 intermediate purication 240– 241

and nal polishing 247 internal- loop airlift reactor (ALR) 204, 205 International Council for Harmonisation (ICH) 11, 96

guidance 96, 97 International Federation of Pharmaceutical Manufacturers

& Associations (IFPMA) 350 intravenous administration 288 inventions

background of 355 description 355 summary 355 title of 354

unpatentable 357 inventive step 363– 364 investigational medicinal product (IMP) 123, 312 investigational new drug (IND) 139 ion exchange chromatography (IEX) 230

Japanese Pharmaceutical Excipients Dictionary (JPED)

277

jurisdiction 360

Kjeldahl absorption 341 Komagataella phafi, aerobic culture 212

labels 31, 42 Laboratory Information Management Systems (LIMS) 329 leadership, providing 314

Index

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395

Index

lifecycles

formulation projections 374 management 144– 145

ligands

binding assays 121– 122

types of 66, 66 liposomes 297– 298 liquid formulations 281 lots

combining 104

equal number side- by- side 104

lot- to- lot variability 88

number of 102– 103

tested 107– 108

types of 103 Lowry assay 256 lyophilized formulations 281– 282

Madin– Darby canine kidney (MDCK) cells 174 major histocompatibility complex (MHC) 126, 132, 139– 140

associated peptide proteomics assays (MAPPs) 130, 134

ligands 131

and peptide complex 140 mammalian cells 170– 174

expression systems 177 mammalian system purication 241– 242 management

CFR cGMP regulations 316, 317

immunogenicity testing 148

responsibilities 314 manufacturing 85

CFR cGMP regulations 322, 322

operations 318

plan and facility 33– 34

recombinant proteins 43– 81, 163, 164

single- use systems 53, 54 master cell bank (MCB) 54, 251 material selection 71 measurement components, and process parameters 224,

224

mechanical methods 233 mechanism of action (MOA) 1, 10, 13– 14, 17, 21, 299– 306 media and solution preparation 203 medical method patents 358 Medicines and Healthcare products Regulatory Agency

(MHRA) 1, 8, 311 membrane ltration, and depth ltration 198, 198 membranes

commercial 253, 254 epoxy- activated 66

types of 66, 66 metabolic control 189– 190 meters 257– 259 method sensitivity 89 methodologies, analytical assessment 82, 83 microltration tangential ow ltration 199– 201 minimum to maximum approach 102 minute virus of mice (MVM) 249, 252

mitigation, by deimmunization and tolerization 135– 136 mixed graphic, numerical data 104 modalities, and immunogenicity risk assessment 136– 139 modeling 137 modes of operation 207– 214 monitoring

critical quality attribute (CQA) 74 downstream processing 73, 74– 75, 258, 258 packaging and labeling processes 319

monoclonal antibodies (mAb)

chimeric 367 oncology testing 96, 99 protein- A chromatography media 246, 246 purication 241, 244 quality attribute testing 96, 98 technology 367

see also immunoglobulins mycoplasma 163, 182, 248, 325, 340– 341 myeloma cells 174

naming 30, 42 nanoparticles 295– 297

drug delivery 298 nasal administration 290– 292, 292 National Conference of State Legislatures (NCSL) 30 natural media 183 nephelometric turbidity units (NTU) 202 nerve growth factor (NGF) 81 neutralization, anti- drug antibodies (ADA) 142 neutralizing antibodies, detection of 145 nicotinamide adenine dinucleotide phosphate (NADPH)

57, 339 non- clinical testing 19– 20 non- conformities, addressing 322 non- disclosure agreement (NDA) 351, 361, 368 non- human cell lines 171– 174 non- inferiority testing 151 non- mechanical physical methods 234 non- patent ofce sources 372 numerical data, mixed graphic 104

oath or declaration 356 ocular drug delivery 293– 294, 293, 296 Ofce of Regulatory Affairs (ORA) 308 on- column refolding 238– 239, 239 oncology monoclonal antibodies, testing 96, 99 online les, commercial 373 online monitoring 73

downstream processing 258, 258 operation modes, comparison of 214, 215 operational parameters, cell culture process 189, 190 operations, perform and monitor 320– 323 opposition after grant 363 Oprelvekin 283, 304 optical density (OD) 63, 194 optical sensors 57– 58 oral administration 290, 290

395

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organizational structure 314 orthogonal studies 107– 108 orthogonal testing 91 osmolality

cell culture media 181, 202, 210 critical quality attributes 92– 93 measurement 56 mechanical disruption 234 metabolic control 189– 190

perfusion 214 out- of- specication (OOS) 308– 310 over- the- counter (OTC) drugs 312 oxidation 273– 276

degradation products 273, 274

source 273, 274 oxygen transfer rate (OTR) 218– 219 oxygen uptake, cell lines 218, 219

packed bed and uidized bed bioreactor 206 particle ltration 261– 262 patent claims, antibody products 369, 369 Patent Cooperation Treaty (PCT) 352, 359– 362 patent dance 347, 348– 352 patent landscape 351– 352 patent law 360– 365

basics 352– 360 patent term

aspects of 371

extension 370– 372

factors affecting 370 Patent Term Adjustment (PTA) 370– 372 patents

assignment 365– 366

biological 366– 369

business methods 358– 359

infringement 365

medical method 358

non- patent ofce sources 372

of originator 373– 374

pharmaceutical variations 370– 371

protecting biopharmaceuticals 344, 344– 345

publication 362– 363

search resources 352, 352

software 357– 358

submarine 373

system expression 373

third- party 374

types of 356

unpatentable inventions 357

USPTO 351, 352 pattern recognition receptors (PRR) 128 pBR322 plasmid, cloning vectors 163, 165 pediatrics 31, 42 peglgrastim 124 peginterferon 10, 304, 344– 345 peptide drugs 129– 130 perfusion 212– 214

ATF bioreactor 212, 213

cell- specic perfusion rate (CSPR) 214 Chinese hamster ovary (CHO) cells 212

osmolality 214 periodic counter- current chromatography (PCC) 67, 76– 77 peripheral blood mononuclear cells (PBMC) 139

assays 96, 98, 132– 133 peripheral equipment 225– 226 pH 270, 278

control 222

monitoring 258

treatment 249 pharmaceutical excipients 277, 277 pharmaceutical patent variations 370– 371 Pharmaceutical Process Qualication (PPQ) 21, 35, 39 pharmacodynamics

assays 122

markers 9, 10

parameters 118– 120

statistics 120– 122

studies 27– 28 pharmacokinetics

analysis 116– 117

and anti- drug antibodies (ADA) 137, 146– 147

dependence on 147

parameters 115– 120, 116

statistics 120– 122

studies 123– 124

waivers 117 pharmacovigilance 29– 30 phase, of study 12 phenyl 66 physical degradation 265– 268 physical methods 233– 234 physicochemical properties 19, 86– 88

Food and Drug Administration (FDA) approved 299– 306 planning, manufacturing 37– 42 plants

transgenic 368

transgenic expression systems 178 plastic lm 71, 71 platelet- derived growth factor (PDGF) 81 policies, objectives, and plans, establishing 315– 316 polishing 241, 247– 248 polyethylene glycols (PEG) 280, 282, 294, 296 polylactic- co- glycolic acid (PLGA) 295– 296 polymers 70 population 146 ports 214, 216 post- translational modications (PTM) 22 precision 143

and accuracy 334, 334 pressure sensors 59– 60, 259 prions 182, 325, 341 probes 214, 216, 257– 259 process

optimization 44– 48

parameters 224, 224

qualication 25, 41

related substances 88 Process Analytical Technology (PAT) 46, 51, 56, 256, 338, 340

Index

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397

Index

continuous manufacturing 78 tools 195, 202

product 11

choice of 33– 35 concentration 253– 256 related substances 88

see also drug product promoters 175, 194 protectants 279– 280 protein

aggregation 267, 267

chemical modications 269, 270

chromatography 229, 230

multistep purication 241, 243

purication E. coli 241, 242

solubilization 165, 168

stability 265, 265

structure 264– 276 protein amplication 178 protein degradation 268, 269

environmental factors 264, 264

formulation factors 264, 264

sequence hotspots 268, 268 protein folding 239, 239 protein production, upstream processes 179– 227 protein- A 66

immunoglobulin binding 244, 244 protein- A chromatography media

binding 246, 247

elution 246, 247

Fc fusion proteins 246, 246

immunoglobulins 246, 247 protein- free culture media 183 provisional application 359– 360 public domain knowledge 16– 17 Public Health Service (PHS) Act 331, 370 pulmonary drug delivery 290– 292 pumps 62– 63, 260– 261

valves, tubes, and pipes 226 pure red cell aplasia (PRCA) 95, 125, 127, 140,

266

purication 65– 67, 240

E. coli protein 241, 242

expressed proteins 241, 243

and in- line ltration systems 77, 77

monoclonal antibodies (mAb) 241, 244 purication media, and antibody subtypes 245, 245 purication strategy, three- stage 228, 229 purity and impurity proles 20 purple book 370

qualication

proposed biosimilar product 13– 17

reference product 13 qualied product 37 quality aspects, regulatory requirements 22– 23 quality assurance (QA) 46, 102, 307– 308, 324, 326

reported data 328– 329

see also Good Manufacturing Practice (GMP)

quality attribute testing, monoclonal antibodies 96, 98 Quality- by- Design (QbD) 195 quality control (QC) 307– 308, 322, 337– 341 quality control unit (QCU) 307, 318 quality ranges (QR) 105– 106

model 101– 102

quality system 313– 324

building 315 quality target product prole (QTPP) 23, 31– 32 Quality- by- Design initiative, critical quality attribute

(CQA) 126 quantitative and qualitative data analyses 99– 106 quantitative systems pharmacology (QSP) 137 quantity 20 quaternary ammonium 66

racemization 269, 271– 272, 339

and isomerization 271– 272 radioimmunoprecipitation assay 144 ranking biologic candidates 131 rapporteur 37 raw data, and graphical data 102 reactors

bubble column 204, 205