Index

Note: Page numbers followed by f indicate figures, and t indicate tables.

A experimental and analytical variability

Absolute humidity (AH), 39 analytical method uncertainty, 199–200
Accelerated degradation tests (ADTs), 148 batch-batch variability, 204
Accelerated life test (ALT), 147–148 duration of exposure, 200
Accelerated predictive stability (APS), 71t, 411 replicate testing, 204
applications temperature and humidity control, 200–202
formulation process development, 8 unit-unit/sample-sample variability, 202–204
formulation prototype rank ordering, 8 failure of, 176
genotoxic degradation product, kinetic investigation of, 10 fixed humidity stability studies
initial retest period, 9–10 protocol design features, 60–62, 61t
initial use period/shelf life for clinical supply, 9–10 saturated salt solutions, use of, 59
in-use stability, 10 water activity determinations, 60
mass balance investigation, 10 historical context of, 3–4
packaging selection, 8–9 humidity- and temperature-sensitivity coefficients, 68–70,
postapproval changes, assessment of, 11–12, 11t 68–69f, 70–71t
product physical changes, prediction of, 6 impact assessment, 232
registration, 10 initial marketing registration, 236–237
salt forms and polymorphs, comparative assessment isoconversional design, 152–153
of, 7–8 packaging selection, 232
small-molecule drug development, 6–7, 7f packaging strategies, dissolution performance
stability OOS investigation, 10 (see Dissolution performance, packaging strategies)
temperature and moisture excursions, evaluation of, 9 physical property characterization techniques, 182t
Arrhenius stability modeling, 253–254 atomic force microscopy, 184
ASAP (see Accelerated stability assessment program DSC, 183
(ASAP)) dynamic vapor sorption, 184
chemical stability, 34 isothermal microcalorimetry, 183
clinical development, 232–233 NIR and Raman spectroscopy, 184
commercial packaging and potential future changes, PXRD, 183–184
238–239, 238t SSNMR spectroscopy, 185
conversion processes (see Degradation processes) SWAXS, 185
CTAs, 232 physical stability processes, 34
drug substance synthetic route, change in, 235, 236t postapproval change submissions, 236–237
initial use period assignment, ASAP data, 233–235 potential opportunities, 239–240
stability-related CTA queries, 236, 236t practical considerations (see Practical considerations,
data processing APS study)
humidity, irregular effects of, 196–198 prediction accuracy and precision, 204, 205f
non-Arrhenius effects of temperature, 195–196 principles of, 4–5
degradation rate (see Degradation rate, APS study) product understanding and modeling algorithms, 232
design of experiment approach, 34, 232 retest period, 231–232
drug product composition selection, 239, 239t shelf-life prediction, basic data processing, 63–64, 63t
drug product use period assignments, 232 SLLA, 232
drug substance containing different particle sizes, solid forms changes
237–238 cocrystal breakback/formation, 179
effects of moisture, Arrhenius model, 148–149 deliquescence, 180, 181t
embedding new process within business (see Embedding APS evaporation and sublimation, 181–182
within business) hydration/dehydration, 178
enabled robust stability protocol design, 232 melting, 181, 181t

471
472 Index
Accelerated predictive stability (APS) (Continued)
polymorph conversion, 178
process-induced disorder/amorphous content, 179–180
salt disproportionation/salt formation, 178
solvate drug product, desolvation of (see Desolvation, DMSO)
stability durations and timepoints, selection of, 57–58
stability testing, purpose of, 231–232
statistical methods, 64–67
storage conditions, 232
temperature and humidity conditions, selection of, 56–57
thermal stress, 148
vs. traditional long-term stability studies, 176
workflow, 76, 77f
Accelerated stability assessment program (ASAP), 85–86, 233,
253–254
ASAPprime® software, 4–6, 254–255, 271
chemical stability screening and prediction, 253–254
drug products
lyophilized drug product, 276–279
solid oral drug product, 279–281
drug substance, starting materials, and intermediates
compound A, 272–276, 274–275t
Impurity X formation, 275, 275t
initial ASAP model prediction vs. long-term stability data,
274, 274f
initial stability assessments, 272
polyethylene packaging, 272–273
second ASAP model prediction vs. long-term stability data,
275, 275f
stress-screening studies, 272, 273t
unmilled and milled compound A, 276, 276t
general process flow, 259, 260t
generic drug development (see Generic drugs)
isoconversional model-free approach, 4
methodology, 270–271
moisture modified Arrhenius equation, 4
nicotine lozenges (see Nicotine lozenges)
package modeling
Arrhenius coefficients, 259
dynamic moisture uptake profile, 256, 257f
dynamic packaged product environment, 258, 259f
experimentally determined inputs, 258
internal Lilly moisture permeability modeling tool, 256
overall percent impurity prediction, 256, 258f
predicted percent impurity change, 256, 258f
predicted rate of degradation change, 256, 257f
water activity, 256, 257f
postapproval environment (see Postapproval environment,
ASAP)
process improvements, 271
sample equilibration
degradation rate constant, 261–262
at desired temperature inside desiccator with saturated salt
solutions, 265–267, 266f, 268–269f
at desired temperature in temperature- and humidity-
controlled oven, 265
humidity-corrected Arrhenius equation, 259–260
pre-equilibration phase, 264, 264f
relative percent errors, 260–261t, 261–262
sample at room temperature in foil bags, 267–270, 270t
temperature error, 259–260, 260t
thermal and humidity equilibration, 259–260, 264
shelf life (see Initial shelf life prediction)
study design, 254–256, 255t
unstable drug candidate, early development (see Unstable
drug candidate, ASAP application)
water activity
Clausius-Clapeyron equation, 262–263, 263f
equilibrium relative humidity, 262
measurements, 262
working group, 271
Accelerated stability modeling (ASM), 4, 411–412, 449
drug product disintegration time, sodium bicarbonate
(see Sodium bicarbonate, drug product disintegration
times)
ionic liquids drug product (see Ionic liquids)
nicotine lozenges, assay loss
accelerated stability study, experimental design for, 450
analysis of, 450–456
ASAPprime®, 449, 457–460
humidity models, 450
kinetic models, 449–450
long-term storage data, 457
nonlinear regression, 449–450
NRT, 449
solvate drug product, desolvation of (see Desolvation, DMSO)
Accelerated tests (ATs), 147–148
Accelerating kinetic model, 416, 429
Active pharmaceutical ingredient (API), 306, 308, 342–345, 388
AFM. See Atomic force microscopy (AFM)
“AH decelerating kinetic model”, 422, 437
Akaike’s information criterion (AIC), 44, 52
Aluminum-aluminum foil blister packaging, 292
AMBERLITE IRP64, 354, 354f
Amlodipine (AMD) besylate tablet, 296–300
Angiotensin-converting enzyme inhibitors (ACE), 289
Antoine equation, 195
API. See Active pharmaceutical ingredient (API)
APS. See Accelerated predictive stability (APS)
AquaLab water activity meter series 3, 292
Area percent-based method, 95
Arrhenius equation, 36–38, 36f, 253–254, 287–288, 306,
323–324, 327, 330, 350, 370–371, 373t, 377, 377t,
457–460

Arrhenius relationship, 369–370
Arrhenius time-scale least squares, 158, 161
ASAP. See Accelerated stability assessment program
(ASAP)
ASAPprime® software, 8–9, 65, 66f, 98, 254–255, 271, 288,
291, 298, 308–311, 308t, 309f, 327, 330, 332, 334, 346,
347t, 358, 365, 370, 381, 386–387
competitive degradation processes, 187–189, 188f
nicotine lozenges
assay loss, ASM, 449, 457–460
modeling, 360
predicted and actual shelf lives, 361–363
ASM. See Accelerated stability modeling (ASM)
Association of South East Asian Nations (ASEAN) guidelines,
21, 24–25, 25t
Atomic force microscopy (AFM), 182t, 184
Atorvastatin tablets, 300–302, 301t
Autocatalytic reactions, 52–54, 53f
Avarami-Erofeyev reaction model, 346
Avrami-Erofeev transform, 450–454, 454t, 456f
B Critical process parameters (CPPs), 384
Bayesian information criteria (BIC), 44, 52, 406, 416, 422,
429, 450
Benazepril hydrochloride tablets, 384–385
Blister packaging, 339–340
Brunauer-Emmet-Teller (BET) equation, 122
C
Charged aerosol detection (CAD), 96
Chilled-mirror dew-point technology, 292
Clausius-Clapeyron equation, 128–129, 262–263, 263f
Clinical stability studies, regulatory guidance
gaining product knowledge, 18
GMP regulations, 17
ICH guidances, 17–18
phase 1 to 3 clinical supplies, stability requirements for,
18–19
stability data, 16–17
storage conditions and time points, 19–20
Clinical trial applications (CTAs), 232
drug substance synthetic route, change in, 235, 236t
initial use period assignment, ASAP data
“ICH-like” stability programs, 233
immediate-release solid oral dosage tablet formulations,
233
initial 12-month clinical use period/retest period without
queries, 233–235
regulatory submissions, 233, 234t
RRT prediction, 233–235, 234–235f
shelf life-limiting degradants, 233–235, 234t
Index 473
storage conditions, 233
unpackaged samples, 233
stability-related CTA queries, 236, 236t
Cocrystals, 179
Colloidal silicon dioxide (CSD), 313
Common solid-state reaction models, 346t
Competitive degradation processes
ASAPprime® software, 187–189, 188f
reactive environment/state, 186
simulation, 186, 187t, 187f
Consecutive degradation processes
identical temperature and humidity sensitivities
curve shapes, 190–192
simulation, 190, 190f, 191t
types of, 189–190
unequal temperature and humidity sensitivities, 193–194, 193t
Containers for Tablets and Capsules—Permeation method,
292–293
Controlled-release matrix tablet, 339–340
Cooks distance, 57
Critical material attributes (CMAs), 384
Critical quality attribute (CQA), 384
Critical relative humidity (CRH), 79–80, 79–80t, 180, 181t, 342,
385
Critical-to-quality (CtQ), 147–148
Crosspolarization (CP), 185
CTAs. See Clinical trial applications (CTAs)
D
Data analysis, shelf life estimation
accelerated shelf-life model, 170–172, 170t, 171f
experimental design space, 168, 169t
linear interpolation, 155–157, 156f
natural logarithm of shelf life, 156–158, 157f
temperature and relative humidity, 150t, 155–156
APS data generation, 153–154
Arrhenius time-scale least squares, 158
classical kinetic model
unweighted second-stage approach, 159
weighted second-stage approach, 160
common intercept multiple slope regression model
unweighted second-stage approach, 160
weighted second-stage approach, 161
data censoring, 163
data rounding, 163
extended nonlinear regression model, 161–162, 167, 168t,
170–172, 170t
model-fitting methods, results of, 163–166
truncated 44 factorial design (Insert symbol), 162, 162t
two-stage approach, 155
474 Index

“Decelerating kinetic model”, 416–417 packaged product, RH prediction, 388

Degradation processes, 149 product sorption effect on RH, 386–388
competitive processes IR tablets, high-humidity sensitivity
ASAPprime® software, 187–189, 188f commercial formulation development, 388–390
reactive environment/state, 186 HDPE bottles, 388–390
simulation, 186, 187t, 187f humidity modeling, 391
complex processes, 194 manufacturing of tablets, 390–391
consecutive processes (see Consecutive degradation testing, 391
processes) packaging design space, 396–399
reversible processes, 189 softest tablets, 392
solid-state reactions, 149–152, 150t stressing tablets, 392
Degradation rate, APS study temperature and humidity, drug release, 384–385
combined temperature and humidity model Dissolution prediction
humidity raised to power of constant, 41–42 accelerated experimental conditions, 375
model selection, 42–44 ASAPprime® software, 374–375
relative humidity, 40–41 data analysis
external/internal factors, 35 ASAP data inputs, 377
humidity, 38–39 dissolution modeling hypothesis, 376–377
linear degradation model, 45–46 modeling results, 377
nonlinear degradation profiles passing specification, predicted probability of, 378
complex chemical degradation mechanisms, 46 methods, 375
degradation profile shapes, 46–48, 47f model verification
heterogeneous physical states, 46 predicted %dissolution vs. real-time stability data, 381
isoconversion methods (see Isoconversion approach) tablet water content, packaged product on stability, 380
kinetic model approach, 48–50 product’s bioavailability, 374–375
limit of degradation, 46 under stressed conditions, 376, 376f
nonfixed humidity environment, 46 tablet water content, 374–375
nonlinear physical and solid-state processes, 46 Drug formulation development
shape parameter approach, 50–54, 51t, 53f controlled-release matrix tablet, 339–340
oxygen level, 44–45, 45f data analysis and modeling, 327
physical state effects, 177–182, 177f degradation rate, 323–324
temperature, 36–38, 36f experimental setup
Design of experiment (DOE) approach, 34, 232 ASAP samples, 325–327
Desolvation, DMSO temperature/humidity control and recording,
API, 463–464 stress stations with, 324–325
content analytical method, 463 in-house stress stations, 328
drug product “M” ASM experiment liquid formulations, 331–333
experimental data, 464, 465f lyophilized formulation
kinetic model fitting and selection process, 465–466, ASAP study, 335–338
465–466f drug substance ASAP study, 333
long-term stability (model) and actual stability (data), prelyophilization solution ASAP study, 334–335
466–468, 467–468f processing stages, 333
temperature-humidity experimental design, 464, 464f shelf-life prediction, 324
Differential scanning calorimetry (DSC), 182t, 183 single accelerated stability studies, 323–324
Diffusion reaction model, 346 suspension formulation, 328–330
Dimethylsulfoxide (DMSO), desolvation. See Desolvation, DMSO Drug product development
Dissolution performance, packaging strategies drug product performance, 210
CQA, 384 early drug product development (see Early clinical drug
hardest tablets, 392 product development, APS testing)
humidity changes in excipient compatibility study, 209–210
desiccants effect on RH, 388 manufacturability, 210
moisture protection, 386 Dry granulation process, 390–391
 Index 475

direct compression approach, 212 Equilibrium relative humidity (ERH), packaging simulations,
excipients, 239, 239t 106
platform formulation chemical degradation rates, 106
compositions, 213, 213t degradation curve shape, 138–140
publications, 212–213 instantaneous humidity, 136–140, 137t
selection process, 214, 215f function of time, 106–107, 107f
roller compaction simulation, 212 humidity excursions, stability risks of, 144
Dynamic moisture sorption microbalance (DMSM), 291 LDPE bags, 115, 116f
Dynamic vapor sorption (DVS) technique, 110–111, 111f, 120, shelf life–limiting attributes, effects on, 144–145
128, 182t, 184, 356–357, 377, 386–387 starting value, estimation of, 109
water activity measurements, 109–110
water content, moisture sorption isotherms
E BET equation, 122
Early clinical drug product development, APS testing DVS technique, 110, 120
advantages, 208 entire packaging contents, 124–127
challenges, 208–209 GAB equation, excipients and desiccants, 120–124, 121f,
chemical incompatibilities, 210 123–124t
FAST formulation approach (see Focused accelerated headspace (air), 119–120
scientific testing (FAST) approach) hygroscopic amorphous drug substance, KF analysis,
goals in, 207–208 111–112, 111f
Electrospray ionization (ESI) interface, 327 Langmuir isotherm, desiccants, 120–122, 121f
Embedding APS within business sorption, desorption, and hysteresis, 127–128
associated gaps/risks, 244–245 temperature, effect of, 128–129
business process construction water activity of product, calculation of, 129–130
appropriate action, 252 Excel kinetic analysis, 347t
design of experiments, 247 Excipient compatibility study, 209–210
models/outcomes interrogation, 252 Expanded Arrhenius model, 153
stability models, 252 “Exp RH Decelerating” model, 450
stability protocol execution, 251 Extended Arrhenius model, 159–160
standardization, 251 Eyring equation, 38
workflow, 251
current stability practices, 244–245
development process, 244–245 F
implementation roll-out approach First-in-human (FIH) clinical trials, 312
“The Chasm”, 248–250 First-order kinetic model, 50
“The Gap”, 248–250 First-order reaction model, 346
lead user model, 248–250, 249f Fisher Scientific Isotemp incubators, 324–325
software package, 250 Fixed-dose combination (FDC) tablet, 374–375
perceived risk, 245–246 Fluid bed-drying process, 345–349
reframing, 246 Focused accelerated scientific testing (FAST) approach
risk aversion, culture change, 243–244 APS stability testing
risk mitigation strategy, 246 advantages, 217–218
stakeholder efficiency gains, 216, 216f
budget holders, 247 four- (or five-) point APS study, 216–217, 217t
internal regulatory, 248 goal, 214–215
manufacturing organization, 248 roller compaction performance, 215–216
map, 246, 247f BCS Class I compound
packaging groups, 248 APS stability data, 221, 221t
product development departments, 247–248 granule particle size distributions, 219, 220f
quality assurance group, 248 hardness vs. compression profile, 219, 220f
senior sponsors, 246 long-term stability data at ICH conditions, 221, 221t
statisticians/internal modeling experts, 247 SF-TS relationship, 219, 219f
476 Index

Focused accelerated scientific testing (FAST) approach H

(Continued) Handerson-Hasselback equation, 354, 354f
BCS Class II compound, amorphous polymer-based Hard gelatin capsule (HGC), 312
dispersion Headspace moisture analyzer model FMS-1400H, 327
granule particle size distributions, 224–226, 225f Heat induction seals (HIS), 116–118, 134
hardness vs. compression profile, 226, 226f High-resolution mass spectrometry (HRMS), 339
ICH chemical stability, 227, 227–228t Hydroxypropyl beta cyclodextrin (HPBCD), 315
physical stability, 226, 227t Hydroxypropyl methylcellulose (HPMC), 312, 339
SF-TS relationship, 224, 225f
temperature/humidity conditions, 226, 227t
BCS Class I/II compound, moderate drug loading I
APS stability data, 222, 223t Initial shelf life prediction
granule particle size distributions, 222, 223f control strategy, 381–382
SF-TS relationship, 222, 222f degradation product analysis, 371
stability data at ICH conditions, 223, 224t early development stage, 370
characterization tests, 211 experimental conditions, 371
fit-for-purpose paradigm, 211 investigational drugs, tablet formulation, 370
nonstandard excipients, 218 isoconversional approach, 370
platform formulations packaging configurations, 371–374, 374t
dry granulation (see Dry granulation process) International Conference on Harmonization (ICH) guidance
intragranular vs. extragranular lubrication, 214 clinical stability studies, 16–18
publications, 212–213 registration stability, 20–23, 22t
precautions, 218–219 Ionic liquids
standardized formulation platforms, 211–212 chromatographic results, 416
Foil-foil blisters, 293, 299–300, 386 data analysis and modeling, 416–445
Food and Drug Administration (FDA), 300 glutaric acid formulation
FreeThink Technology, 360 accelerated stability experimental results for, 414t
analysis of, 417
lactic acid formulation
G accelerated stability experimental results for, 415t
GAB equation. See Guggenheim-Anderson-de Boer (GAB) analysis of, 417–445
equation materials, 412
Gas chromatography (GC)-based methods, 96 methods
Gaussian distribution, 153, 198–199 analytical methodology, 413
GCC guidelines. See Gulf Cooperation Council (GCC) experimental methodology, 412–413
guidelines Isoconversional model-free approach, 4
Generic drugs Isoconversion approach
experimental design, 342 advantage of, 54
granulation/drying process change on stability, 345–349 degradation level of interest, 54, 54f
milling process, API, 342–345 disadvantage of, 54
preservative system degradation route, liquid formulation, interpolation and extrapolation, 55
349–351 isoconversion time, 54–55, 54f
Geometric contraction model, 149–150, 150t time to failure, 54
Glass transition, 80–82, 81f zero-order kinetics, 55
Glass transition temperature, 179–180 Isoconversion principles, 187–189, 191
Glutaric acid formulation, 412 Isothermal calorimetry, 209
accelerated stability experimental results for, 414t Isothermal microcalorimetry, 182t, 183
analysis of, 417
Good manufacturing practices (GMP), 17
Guggenheim-Anderson-de Boer (GAB) equation, 120–124, K
121f, 123–124t, 126–127, 291, 298, 356–357, 377, Karl Fischer (KF) analysis, 111–112, 111f
386–387 Kinetic model
Gulf Cooperation Council (GCC) guidelines, 21, 26 drug product “M” ASM experiment
 Index 477

actual vs. predicted, 466, 466f crystalline solids, hydration and dehydration of, 82, 83f
parameter estimates, 466, 466f deliquescent excipients, CRH of, 79–80, 79–80t
selection process, 465–466, 465f melting point, 78, 78t
nonlinear degradation profiles, 48–50 physical changes, 76–77
temperature-/humidity-induced polymorph conversion, 83
Maximum daily dosage (MDD), 350–351
L Mean kinetic temperature (MKT), 9, 36
Lactic acid formulation, 412 Microcrystalline cellulose (MCC), 339
accelerated stability experimental results for, 415t Minitab software package (version 16), 302
analysis of Moisture modified Arrhenius equation, 4
assay data, 417–422 Moisture permeability, packaging simulations
“Deg9” degradation product, 437 MVTR/WVTR, 107, 112–113
N-oxide degradation product, 422 permeability
RRT 0.51 degradation product, 422 applications, 113–114
RRT 0.72 degradation product, 422–428 bottle size, 118
RRT 0.84 degradation product, 429 definition, 113
RRT 0.90 degradation product, 429 example coefficients, 114, 114t
RRT 0.97 degradation product, 429–436 HIS for bottles, 116–118
RRT 1.22 degradation product, 437 intrinsic permeability, 113–114
RRT 1.35 degradation product, 437 LDPE bags, 114–115
RRT 2.02 degradation product, 437–445 multiple packaging layers, 115–116
storage conditions, optimization of, 446–448 Moisture sorption isotherms, 291–292, 356–357
Langmuir isotherm, 120–122, 121f ERH and water content, packaging simulations
Lean stability strategy, 16 BET equation, 122
clinical development, 30 DVS technique, 110, 120
global reception, 31 entire packaging contents, 124–127
line extensions and postapproval changes, 31 GAB equation, excipients and desiccants, 120–124, 121f,
registration, 30–31 123–124t
science and risk based, 30 headspace (air), 119–120
SRQA and SLLA, 30 hygroscopic amorphous drug substance, KF analysis,
Limit of detection (LoD), 151 111–112, 111f
Limit of linearity (LoL), 151 Langmuir isotherm, desiccants, 120–122, 121f
Limit of quantitation (LoQ), 151 sorption, desorption, and hysteresis, 127–128
Linear Arrhenius model, 9 temperature, effect of, 128–129
Linear degradation model, 45–46 water activity of product, calculation of, 129–130
“Linear Time Kinetic Model”, 416, 422 nicotine lozenges, 356–357
Liquid formulations, 331–333, 332t pharmaceutical solids, 297–298
LTQ Orbitrap, 327 Moisture vapor transmission rate (MVTR), 8–9, 100, 107,
Lyophilized drug product, 276–279 112–113, 238, 238t, 292–293, 384–386
Lyophilized formulation, 276–278, 278t Monte Carlo method, 157–158, 198–199, 293, 298, 302
ASAP study, 335–338 Multilinear regression analysis, 40–41, 52
drug substance ASAP study, 333 Multinonlinear regression analysis, 40–41, 53–54
prelyophilization solution ASAP study, 334–335
processing stages, 333
N
Near-infrared spectroscopy (NIR), 182t, 184, 190
M Nicotine lozenges
MadgeTech, 356 ASAPprime® modeling, 360
Marketing authorization (MA), 236–238 ASAP study design, 356
Mass spectrometry detection (MSD), 96 assay loss, ASM
Material attributes, APS study accelerated stability study, experimental design for, 450
amorphous drugs, glass transition and crystallization, 80–82, analysis of, 450–456
81f ASAPprime®, 449, 457–460
478 Index

Nicotine lozenges (Continued) intrinsic permeability, 113–114

humidity models, 450
kinetic models, 449–450
long-term storage data, 457
nonlinear regression, 449–450
NRT, 449
bioavailability of, 354
desiccant strip (molecular sieve), 354–355
dosage forms, 353
HPLC, 358
instability, 366
isoconversion points estimation, 358–359
lipophilic mucosal tissues, 354
long-term stability/nicotine assay of, 355f
moisture sorption isotherm, 356–357
oromucosal tissues, 354
pH, 353
polymethyacrylate polymer, 354f
polypropylene vial, 355f
predicted and actual shelf lives
calculation, 361–363
discrepancies, 363–365
PVdC blisters, 354–355, 355f
stability limit, 358
temperature and humidity, 355–356
Nicotine polyacrilex (NPA), 354, 354f
Nicotine replacement therapy (NRT), 353
NIR. See Near-infrared spectroscopy (NIR)
Nonlinear regression model, 158, 161–162
Nonmoisture-equilibrated tablets, 375
Nucleation models, 149–150, 150t
O commercial space, 288
Optical microscopy (OM), 182t, 184
Out-of-specification (OOS) stability, 288–296
P multilinear regression approach, 288
Packaging simulations
accuracy assessment, experiment, 135–136
bottle count, moisture protection, 141, 142f
equilibrium relative humidity (see Equilibrium relative
humidity (ERH), packaging simulations)
in-use stability study, 142–143, 143f
multiple packaging layers, 132–133
MVTR/WVTR, 107, 112–113
packaging selection, 141
permeability
applications, 113–114
bottle size, 118
definition, 113
example coefficients, 114, 114t
HIS for bottles, 116–118
LDPE bags, 114–115
multiple packaging layers, 115–116
steps for, 130–131
typical process for, 108–109, 108f
user-intervention events
adding/refreshing desiccant, 134
air exchange, 133–134
HIS bottle, permeability of, 134
removing product/desiccant, 134
Parahydroxybenzoic acid (PhBA), 350
Permeability, packaging simulations
applications, 113–114
bottle size, 118
definition, 113
example coefficients, 114, 114t
HIS for bottles, 116–118
intrinsic permeability, 113–114
LDPE bags, 114–115
multiple packaging layers, 115–116
Pharmacokinetics (PK), 384
Photodiode array detection (PDA), 96
PIB. See Powder-in-bottle (PIB)
PIC. See Powder-in-capsule (PIC)
Polychlorotrifluoroethylene (PCTFE), 386
Polymer excipients, 81–82
Polynomial equations, 291
Polyvinyl chloride (PVC), 386
Polyvinylidine chloride (PVDC), 386
Postapproval environment, ASAP
amlodipine besylate tablet, 296–300
Arrhenius kinetics, 287–288
degradation kinetics, 288
ICH conditions, 289
in-processed samples, sampling scheme for, 295t
magnesium carbonate, 289, 294
OOS stability issues, 289–296
packaging configuration changes, 300–302
pharmaceutical production, 288
proposed package change, 299–300, 302
stability data, 288
temperature and relative humidity, 287–288
water activity, 292
Postapproval Stability Protocol and Stability Commitment,
236–237, 239
Powder for oral solution (PfOS) prototype formulations
capsule shell, PIC assessment, 312
excipients effects and capsule shell, 313–314
Powder-in-bottle (PIB), 312, 314t
Powder-in-capsule (PIC), 312, 314t
Powder X-ray diffraction (PXRD), 182t, 183–184
 Index 479

Power model, 416 Reaction order model, 149–150, 150t

Practical considerations, APS study, 76, 77f Registration stability studies
analytical testing methods, 96t aim of, 20
appearance/description, 95–96, 96t ASEAN guidelines, 21, 24–25, 25t
artificial degradation product, 97 data analysis, 28
assay and degradation products, 96, 96t GCC guidelines, 21, 26
degradation product, identification of, 96–97, 96t ICH guidance, 20–23, 22t
physical tests, 96, 96t lean stability strategy, 30–31
report of results, 97 minimum data requirements, principles for,
suitability of, 95 27–28
data fitting, 97–100, 99–100t postapproval stability requirements
material attributes, evaluation of changes, classification of, 29, 29t
amorphous drugs, glass transition and crystallization, commitment, 28
80–82, 81f regional/country-specific guidance documents, 21,
crystalline solids, hydration and dehydration of, 82, 83f 26–27
deliquescent excipients, CRH of, 79–80, 79–80t stability testing, purpose of, 20
melting point, 78, 78t WHO guidelines, 21, 23–24, 24t
physical changes, 76–77 Regulatory stability guidance
temperature-/humidity-induced polymorph clinical stability studies
conversion, 83 gaining product knowledge, 18
moisture sorption/desorption isotherm of product, 100 GMP regulations, 17
MVTR of packaging, 100 ICH guidances, 17–18
protocol design phase 1 to 3 clinical supplies, stability requirements
comprehensive approach, 90, 90t for, 18–19
information, 84 stability data, 16–17
isoconversion limit, 84–85 storage conditions and time points, 19–20
lean approach, 86–87, 87t lean stability strategy, 16
storage conditions, time points, and repeats, 85–90, 86f clinical development, 30
temperature and relative humidity limits, 84 global reception, 31
two-step approach, 87–90, 88t, 89f line extensions and postapproval changes, 31
sample storage, 90–91 registration, 30–31
and pull schedule, 94–95 science and risk based, 30
saturated salt solution, use of, 91, 92t, 93f SRQA and SLLA, 30
temperature and RH stability chambers, use of, 91–94, registration (see Registration stability studies)
93t, 94f Relative humidity (RH), 106, 292
Prediction error sum of squares (PRESS), 67 degradation rate, 37–42
Prior approval supplement (PAS), 237 limits, 84
Process-induced disorder, 179–180 packaged products
Prout-Tompkins data transformation, 450–454, 454t, 455f, ERH (see Equilibrium relative humidity (ERH),
457–460 packaging simulations)
Prout-Tompkins model, 149, 150t moisture sorption/desorption isotherm, 100
Pseudo-zero-order model, 159 MVTR, 100
PXRD. See Powder X-ray diffraction (PXRD) stability chambers, use of, 91–94, 93t, 94f
PyroButton-SQL software, 325, 328 Relative standard deviation (RSD), 199–200
Resodyn Acoustic Mixer (RAM), 316–317
Q Reversible degradation processes, 189
RH accelerating model, 453
Quality-by-design (QbD) perspective, 384–385
RH linear time model, 450
Quinapril tablets, 289–292, 291t, 294–296
“RH Power” model, 422, 453
Risk-based predictive stability (RBPS), 5–6
R Risk mitigation strategy, 246
Raman spectroscopy, 182t, 184 Root mean square error (RMSE), 66
Raoult’s law, 180 Ross equation, 80
480 Index

S trona hypothesis, 409

Sample storage, APS study, 90–91 Sodium dodecyl sulfate (SDS), 326
and pull schedule, 94–95 Solid fraction tensile strength (SF-TS) relationship
saturated salt solution, use of, 91, 92t, 93f BCS Class I compound, 219, 219f
temperature and RH stability chambers, use of, 91–94, 93t, BCS Class II compound, amorphous polymer-based
94f dispersion, 224, 225f
SAXS. See Small-angle X-ray scattering (SAXS) BCS Class I/II compound, moderate drug loading, 222,
Scanning electron microscopy (SEM), 404 222f
Second-order reaction model, 346 Solid oral drug product, 279–281
SF-TS relationship. See Solid fraction tensile strength (SF-TS) Solid oral formulation (SOF) assessment, 311–312,
relationship 314–315
Shape parameter approach, 192 Solid-state NMR (SSNMR) spectroscopy, 182t, 185
AIC and BIC, 52 Sorption-desorption moisture transfer model (SDMT), 291
Avrami-Erofeyev process, 50–51 SOTAX DT 2 Disintegration Tablet Tester, 391
curve shapes, 50, 51f Stability-related material attributes (SRMAs), 7–8, 11–12
limitation, 51 Stability-related quality attributes (SRQA), 30, 237
multilinear regression, 52 Suspension formulation, 328–330
sigmoidal and exponential kinetics, 52–54, 53f SWAXS. See Small- and wide-angle X-ray scattering
solid-state degradation processes, kinetic expressions for, (SWAXS)
50–51, 51t
Shelf life T
data analysis (see Data analysis, shelf life estimation) Tablets development
definition, 147–148 API-excipient binary system, 314
initial shelf life (see Initial shelf life prediction) binary excipient compatibility study, results of,
predictions 315–316t
atorvastatin tablets, 300–302 degradation-free excipients, 314–315
based on 30ºC/75%RH conditions, 293f, 295f prototype tablet formulations
confidence intervals, 293, 302 basic stabilizers, 320–321
degradant A, 296, 298 common excipients, 317–319
degradant B, 302 SOFs, 314–315
extrapolations, 293, 299, 302 tablet stability process, 316–317
packaging, 299–300 Thermogravimetric analysis (TGA), 183
quinapril tablets, 289–290, 292, 295–296 Trifluoroacetic acid (TFA), 326
real-time data, 289 Turbula-blending process, 316–317, 317t
stability data, 288
Shelf life-limiting attributes (SLLAs), 5, 7, 30, 232
Sigmoidal degradation profiles, linearization of, 450–456
U
Unstable drug candidate, ASAP application
Simulations, packaged products. See Packaging simulations
Arrhenius equation, 306
Single-pot process, 345–349
drug product stability assessment
Small- and wide-angle X-ray scattering (SWAXS), 182t, 185
PfOS prototype formulations, 312–314
Small-angle X-ray scattering (SAXS), 182t, 185
tablets development, 314–321
Sodium bicarbonate, drug product disintegration times
drug substance stability assessment
accelerated stability data, 405
API initial retest period, 307–309
activation energy, 404
ICH stability data, 309–310
analysis of, 405–407
long-term storage condition, 306–307
curvature types, 404
model-free isoconversional kinetic approach, 306
decomposition reaction, 403–404
short single temperature stress testing protocol, 306
humidity mechanisms, 404
stability testing, 305
long-term disintegration time, 408–409
primary accelerated stability study experimental
design, 405 V
SEM observation, 404 Vapor pressure (VP), 39, 41–42
 Index 481

W X
Water vapor transmission rate (WVTR). See Moisture vapor XLfit software, 98, 98f
transmission rate (MVTR)
Wet granulation process, 212, 289, 294–296, 385 Z
Whole-vial-assay approach, 413 Zero-order reaction model, 346
World Health Organization (WHO) guidelines, 21, 23–24, 24t