Index

A risk, 69–70
Accelerated stability, 276, 279 transgenic animals, 78–79
Accelerated storage, 272 transgenic plants, 78
Adventitious agent control virus-based biologic medicines, 83–84
bacteria/fungi Affinity chromatography (AC), 162–163
animal-derived materials, 94 Aggregation, 226
cell-based biologic medicines, 95–96 Allogeneic cell-based medicine cell banks, 130
cell culture processes, 94–95 Amide hydrolysis, 223
CMC strategy tip, 96–97 Analytical comparison
detection, 93–94 outcomes, 295–298
human threat, 91 physicochemical, in vitro/in vivo biological testing, 293
risk, 91–93 sequential approach, 295
definition, 59 Animal/human cell expression, 140–142
mycoplasma Antibiotics, 207
animal-derived materials, 88 Assays, functional activity
biopharmaceuticals, transgenic processes, 89–90 caution, surrogate assays, 245–246
cell-based biologic medicines, 90 cellular and gene therapy (CGT) biologics, 247–248
cell culture processes, 88–89 enzymatic chromogenic substrate assays, 244–245
CMC strategy tip, 90–91 HPLC assays, 245
detection, 86–87 immunochemical binding assays, 244
human threat, 86 monoclonal antibodies, 246
risk, 86 in vitro bioassays, 242–244
prions in vivo bioassays, 240–242
animal-derived materials, 62–64 Autologous cell final product, 268, 269
biopharmaceuticals, transgenic animals, 66–67 Autologous cellular therapy manufacturing process, 40, 42
cell-based biologic medicines, 67–68
CMC strategy tip, 68
detection, 61 B
natural-sourced human plasma-derived proteins, Baby hamster kidney (BHK), 5, 73, 119
65–66 Bacteria/fungi
risk, 61 animal-derived materials, 94
transmissible spongiform encephalopathy (TSE) cell-based biologic medicines, 95–96
illness, 60 cell culture processes, 94–95
proper risk assessment, 59 CMC strategy tip, 96–97
risk minimization plans, 97–98 detection, 93–94
virus human threat, 91
animal-derived materials, 71 risk, 91–93
bacterial/yeast cell lines, 72–73 Bacterial cell expression, 140–142
cell-based biologic medicines, 81–83 Bioburden testing, 93
CMC strategy tip, 84–85 Biogeneric, 27
detection, 70 Biologic active pharmaceutical ingredient (API)
human threat, 69 bioreactor cell culture production
insect/animal/human cell lines, 73–78 clinical phase-appropriate cell culture control,
natural-sourced human plasma-derived proteins, 150–154
79–81 criticality, genetic stability, 145–150
plant cell lines, 73 design/operational mode choice, 143–145

J. Geigert, The Challenge of CMC Regulatory Compliance for Biopharmaceuticals and Other Biologics, 331
DOI 10.1007/978-1-4614-6916-2, © Springer Science+Business Media New York 2013
332 Index

Biologic active pharmaceutical ingredient (API) (cont.) Biologics License Application (BLA), 6
cell-based medicines production, 159–160 Bioreactor cell culture production
expression clinical phase-appropriate cell culture control, 150–154
animal/human cell, 140–142 criticality, genetic stability
bacterial cell, 140–142 EMA withdrawal assessment report, 148
insect cell, 140–142 FDA BLA Review, 148–150
transgenic animal, 141, 142 in vitro cell age, 145
yeast cell, 140–142 design/operational mode choice, 143–145
genetically engineered viruses, 158–159 Biosimilar User Fee Act (BsUFA) meetings, 322
process validation Bovine spongiform encephalopathy (BSE), 60, 62
biologic substance manufacture, 169–170
EU GMP annex, 170–171
ICH Q11, 170 C
monoclonal antibody, 171 Cell banks, protein manufacture
recombinant protein, 171–172 adequate and appropriate characterization, 117–119
protein purification criticality, proper cloning, 109–113
chromatography, 161–163 gene activation, 108
clinical phase-appropriate purification process genetic construction, 107–109
control, 163–168 Good Manufacturing Practice (GMP)
monoclonal antibody, 163 maintenance, 119–124
physical separation methods, 160–161 preparation, 117
transgenic animals, 155–156 importance, adequate documentation, 113–116
transgenic plants, 156–157 Cell-based medicines production, 213
viral vaccines, 157–158 biologic API, 159–160
virus purification, 168–169 viruses, 81–83
Biologic final product process Cellular and gene therapy (CGT) biologics, 247–248
assembly Cell viability, 117, 121, 122, 258
control strategy, 193–196 Center for Biologics Evaluation and Research (CBER), 15
stringent aseptic processing, 192–193 Center for Drug Evaluation and Research (CDER), 15
chemical modifications, protein API Chemical adducts, 224
chemical linker, 181–182 Chemical modifications, protein API
conjugate vaccines, 182–183 chemical linker, 181–182
pegylation, 180–181 conjugate vaccines, 182–183
container closure materials pegylation, 180–181
abundance, 189 Chinese hamster ovary (CHO)
extractables and leachables, 191 animal/human cell expression, 140
pure red blood cell aplasia (PRCA), 192 production runs, 74
two-way interactions, 189–191 Clinical phase-appropriate approach
formulation bioreactor cell culture production, 150–154
Bayer Corporation, 188–189 comparability study design
development, 187–188 early-stage, 229–300
excipients, 183–186 late-stage, 302–304
regulatory risk, 186–187 phase 1, 299
Biologics phase 3/after market approval, 302–303
differences complex process-related impurities, 201–202
complexity, 26–27 expiry dating strategy
living production systems, 24–25 early-stage clinical development, 275–277
manufacturing process, 25–26 late-stage clinical development, 277
dogma, regulatory authority, 31 market approval, 277–278
EMA, biosimilar medicines, 27–28 molecular structural analysis
FDA early clinical stage, 227
biosimilar biological products, 30–31 later clinical stage, 227
follow-on proteins, 29–30 market approval stage, 227–231
Health Canada, subsequent entry biologic (SEB), protein purification
28–29 control strategy, 168
regulatory authorities viewpoint PIC/S regulatory aid, 163, 166
EMA, 22–23 process validation/evaluation, 167–168
FDA, 22 purification and modification reactions, 163, 167
ICH, 23–24 quality control (QC) testing
WHO, similar biotherapeutic product (SBP), 29 early-stage clinical development, 260–261
Index 333

late-stage clinical development, 261 European Union (EU) legal system

market approval, 261 clinical development, 16–17
CMC-focused regulatory meetings embracement, 18
Biosimilar User Fee Act (BsUFA), 322 legal definition, 16
EMA, 323 MAA regulatory drug development pathway, 16
first-cycle review, 319–321 market approval, 17–18
NDA/BLA submissions, 323–324 United States legal system
Prescription Drug User Fee Act (PDUFA) biological product deviations, 14
end-of-phase 2 (EOP2), 321 Biologics License Application (BLA) pathway, 6
FDA instructions, 320, 321 Center for Biologics Evaluation and Research
pre-Investigational New Drug (pre-IND), 320–321 (CBER), 15
pre-NDA/BLA submission, 320–321 Center for Drug Evaluation and Research
CMC regulatory compliance strategy (CDER), 15
clinical phase-appropriate conjugated monoclonal antibodies, 7–8
EMA strategy, 54–55 FDA batch prerelease, 13–14
FDA strategy, 53–54 Food, Drug, and Cosmetic (FD&C) Act, 4
ICH strategy, 55 general safety, 8–10
industry strategy, 55 identity test, 10–12
definition, 35 license suspension, 14–15
five core strategic elements NDA regulatory drug development pathway, 4
address, biologic products, 40–43 pharmaceutical laws, 6–7
align to strategic ICH guidance, 42–47 Public Health Service (PHS) Act, 4–6
autologous cellular therapy manufacturing specified biologics, 6
process, 40, 42 sterility testing, 8
CGMP requirements, 47–52 Complex process-related impurities
embrace, 39–40 biosimilar impact, 216
gene therapy manufacturing process, 40, 42 extractables and leachables, 214–216
monoclonal antibody manufacturing process, 40 living system-related impurities
transgenic goat manufacturing process, 40, 41 cell-based medicine processes, 213
forces that shape gene therapy, virus vaccine, 211–213
resource allocation, 37–38 residual culture media components, 207–208
resources, 38–39 residual host cellular proteins (HCPs), 204–207
risk tolerance, 36–37 residual host genomic DNA, 203–204
one-size-fits-all approach, 55–56 success and failure, impurity control, 208–209
Colony-forming units (CFUs), 93, 264 transgenic animal processes, 209–210
Comparability study design transgenic plant processes, 210
analytical comparison virus vaccine, 210–211
outcomes, 295–298 purification-related, 213–214
physicochemical and in vitro/in vivo biological Quality Risk Management (QRM), 200
testing, 295 road map
sequential approach, 295 biologics, 201
clinical phase-appropriate chemical drugs, 200–201
early-stage, 299–300 clinical phase-appropriate approach,
late-stage, 300–302 201–202
phase 1, 299–300 definitions, 200
phase 3/after market approval, 302–303 Container closure materials
FDA, 398–299 abundance, 189
nonclinical/clinical comparison, 398 extractables and leachables, 191
nonprotein biologics, 302–304 pure red blood cell aplasia (PRCA), 192
risk-based two-way interactions, 189–191
general risk factors, 292–293 Contract manufacturing organizations (CMOs),
regulatory authority’s risk perspective, 292–293 37–38
Complexity, biologic CMC regulation Contract testing labs (CTLs), 37, 119
definitions Creutzfeldt–Jakob Disease (CJD), 60
biopharmaceutical, 2–3 Critical process parameters (CPP)
biotechnology-derived, 2–3 ‘’3 run’’ formula, 172
European Medicines Agency (EMA), 2 control strategy
Food and Drug Administration (FDA), 2 biologic final product process, 194, 195
Health Canada, 2 cell culture production process, 153, 154
landscape, pharmaceutical terminology, 3 purification process, 167, 168
334 Index

Critical quality attributes (CQAs) in-use period assignment, 278–279

‘’3 run’’ formula, 172 long-term and accelerated storage conditions,
control strategy 272–273
biologic final product process, 194 problems, 281–282
cell culture production process, 153 regression line analysis, 274–275
purification process, 167 significant change, 274
potency, 248 six-month minimum stability data requirement,
process-related impurities, 200 273–274
product comparability, 297, 298 stability-indicating profile, 272
QC testing, 254 stress conditions, 273
Current Good Manufacturing Practice (CGMP) successful expiry dating, 280–281
application transportation qualification studies, 279–280
API manufacturing, 47, 48 Expression construct
biologic manufacturing, 47, 49 genetic construction, 108, 109
phase 1 clinical stage genetic sequences, 145
European Union, 50–52 ICH Q5B, 114, 115
FDA, 48–50 Extractables and leachables, 214–216

D F
Deamidation, 222 Failure mode effects analysis (FMEA), 44
Design of experiments (DOE), 43 Fetal bovine serum (FBS)
Diafiltration, 161, 167–169 biologic manufacturers, 71
Disulfide scrambling, 225 residual culture media components, 207–208
Drug master file (DMF), 321, 322 Food, Drug, and Cosmetic (FD&C) Act, 4
Food and Drug Administration (FDA)
biosimilar biological products, 30–31
E comparability protocol, 305–306
End-of-phase 2 (EOP2) meeting, 321 comparability study design, 298–299
Endotoxin, 162, 167, 200 definitions, 2
Enzymatic chromogenic substrate assays, 244–245 follow-on proteins (FOPs), 29–30
Enzyme-linked immunosorbent assays (ELISAs), regulatory authorities viewpoint, 22
244, 263 strategy, clinical phase-appropriate, 53–55
European Medicines Agency (EMA) Warning Letter, 51–52, 125, 174
biosimilar medicines, 27–28 Functional activity
CMC-focused regulatory meetings, 323 assays
comparability protocol, 305 caution, surrogate assays, 245–246
definitions, 2 cellular and gene therapy (CGT) biologics,
refusal to approve assay matrix, 247–248
monoclonal antibody, 171 enzymatic chromogenic substrate assays, 244–245
natural-sourced protein, 194 HPLC assays, 245
regulatory authorities viewpoint, 22–23 immunochemical binding assays, 244
strategy, clinical phase-appropriate, 55 monoclonal antibodies, assay matrix, 246–247
withdrawn application in vitro bioassays, 242–244
autologous protein complex, 195 in vivo bioassays, 240–242
recombinant protein, 171–172 pharmaceutical strength, 237–238
European Pharmacopoeia (Ph. Eur.), 87, 93 potency-assigning issues, 250–252
European Union (EU) legal system priceless potency, 238–239
clinical development, 16–17 progressive potency assay implementation
embracement, 18 early-stage clinical development, 249
legal definition, 16 late-stage clinical development, 249–250
MAA regulatory drug development pathway, 16 market approval, 250
market approval, 17–18
Expiry dating strategy
clinical phase-appropriate approach G
early-stage clinical development, Garnick, R., 37
275–277 Gene activation, 108
late-stage clinical development, 277 General safety test (GST), 8–10
market approval, 277–278 Gene therapy, 211–213
extrapolation, shelf life, 274 Gene therapy manufacturing process, 40, 42
frequency of testing, 273 Gene therapy vectors, 232–233
Index 335

Genetically engineered viruses, 158–159 M

Genetic construction, 107–109 Mammalian cell expression. See Animal/human cell
Glycosylation, 224–225 expression
Good manufacturing practice (GMP) Marketing Authorisation Application (MAA), 16
maintenance, 119–124 Mass spectrometry, 220
preparation, 117 Master cell bank (MCB), 131
Medicines and Healthcare Products Regulatory Agency
(MHRA), 52, 278
H Method validation, 38, 55
Health Canada Microbial enumeration testing. See Bioburden testing
definitions, 2 Miller, R., 37
subsequent entry biologic (SEB), 28–29 Mistranslated sequence, 224
High performance liquid chromatography (HPLC), 245 Molecular structural analysis
Host cell proteins (HCP). See Residual host cellular clinical phase-appropriate characterization
proteins (HCPs) early clinical stage, 227
Hydrophobic interaction chromatography (HIC), 162 later clinical stage, 227
Hydrophobicity market approval stage, 228–231
hydrophobic interaction HPLC, 220 consequences, variants, 227
reversed-phase chromatography (RPC), 162, 222 gene therapy vectors, 232–233
posttranslational modification variants
aggregation, 226–227
I disulfide scrambling, 225–226
Immunoassay, 256, 263 glycosylation, 224–225
Immunochemical binding assays, 244 phosphorylation and formylation, 225
Immunogenicity, 311 secondary folding, 226
Insect cell expression, 140–142 primary amino acid sequence variants
International Conference on Harmonisation (ICH) amide hydrolysis (fragmentation), 223
regulatory authorities viewpoint, 23–24 chemical adducts, 224
strategy, clinical phase-appropriate, 55 deamidation and isomerization, 222
Investigational Medicinal Product Dossier (IMPD), mistranslated sequence, 224
16, 173 N-terminus modification, 223–224
In vitro bioassays, 242–244 oxidation, 222–223
In vivo bioassays, 240–242 terminus truncation, 222
Ion exchange chromatography (IEC), 162 protein characterization methods
Isomerization, 222 analytical methods, plethora, 220–221
measurement of quality, 221
proteins, 231–232
K whole cells, 233
Key Process Parameters (KPPs) Molecular variants, 225, 227
control strategy Monoclonal antibody
biologic final product process, 194, 195 conjugated, 7–8
cell culture production process, 154 functional activity, 246
purification process, 167, 168 manufacturing process, 40
risk assessments, 46 process validation, 171
protein purification, 163
quality control (QC) testing, 268
L Mouse minute virus (MMV), 74, 84
Limulus Amebocyte Lysate (LAL), 258, 262 Mycoplasma
Living system-related impurities animal-derived materials, 88
cell-based medicine processes, 213 biopharmaceuticals, transgenic processes, 89–90
gene therapy, virus vaccine, 211–213 cell-based biologic medicines, 90
residual culture media components cell culture processes, 88–89
antibiotics, 207 CMC strategy tip, 90–91
culture additives, 208 detection, 86–87
fetal bovine serum (FBS), 207–208 human threat, 86
residual host cellular proteins (HCPs), 204–207 risk, 86
residual host genomic DNA, 203–204 Myth busting
success and failure, impurity control, 208–209 master cell bank (MCB), 131
transgenic animal processes, 209–210 MCB and WCB, 130
transgenic plant processes, 210 multiple master cell banks, 131–132
virus vaccine, 210–211 working cell bank (WCB), 132–133
336 Index

N CMC strategy tip, 68

Nanofiltration, 161 detection, 61
New Drug Application (NDA) regulatory drug natural-sourced human plasma-derived proteins, 65–66
development pathway, 4 risk, 61
Nonprotein biologics, 303–304 transmissible spongiform encephalopathy (TSE)
N-terminus modification, 223–224 illness, 60
Nuclear Magnetic Resonance (NMR), 221 Process analytical technology (PAT), 43
Process-related impurities. See Complex process-related
impurities
O Product comparability
Office of Regulatory Affairs (ORA), 15 biosimilarity
Oxidation, 222–223 analytical demonstration, 307
expression system, 308
failures, 310–311
P limitations, manufacturing knowledge, 307–308
Parenteral Drug Association (PDA), 279 successes, 309–310
Pegylation, 180–181 goal, 289–290
Peptide mapping, 26, 27 limitations, 311–312
Pharmaceutical Research and Manufacturers of America process change
(PhRMA), 3, 5 after market approval, 289
Phosphorylation and formylation, 225 during clinical development, 288–289
Polymerase chain reaction (PCR), 76, 89 value added, 288
Porcine trypsin, 69, 72 protocol
Posttranslational modification variants elements, 304
aggregation, 226–227 EMA approach, 306
disulfide scrambling, 225–226 FDA agreement, 305–306
glycosylation, 224–225 value added, 304–305
phosphorylation and formylation, 225 study design
secondary folding, 226 analytical comparison, 293–298
Potency clinical phase-appropriate, 299–303
potency-assigning issues, 250–252 FDA, 298–299
priceless potency, 238–239 general risk factors, 291–292
progressive potency assay implementation nonclinical/clinical comparison, 298
early-stage clinical development, 249 nonprotein biologics, 303–304
late-stage clinical development, 249 regulatory authority’s risk perspective, 292–293
market approval, 250 Progressive potency assay implementation
quality control (QC) testing, 259–260 early-stage clinical development, 249
Pre-approval inspection (PAI), 133 late-stage clinical development, 249–250
Pre-Investigational New Drug (pre-IND) meeting, market approval, 250
320–321 Protein API. See Chemical modifications, protein API
Prescription Drug User Fee Act (PDUFA) meetings Protein characterization methods
end-of-phase 2 (EOP2), 321 analytical methods, plethora, 220–221
FDA instructions, 319, 320 measurement of quality, 221
pre-Investigational New Drug (pre-IND), 320–321 Protein purification
pre-NDA/BLA submission, 321–322 chromatography, 161–163
Primary amino acid sequence variants clinical phase-appropriate, API
amide hydrolysis (fragmentation), 223 control strategy, 168
chemical adducts, 224 PIC/S regulatory aid, 163, 166
deamidation and isomerization, 222 process validation/evaluation, 167–168
mistranslated sequence, 224 purification and modification reactions, 163, 167
N-terminus modification, 223–224 monoclonal antibody, 163
oxidation, 222–223 physical separation methods, 160–161
terminus truncation, 222 Public Health Service (PHS) Act, 4–6
Prions Purification-related impurities, 213–214
animal-derived materials
nature and procedures, 64
production process, 64 Q
source animals and geographical origin, 62–64 Quality by design (QbD), 43, 45
biopharmaceuticals, transgenic animals, 66–67 Quality control (QC) testing
cell-based biologic medicines, 67–68 biosimilar specification, 271
Index 337

categories Source material

appearance/description, 255–256 allogeneic cell-based medicine cell banks, 130
general quality attributes, 259 biologic, 106–107
identity, 256–257 cell banks, protein manufacture
potency, 258–259 adequate and appropriate characterization, 117–119
purity/impurities, 257–258 criticality, proper cloning, 109–113
quantity, 259 gene activation, 108
recommended testing programs, 259 genetic construction, 107–109
clinical phase-appropriate approach GMP maintenance, 119–124
early-stage clinical development, 260–261 GMP preparation, 117
late-stage clinical development, 261 importance, adequate documentation, 113–116
market approval, 261 chemical drug, 105–106
general principles myth busting
characterization, 255 master cell bank (MCB), 131
color descriptors, 255, 256 MCB and WCB, 130
critical quality attributes (CQAs), 254 multiple master cell banks, 131–132
overall control strategy, 253–254 working cell bank (WCB), 132–133
release, 255 transgenic banks
stability, 255 animal, 127–128
market approval specifications plant, 128–129
quantitative range, 265–267 virus seed banks
upper limit, 262 gene therapy vector production, 125–126
upper/lower limit, 263–265 viral vaccine production, 124–125
post-market approval specifications adjustment, 267–268 Sterility testing, 8
problems, 270 Stress, 273
release specifications Surrogate assays, 245
autologous cell final product, 268, 269
monoclonal antibody fragment drug substance, 268
recombinant fusion protein final product, 268, 269 T
Quality risk management (QRM), 200 Terminus truncation, 222
Quality target product profile (QTPP), 46, 172 Transgenic animal
biologic API, 141, 142, 155–156
living system-related impurities, 209–210
R Transgenic banks
Recombinant fusion protein final product, 268, 269 animal, 127–128
Reference material, 239 plant, 128–129
Reference standard Transgenic goat manufacturing process, 40, 41
ICH, 238 Transgenic plants
recombinant protein Erwinaze, 305–306 biologic API, 156–157
Refusal-to-file (RTF), 322 living system-related impurities, 210
Regression line analysis, 274–275 Transmissible spongiform encephalopathy (TSE), 60
Replication competent virus (RCV), 159
Residual culture media components
antibiotics, 207 U
culture additives, 208 Ultrafiltration, 161, 167–169
fetal bovine serum (FBS), 207–208 United States legal system
Residual host cellular proteins (HCPs), 204–207 biological product deviations, 14
Residual host genomic DNA, 203–204 BLA pathway, 6
Resource allocation, 37–38 Center for Biologics Evaluation and Research
Reversed-phase chromatography (RPC), 162, 222 (CBER), 15
Risk ranking (RR), 46, 205 Center for Drug Evaluation and Research (CDER), 15
Risk tolerance, 36–37 conjugated monoclonal antibodies, 7–8
Roosevelt, F.D., 70 FDA batch prerelease, 13–14
Rumsfeld, D., 216 FD&C Act, 4
general safety, 8–10
identity test, 10–12
S license suspension, 14–15
Secondary folding, 226 NDA regulatory drug development pathway, 4
Sequential approach. See Analytical comparison pharmaceutical laws, 6–7
Size exclusion chromatography (SEC), 161–162 PHS Act, 4–6
338 Index

United States legal system (cont.) natural-sourced human plasma-derived proteins,

specified biologics, 6 79–81
sterility testing, 8 plant cell lines, 73
United States Pharmacopoeia (USP), 4, 269 purification, 168–169
risk, 69–70
vaccine
V gene therapy, 211–213
Viability. See Cell viability living system-related impurities,
Virus 210–211
animal-derived materials, 71 virus-based biologic medicines, 83–84
bacterial/yeast cell lines, 72–73 Virus seed banks
biologic API, 157–158 gene therapy vector production, 125–126
biopharmaceuticals viral vaccine production, 124–125
transgenic animals, 78–79
transgenic plants, 78
cell-based biologic medicines, 81–83 W
clearance, 50, 77, 78 Whole cells, 233
CMC strategy tip, 84–85 Working cell bank (WCB), 132–133
detection, 70 World Health Organization (WHO)
human threat, 69 guidelines, 111
insect/animal/human cell lines residual host genomic DNA, 203
contamination, 73–74 similar biotherapeutic product (SBP), 29
EMA guideline, 75
ICH Q5A and FDA, 78
model, 76 Y
nonspecific model, 77
relevant viruses, 76
risk factors, 74 Yeast cell expression, biologic API, 140–142