List of Abbreviations
Acronym DefinitionACN AcetonitrileACVA azobis-cyan valeric acidAFM atomic force microscopeAIBN 2,2-azobisisobutyronitrileAMPD azobis methyl propionamidine dihydrochlorideANDA Abbreviated New Drug ApplicationANVISA Agencia Nacional de Vigilancia SanitariaAPI Active Pharmaceutical IngredientAR & D Analytical Research & DevelopmentASEAN Association of South East Asian NationsASTM American Society for Testing and MaterialsATR Attenuated total reflectanceBA BioavailabilityBE BioequivalenceBLA Biologics License ApplicationCAPA Corrective and Preventive ActionsCBE Changes Being EffectedCBE-30 Changes Being Effected – 30 DaysCBER Center for Biologics Evaluation and ResearchCDER Center for Drug Evaluation & ResearchCDRH Center for Devices and Radiological HealthCE Capillary ElectrophoresisCE Conformite EuropeenneCFR Code of Federal RegulationscGMPs current Good Manufacturing PracticesCHMP Committee for Medicinal Products for Human UseCI confidence intervalCMC Chemistry, Manufacturing & ControlsCOA Certificate of AnalysisCQA Critical Quality AttributeCR Child ResistantCRH Critical relative Humidity
371
372 List of Abbreviations
CRO Contract Research OrganizationCRT Controlled Room TemperatureCTD Common Technical DocumentDES Drug eluting stentDMF Device Master FileDMSO DimethylsulfoxideDPI Dry powder inhalerDRIFTS Diffuse reflectance infrared Fourier-transform spectroscopyDSC Differential scanning calorimetryECMWF European Centre for Medium-Range Weather ForecastsEEC European Economic CommunityELISA Enzyme-linked immunosorbent assayEMEA European Medicines AgencyEMRO World Health Organization (WHO) Regional Office for the
Eastern MediterraneanEP European PharmacopoeiaERH Equilibrium relative humidityEU European UnionFAR Field Alert ReportFDA Food and Drug AdministrationFID Flame Ionization DetectorFMEA Failure Mode and Effects AnalysisFT-IR Fourier Transform Infrared spectroscopyGC Gas ChromatographyGCC Cooperation Council for the Arab States of the GulfGHTF Global Harmonization Task ForceHDPE High density polyethyleneHMG 3-hydroxy-3-methyl-glutarylHPLC High performance liquid chromatographyICH International Conference on HarmonizationIEF Isoelectric focusingIFPMA International Federation of Pharmaceutical Manufacturers &
AssociationsIFU Instructions for useIGC Inverse gas chromatographyIND Investigational New DrugIP Intellectual propertyIPAC-RS International Pharmaceutical Aerosol Consortium on Regulation
and ScienceIQ Installation qualificationIRA Interim Revision AnnouncementISO International Organization for StandardizationITFG Inhalation Technology Focus GroupJ-NDA (Japan) New Drug ApplicationJPMA Japan Pharmaceutical Manufacturers Association
List of Abbreviations 373
KBr Potassium bromideLC/MS-MS Liquid chromatography/Mass spectroscopy-Mass spectroscopyLC-NMR Liquid chromatography/Nuclear magnetic resonanceLC-PDA Liquid chromatography/photo-diode arrayLIMS Laboratory information management systemLOD Limit of DetectionLOD Loss on DryingLOQ Limit of QuantitationLVP Large Volume ParenteralMDD Medical Devices DirectiveMDI Metered Dose InhalerMHLW (Japan) Ministry of Health, Labour and WelfareMKT Mean Kinetic TemperatureMPD Medicinal Products DirectiveMRI Magnetic Resonance ImagingMS/ELSD/CAD Mass Spectrometry/Evaporative Light
Scattering Detector/Charged Aerosol DetectorMVA Multi-variate analysisMVTR Moisture vapor transmission rateNCEs New Chemical EntitiesNDA New Drug ApplicationNIR Near-infrared (IR)NIST National Institute of Standards and TechnologyNMP N-methylpyrrolidoneNMR Nuclear Magnetic ResonanceOCP Office of Combination ProductsOINDP Orally Inhaled and Nasal Drug ProductsOOS Out of SpecificationOOT Out-of-TrendOQ Operational qualificationOTC Over-the-counterP & IDPAC-ATLS Post-Approval Changes – Analytical Testing Lab SitePAL (Japan) Pharmaceutical Affairs LawPAS Prior Approval SupplementPAT Process analytical technologyPCA Principal component analysisPDA Photo-diode arrayPh. Eur. European PharmacopoeiaPLS Partial least squaresPMDA (Japan) Pharmaceutical and Medical Devices AgencyPMOA Primary Mode of ActionPQ Performance qualificationPQRI Product Quality Research InstitutePTI Parametric tolerance interval
374 List of Abbreviations
PVC Polyvinyl chlorideQA Quality AssuranceQA/QC Quality Assurance/Quality ControlQbD Quality by DesignQL Quantitation LimitRA Regulatory AffairsrDNA Recombinant DNARFD Request for DesignationRH Relative humidityRMS Root-mean-squareRS Reference StandardsRSD Relative standard deviationSADC Southern African Development CommunitySBI Significant Body of InformationSDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresisSEC Size-exclusion chromatographySE-HPLC Size-exclusion HPLCSEP Standard error of predictionSFC Supercritical fluid chromatographySIM Stability-indicating methodSOP Standard Operating ProcedureSUPAC Scale Up and Post-Approval ChangesTGA Thermogravimetric analysisTLC Thin layer chromatographyUHPLC Ultra High Performance Liquid ChromatographyUPLC Ultra Performance Liquid ChromatographyUSP United States PharmacopeiaUSP/NF United States Pharmacopeia/National FormularyUTC Coordinated Universal TimeUV UltravioletWFI Water for InjectionWHO World Health OrganizationXRPD X-ray powder diffractionYPD Yearly mean partial water vapor pressure
Index
AAccelerating aging
combining relative humidity andtemperature, 130–131
humidity, 129–130pharmaceutical product shelf-life and,
124–131precision with, 133temperature effects, 124–129
heterogeneous systems, 127–129physical stability, 129simple chemical degradation, 124–127
Accuracyfor analytical method validation, 165–166definition, 165–166
Active pharmaceutical ingredient (API), 2chemical and solid-state forms, 243degradation in pharmaceutical systems, see
Pharmaceutical product shelf-lifeERH effect on stability, 130–131stability requirements for changes,
103–104stability studies, 11–12temperature effect on stability, 130–131
Addition of new strength, stabilityrequirements, 102
Aggregation, 358American Society for Testing and Materials
(ASTM) Raman standardmaterial, 236
Amorphous formdrug substance physical stability, 246–249formation, 247hygroscopicity, 248techniques for physical properties and
stability, 249Analytical method, changes stability
requirements, 107–108Analytical method transfer
acceptance criteria, 179assay, 179–180dissolution, 181–182examples, 184–186experimental design, 179–182impurities and degradation products,
180–181issues, 183process, 176–183protocol, 177–179report, 182
Analytical method validationaspects of, 164–165ICH guideline on, 164method transfer process, 176–183regulatory requirements, 184re-validation, 174with stage of development, 174–175technology transfer, 176in USP, 164–165validation parameters, 165–173
accuracy, 165–166detection and quantitation limits, 171linearity, 167–168precision, 166–167range, 168–169robustness, 171–173specificity, 169–171system suitability criteria, 173
Appearanceand pharmaceutical product shelf-life, 120testing for stability program, 202–207
Approved NDA (ANDA), 94, 184, 280changes in, see Changes to ANDA
Arabian Peninsula, stability guidelines, 71,75–76
Arithmetic mean temperature and MKT, 36ASEAN Guideline on Stability Testing of Drug
Product, 340
375
376 Index
ASEAN member countriesclimatic data for, 56–57stability guidelines, 53–58, 340
development of, 55, 57–58Indonesia, 53–54Philippines, 54
stability requirements, 5testing conditions for, 55, 57
Aspirin tablets, chemical degradation, 242Assay, 334–335Atomic force microscopy (AFM), 248–249
BBeer-Lambert law, 217Beer’s Law, 217Bioanalytical techniques, for biologics stability
testing, 363Bioassays, 355, 363Biologics
ICH Q5C guideline, 360–366drug product stability, 361drug substance stability, 360–361matrixing and bracketing, 361–362stability protocols, 363–366stability tests, 362–363
process changes stability, 367products, 353–354proteins degradation pathways, 356–358and small molecules, 355–356specification setting, 366–367stability considerations, 358–360
Biologics License Application (BLA),360–361
Bracketing, 315–316for biologics, 361–362for drug-device combination products, 344guidelines, 24
Brazilclimatic data, 61–62partial vapour pressure fluctuations in, 59stability guidelines for, 58–63stability testing requirements, 62temperature fluctuations in, 59
Brazilian National Health Authorities, 60Bulk stability studies, 33
CCapillary electrophoresis (CE), 155Capsules stability program, 204–205, 215–216
brittleness testing, 204–205physical tests, 215–216
Caribbean islands, stability guidelines in,86–87, 90
Center for Biologics Evaluation and Research(CBER), 325, 341
Center for Devices and Radiological Health(CDRH) guidance, 324–325,341–342
Center for Drug Evaluation and Research(CDER), 325, 334, 341–342
Central Americastability guidelines in, 84–86, 89–90testing conditions for, 85–86, 89
Certificate of Analysis (COA), 176, 178, 180CGMP stability requirements, 4, 15–17
expiration dating, 17reserve samples, 16–17stability testing program, 15–16
Change in critical excipient, stabilityrequirements, 100, 102
Changes Being Effected (CBE), 95, 97, 184Changes to ANDA
comparability protocols, 111evaluation of, 94–96major changes, 97minor changes, 96moderate changes, 96–97multiple changes, 109–110pharmaceutical development considera-
tions, 111–112stability requirements for, 99–108
analytical method changes, 107–108changes to API, 103–104expiration date changes, 106–107formulation changes, 100, 102manufacturing changes, 99–101packaging changes, 102–103specifications method changes,
107–108stability protocol changes, 104–106
that affects multiple products, 109–110types and
filing requirements, 96–97global filing requirements, 97–99type I variation, 97–98type II variation, 98–99
Chemical form of API, 243Chemical stability, and pharmaceutical product
shelf-life, 116–118, 342Chemistry and Manufacturing Controls (CMC)
dossierdrug product and substance stability
sections in, 282requirement of stability reports, 280–282
Chemometrics, 224, 228–234, 236–237China
Index 377
climatic data for, 64partial vapour pressure fluctuations in, 65stability guidelines for, 63–67temperature fluctuations in, 64–65
Chinese Pharmacopoeia 2005, 65Chiral detectors, 150Climatic data, 47–48
ASEAN member countries, 56–57Brazil, 61–62China, 64equations for, 48–50
dewpoints, 48Mean kinetic temperature, 49–50partial water vapour pressure, 48–49relative humidity, 49saturation water vapour pressure, 48–49temperature, 48
India, 67–69Middle East, 78–79Northern and Eastern Africa, 72–74SADC, 86South Africa, 84Southern Asia, 80
Climatic zonesconcept, 44–45criteria to classify, 45
Chinaclimatic data for, 64partial vapour pressure fluctuations in, 65stability guidelines for, 63–66temperature fluctuations in, 64–65
Chinese Pharmacopoeia 2005, 65Chiral detectors, 150Climatic data, 47–48
ASEAN member countries, 56–57Brazil, 61–62China, 64equations for, 48–50
dewpoints, 48Mean kinetic temperature, 49–50partial water vapour pressure, 48–49relative humidity, 49saturation water vapour pressure, 48–49temperature, 48
India, 67–69Middle East, 78–79Northern and Eastern Africa, 72–74SADC, 86South Africa, 84Southern Asia, 80
Climatic zonesconcept, 44–45criteria to classify, 44–45
for Eastern Mediterranean region,81–82
of India by WHO criteria, 70Koppen–Geiger classification, 45by Schumacher and Grimm, 44and testing conditions, 44WHO classification, 45
Clinical materials expiry dating, 277Clinical supplies of drug, stability studies to
support, 12–13Code of Federal Regulations, 324Color testing, for stability program, 203Combination drugs, and stress testing, 151Combination of drug and device, see
Drug-device combination productsCommercial stability commitment, for
drug-device combinationproducts, 348
Committee for Medicinal Products for HumanUse (CHMP), 23, 27, 325
Common Technical Document (CTD),165, 281
Confocal Raman spectroscopy, 227Congo, partial vapour pressure fluctuations
in, 85Contaminants testing, for stability
program, 203Content uniformity testing, for stability
program, 216–217Corrective actions and preventive actions
(CAPA), 293, 308Creams testing, 206Critical quality and performance attributes
(CQAs), 112Critical relative humidity (CRH), 127–128Current Good Manufacturing Practices
(cGMPs), 164CypherTM, 342
DDeamidation, 357–358Decision tree, for registration of drug-device
combination products, 330–332Deliquescence process, 127Delivered-dose uniformity, in nasal spray and
inhaled products, 335–337Delivery volume testing, for stability program,
213–214Denaturation, 357Density testing, for stability program, 218Design Qualification (DQ), 289Detection and quantitation limits, for analytical
method validation, 171
378 Index
Development of SOPs, 304–309sample
destruction and disposition, 308–309inventory maintenance, 309pulling, 306–307testing turnaround, 307
studyactivation, 306amendment, 308cancellation, 308completion, 308deviation, 308set-up, 305–306
Dewpoints, equations for, 48Differential scanning calorimetry (DSC), 244,
249–250Diffuse reflectance infrared Fourier-transform
spectroscopy (DRIFTS), 245, 249Disintegration testing, for stability
program, 217Disordered forms formation, 247Dissolution testing, for stability program, 202,
219–221Dose content uniformity, in nasal spray and
inhaled products, 333–334, 335Drug-carrier systems, 248Drug development process
clinical phase, 2–3purpose of phases, 2–3registration phase, 3–4stability role in, 10–11toxicological phase, 2
Drug-device combination productsadditional considerations, 328bracketing, 345commercial stability commitment, 348decision tree for registration of, 330–332definition, 324drug eluting stents, 342–343guidance and regulatory framework
available, 324–328implantable delivery systems, 343leachables studies, 344–345matrixing, 345nasal spray and inhaled products, 333–340
assay, 334–335classification, 333delivered-dose uniformity, 335–337dose content uniformity, 335–337in-use testing, 339–340moisture, 338particle–droplet size and fine particle
mass, 337–338
particulate matter-foreign particles inMDIs and DPIs, 338–339
stability considerations-requirements,340
stability tests for, 334storage conditions, 339
pen-injectors, 340–342stability strategies for, 328–333storage orientation, 345–346temperature cycling, 346transdermal products, 343–344transportation studies, 346–347
Drug eluting stents (DES), 342–343Drug instability with time
extrapolation and, 121–123heterogeneous systems, 123and lag time behavior, 123–124shelf-life of, 121–124
Drug productsprotocol, 364–366stability for biologics, 360–361time and temperature schedule for, 365See also Drug substance
Drug registration, stability studies tosupport, 13
Drug substanceacid and base hydrolysis, 148–149oxidation, 149physical stability, 251–258
amorphous form, 246–249chemical and solid-state forms, 243hydrate, 245–246liquid dosage forms, 255–258polymorphism, 244–245powder mixtures and blends, 253–254solid dosage forms, 253–255and solid-state characteristics, 242–251solid-state physical change, 249–251solutions, 255–256suspensions, 256–258tablets, 254–255
protocol, 363–366reaction mechanism and degradation
pathway, 149stability for biologics, 360–361stress testing
parameters, 146recommendation, 29
time and temperature schedule for, 364Drug substance solid-state characteristics
amorphous form, 246–249chemical and solid-state forms, 243hydrate, 245–246
Index 379
and physical stability, 242–251polymorphism, 244–245solid-state physical change, 249–251
Dry powder inhalers (DPIs), 252,333–340, 345
particulate matter-foreign particles in,338–339
registration stability protocol for, 340stability tests for, 334
EEastern Mediterranean region (EMR)
stability guidelines, 70–82Arabian Peninsula, 71, 75–76climatic zones for, 81–82long-term stability testing conditions
for, 81–82Middle East, 71, 78–79Northern and Eastern Africa, 71–74Saudi Arabia, 71, 77Southern Asia, 71, 80
Electrophoretic gel method, 355Emulsion, 252Enzyme-linked immunosorbent assay
(ELISA), 355Equilibrium relative humidity (ERH), 130–131European Agency for the Evaluation of
Medicines (EMEA), 94, 325,327, 333
European Centre for Medium-Range WeatherForecasts (ECMWF), 48
Eutonic mixture, 127Excipient compatibility, 12Excursions, studies to support, 34Expert Working Group (EWG), 23Expiration dating
changes stability requirements, 106–107of clinical materials, 277commercial specifications and extension
of, 277stability program for, 17
FFailure Mode and Effects Analysis
(FMEA), 347FDA draft guidance status, 25–26Federal Register, United States, 23, 27Field Alert Report (FAR), 100, 274Fill volume and delivery volume testing, for
stability program, 213–214Fine particle mass, in nasal spray and inhaled
products, 337–338Finished product forms testing
capsules, 204–205
creams, 206lotions, 206lyophilized products, 206non-sterile solutions, 205–206parenteral, 205–206pressurized delivery systems, 206–207reconstitution time, 206for stability program, 204–207tablets, 204
Flowability testing, for stability program, 203Forced degradation studies
acid and base hydrolysis of drug substancein solution, 148, 150
experimental approach to, 146–149FDA, EMEA guidelines and pharma-
copeias, 144–145ICH guidelines, 142–143reaction mechanism and degradation
pathway, 149for specificity, 169–171for stability-indicating method, 141–151stress testing
conditions, 146–149protocol for, 146
timeline for conducting, 141, 146Formulation
changesaddition of new strength, 102change in critical excipient, 100, 102product reformulation, 100stability requirements, 100, 102
developmentstability studies to support, 12–13
Fourier transform infrared spectroscopy(FTIR), 207, 224, 226, 249
testing for stability program, 207–208Freeze–thaw testing, 34, 359, 365–366Friability testing, 215FT-NIR instrument, 226FT-Raman, 249
GGliadelTMWafer, 343Global Harmonization Task Force
(GHTF), 324Good Manufacturing Practice (GMP)
activity, 362requirements for stability reports,
277–278Guidance and regulatory framework, available
for drug-device combinationproducts, 324–328
380 Index
HHard gelatin capsules, 252Hardness testing, 215–216Health Canada, 94, 333Heterogeneous systems, and drug
instability, 123HPLC stability-indicating method
developmentapproach, 154–155process, 151–158report, 158
mass balance, 157–158on-column degradation and
rearrangement, 157optimization, 155–156peak purity, 155preliminary requirements, 152–154
functional group effects, 153–154physico-chemical properties of
drugs, 153related structures, 154samples of drug, 153
sample stability, 157scope of, 152–153stability-indicating chromatography
conditions, 154–155Humidity
chemical stability and, 129–130and pharmaceutical product shelf-life,
129–130Humidity-controlled thermogravimetric
analysis (TGA), 245, 250Hydrate drug substance
control during drying process, 246physical stability, 245–246
IICH Expert Working Group, 51ICH Q1A(R2) guidelines, 4, 22–39, 51, 94,
164, 325, 360container closure system, 30data evaluation, 33light exposure study, 28selection of batches, 29specifications, 30stability commitment, 32–33storage conditions, 31–32stress testing, 27–29
drug product, 28–29drug substance, 27–29
summary of, 22–32testing frequency, 30–31
ICH Q6B guideline, 362, 367
ICH Q5E guideline, 367ICH stability guidelines, 4, 22–39, 51
applicable to stability testing, 22–39bracketing and matrixing, 25development of, 22–25evaluation of stability data, 25history of, 22–23ICH Q1A(R2), 22–33parent guideline, 24photostability testing, 24stability testing for new dosage forms,
24–25stability testing of biotech products, 25steps in, 23
Identification threshold, definition of, 116Immunoblot method, 355Implantable delivery systems, for drug-device
combination products, 343India
climatic data for, 67–69climatic zone according to WHO
criteria, 70long-term stability test conditions
calculations, 67–70physical and climatic conditions, 67stability guidelines for, 67–70
Indonesia, stability guidelines for, 53–54Inhaled products, 333–340
assay, 334classification, 333delivered-dose uniformity, 335–337dose content uniformity, 335–337FDA guideline for, 339in-use testing, 339–340moisture, 338particle–droplet size and fine particle mass,
337–338particulate matter-foreign particles in MDIs
and DPIs, 338–339stability considerations-requirements, 340stability tests for, 334storage conditions, 339See also Nasal sprays
In-house training, 309In-process testing studies, 33Installation Qualification (IQ), 289–290International Conference on Harmonization
(ICH) guidelines, see ICH stabilityguidelines
International Federation of PharmaceuticalManufacturers & Associations(IFPMA), 55
Index 381
International Organization for Standardization(ISO), 328
International Pharmaceutical AerosolConsortium on Regulation andScience (IPAC-RS), 337–339, 345
Intravenous (IV) solutions, particulate matterin, 218
Intrinsic dissolution, 249In-use testing
for nasal spray and inhaled products,339–340
studies, 34Inverse gas chromatography (IGC), 249Investigational New Drug (IND) guidance,
2, 175IR absorbance spectroscopy, 224Isoelectric focusing (IEF), 355Isothermal microcalorimetry, 249
JJapanese Pharmaceutical Affairs Law
(PAL), 328Japan Pharmaceutical Manufacturers
Association (JPMA), 328
KKarl Fischer testing, 202, 239Karl Fischer titration
blanking of vessel, 209–210handling cautions, 210moisture testing by, 208–210, 246percent recovery standard, 210sample analysis, 210standardization, 210
KIT Drug and Medical DeviceCertification, 327
LLaboratory controls, 17, 310Laboratory information management system
(LIMS), 278, 280, 305, 230Laboratory records, for stability program, 18Lag time behavior, and drug instability,
123–124Large volume parenterals (LVPs), 252Leachables studies, for drug-device
combination products, 344–345Limit of Detection, 171Limit of Quantitation (LOQ), 171, 268–269Linearity, 237
for analytical method validation, 164–165definition, 165
Liquid drug product, physical stability,255–258
Liquids, FTIR spectroscopic testing, 208Liquid sample cells, FTIR spectroscopic
testing, 208Loss on drying (LOD), moisture testing by,
208–209, 246Lotions testing, 206Low solubility drugs, and stress testing, 150Lyophilization cycles, 359Lyophilized products, 206, 358
MManufacturing changes, stability requirements,
99–101Marketing Authorization Application
(MAA), 3Matrixing, 316–319
for biologics, 362design, 315for drug-device combination products,
346–347guidelines, 24
Mean kinetic temperature (MKT)arithmetic mean temperature and, 36calculation, 35–36concept, 34–40definition, 34equations for, 48–50limitations, 39–40temperature
excursions, 39fluctuations, 36–39
Medical Device Certification, 327Medical Device Directive (MDD), 326–327Medical Product Directive (MPD), 326Melting point testing, for stability
program, 218Metered dose inhalers (MDIs), 333,
338–339, 345particulate matter-foreign particles in,
338–339stability tests for, 336
Method transferacceptance criteria for, 179of dissolution, 181–182example, 184–186experimental design, 179–182issues, 183process, 176–183protocol, 177–179report, 182–183
Method validationdocumentation, 175with stage of development, 174–175
382 Index
Microbial growth, and pharmaceutical productshelf-life, 120
Microbiological stability, 242Microscopic image analysis, 249Middle East
climatic data for, 78–79stability guidelines for, 71, 78–79
Ministry of Health, Labour and Welfare(MHLW), Japan, 23, 27
Modulated differential scanning calorimetry(MDSC), 249
Moisture testingin nasal spray and inhaled products, 338for stability program, 208–210
Monographsstandards development process, 191–192validation requirements for
submission, 192Monte-Carlo method, 133Multiple products changes, 109–110Multivariate analysis (MVA), 224–225,
228–233, 236–237
NNasal sprays, 252, 333–340
assay, 334classification, 333delivered-dose uniformity, 335–337dose content uniformity, 335–337FDA guideline for, 339in-use testing, 339–340moisture, 338particle–droplet size and fine particle mass,
337–338particulate matter-foreign particles in MDIs
and DPIs, 338–339stability considerations-requirements, 340stability tests for, 334storage conditions, 339
National Institute of Standards and Technology(NIST)
standard reference materials for NIR, 235Near infrared (NIR) spectroscopy, 225–227,
233–236, 239, 245–246, 249, 254method validation, 236–239NIST standard reference materials for, 235
New Chemical Entities (NCEs), 2, 4, 264New Drug Application (NDA), 94, 165
See also Approved NDA (ANDA)New drug products
degradant allowed for, 117stability studies to develop, 10–11
New drug substance
degradation product in, 277specified impurity in, 276
New employee training, 310Non-chromatographic methods for stability
programappearance testing, 202–207content uniformity, 216–217density, 218disintegration, 217dissolution, 219–221fill volume and delivery volume, 213–214FTIR spectroscopic testing, 207–208melting point, 218moisture testing, 208–210particulate matter, 218pH, 212–213residual solvents analysis, 211–212specific gravity, 218tablet and capsule physical tests, 215–216UV/Vis spectroscopy, 217weight variation, 213–214
Non-sterile solutions testing, 205–206Northern and Eastern Africa
climatic data for, 72–74stability guidelines for, 71–74
OOffice of Combination Products (OCP), 325Operation Qualification (OQ), 289, 290–291Oral solution, 252Oral suspension, 252Ostwald ripening, 119, 257Out-of-Specification (OOS) investigations, 5,
9, 180, 186, 263, 269–275at accelerated conditions, 274checklist, 271confirmation of result, 274form, 273full-scale investigation, 272–274identification of results, 265laboratory investigation, 270–272at long-term storage conditions, 275outlier testing, 274retesting, 272–274trending results, 275
Out-of-Trend (OOT) investigations, 5by-time-point method, 268evaluation for stability, 263, 265–268graphical evaluation, 266–267regression control chart method, 267slope control chart method, 268statistical evaluation, 267
Outside training, 310
Index 383
Over-The-Counter (OTC) drugs, 16Oxidation, 357
PPackaged product, stability prediction in,
133–134Packaging changes, stability requirements for,
102–103Paclitaxel, 342Panama
stability guidelines in, 84–86, 89–90testing conditions for, 85–86, 89
Parametric tolerance interval (PTI) test, 337Parenterals
particulate matter for stabilityprogram, 218
particulate matter in, 218testing, 205–206
Parent ICH stability guidelines (ICH Q1A), 24Partial water vapour pressure (PD)
equations for, 48–49fluctuations
in Brazil, 59in China, 64in Congo, 85in Philippines, 54in Saudi Arabia, 77for South Africa, 83
Particle–droplet size, in nasal spray and inhaledproducts, 337–338
Particulate matterand foreign particles in MDIs and DPIs,
338–339for stability program, 218
Peak purity analysis, 155Pen injectors, 340–342Peptide digest mapping, 355Performance Qualification (PQ), 289, 291–293PH
calibration, 213measurement, 213for stability program, 212–213
Pharmaceutical and Medical Devices Agency(PMDA), 327
Pharmaceutical development, considerationsand changes to ANDA, 111–112
Pharmaceutical dosage forms, physicalattributes in, 252
Pharmaceutical productsstability testing program for, 15–16testing and release for distribution, 17–18
Pharmaceutical product shelf-lifeaccelerating aging and, 124–131
combining relative humidity andtemperature, 130–131
humidity, 129–130temperature effects, 124–129
appearance and, 118–120chemical stability and, 116–118drug instability with time and, 121–124
extrapolation, 121–123heterogeneous systems, 123lag time behavior, 123–124
factors determining, 116–121microbial growth and, 120photochemical degradation and, 121physical stability and, 118precision and, 132–133
with accelerated aging, 133extrapolation with time, 132–133
prediction of stability, 133–134temperature effects
heterogeneous systems, 127–129physical stability, 129simple chemical degradation, 124–127
Pharmacopeial Forum (PF), 191Pharmacopeial harmonization efforts, 359Pharmacopeia of the United States of
America-National Formulary(USPA-NF)
glossary of terms, 190–191history, 190monographs
standards development process,191–192
validation requirements forsubmission, 192
reference standardsqualification process flow, 193in stability testing, 192–193
requirements for stability, 189–199stability requirements, 189–199
case study, 198–199compendial procedures, 195–198compendial tests, 197General Information Chapter 1150
Pharmaceutical Stability, 195information on general notices and
requirements, 194–195parenteral, 198–199solid oral dosage form, 197–198
stability requirements in, 189–199Philippines
partial vapour pressure fluctuations in, 55stability guidelines for, 54–55temperature fluctuations in, 54
384 Index
Photochemical degradation, andpharmaceutical productshelf-life, 121
Photostabilitystudies, 365
Photo-stability chambers, 295–300calibration, 299–300monitoring and alarms, 300options, 295–298preventative maintenance and back-up, 300qualification, 298–299
Physical stability, 242of drug products, 251–258
liquid dosage forms, 255–258powder mixtures and blends, 253–254solid dosage forms, 253–255solutions, 255–256suspensions, 256–258tablets, 254–255
of drug substance, 242–251amorphous form, 246–249chemical and solid-state forms, 243hydrate, 245–246polymorphism, 244–245and solid-state characteristics, 242–251solid-state physical change, 249–251
and pharmaceutical product shelf-life, 118temperature effects on, 129
Polarized light microscopy (PLM), 249Polymorphism and
physical stability of drug, 244–245stress testing, 150
Post-Approval Changes-Analytical TestingLab Site (PAC-ATLS), 184
Powder inhalers (DPIs), 333, 338–339particulate matter-foreign particles in,
338–339Powders, 252
mixtures and blends drug product, 253–254physical stability, 253–254testing for stability program, 203
Pre-approval inspection (PAI), 184Precision, 237
with accelerated aging, 133for analytical method validation, 166–167definition, 166extrapolation with time, 132–133and pharmaceutical product shelf-life,
132–133Pre-clinical supplies of drug, stability studies
to support, 12–13Pressurized delivery systems testing, 206–207Primary Mode of Action (PMOA), 325, 342
Prior approval supplement (PAS), 95, 106Process analytical technology (PAT), 112,
223–224, 245–246, 254Product Quality Research Institute
(PQRI), 345Product reformulation, stability
requirements, 100Prolifeprosan 20 with carmustine implant, 343Proposed changes, evaluation of, 94–96Proteins
degradation pathways, 356–358problems with stability of, 357
Pure Food and Drug Act, 190
QQualification threshold, definition of, 116Quality assurance (QA), 94–95, 112Quality by Design (QbD) concepts, 112,
156–157, 171, 224, 241–242Quality Risk Management guidance, 112Quantitative analysis
and equipment, 224–228equipment qualification, 234–236method validation, 236–239MVA and chemometrics, 228–234vibrational spectroscopy methods for,
223–239
RRaman scattering, 226Raman spectroscopy, 225–228, 236, 239, 254
method validation, 236–239Range, 239
for analytical method validation, 168–169definition, 168
Reach-in stability chambers, 286–287Reconstitution time testing, 206Regional stability guidelines, 53–90
in ASEAN member countries, 53–58Indonesia, 53–54Philippines, 54–55testing conditions for, 55
in Brazil, 58–63in Caribbean islands, 86–87, 90in Central America, 84–86, 89–90in China, 63–67in Eastern Mediterranean region, 70–82
Arabian Peninsula, 71, 75–76climatic zones for, 81–82long-term stability testing conditions
for, 81–82Middle East, 71, 78–79Northern and Eastern Africa, 71–74Saudi Arabia, 71, 77
Index 385
Southern Asia, 71, 80testing condition humidity, 77, 79, 81testing condition temperature, 74,
76–77global stability testing protocols, 87, 90in India, 67–70in Panama, 84–86, 89–90in South Africa, 82–84in South American countries, 63–64in Southern Africa, 82–85
Registration, of drug-device combinationproducts, 330–332
Regulatory framework, available fordrug-device combination products,324–328
Relative humidity (RH), equations for, 49Reporting threshold, definition of, 116Reserve samples, for stability program, 16–17Residual solvents analysis
instrumentation, 211miscibility of solvents, 212in pharmaceutical API and excipients,
211–212for stability program, 211–212standard preparation, 211–212
Ritonavir, 244Robustness, for analytical method validation,
171–173, 239
SSalt plates, FTIR spectroscopic testing, 208Sample inventory form, 307Saturation water vapour pressure (PS),
equations for, 48–49Saudi Arabia
partial vapour pressure fluctuations, 77stability guidelines for, 71, 77temperature fluctuations, 77
Scale Up and Post-Approval Changes (SUPAC)guidance, 94–95, 184
Scan electron microscopy (SEM), 249Semi-permeable container, conditions for, 32Semisolids, 252Shelf-life of pharmaceutical product, see
Pharmaceutical product shelf-lifeShort-term heat–stress studies, 359Significant Body of Information (SBI), 99Significant changes, definitions of, 31Single-needle technique, for stability
program, 214Sirolimus, 342Size-exclusion chromatography (SEC), 158Size-exclusion HPLC (SE-HPLC), 355
Small-angle X-ray scattering (SAXS), 249Small volume parenterals (SVPs), 252Sodium dodecyl sulfate polyacrylamide gel
electrophoresis (SDS-PAGE), 355Soft gelatin capsules, 252Solid drug product, physical stability, 253–255Solids, FTIR spectroscopic testing, 207Solid-state
API, 243characteristics of drug substance and
physical stability, 242–251NMR, 249physical change mechanism and stress
stability, 249–251Solutions drug product, physical stability,
255–256South Africa
climatic data for, 84partial vapour pressure fluctuations, 83stability guidelines for, 82–83temperature fluctuations in, 83
South American countrieslong-term testing conditions for, 64stability guidelines for, 63–64
Southern Africa, for stability guidelines, 82–85Southern Asia
climatic data for, 80stability guidelines for, 71, 80
Specificationsetting for biologics, 366–367
Specificationscommercial specifications, 277expiry dating of clinical materials, 277and extension of expiration dating, 277refinement using stability studies, 275–277and stability data, 275–277stability requirements for changes,
107–108Specific gravity testing, for stability
program, 218Specificity, 238
for analytical method validation, 169–171definition, 169
Stabilityfor biologics process changes, 367chronological order of activities, 320compendial tests for, 197concept, 242data evaluation, 263–282
by-time-point method, 268flow diagram, 264graphical OOT evaluation, 266–267guidelines, 25
386 Index
Stability (cont.)importance, 269regression control chart method, 267reviewing impurity assay results,
268–269slope control chart method, 268specifications setting and, 275–277statistical evaluation of OOT, 267and trending, 264–265
data sheet elements, 278–279indicating chromatography conditions,
154–155methodologies, 5OOS results, 265, 269–275OOT results, 263, 265–268practices, 5, 43–90prediction in packaged product, 133–134protocols for biologics, 363–366regulations, 4reports, 277–282
anatomy, 279–280GMP requirements, 277–278requirement for CMC, 280–282stability data sheet elements, 278–279
requirementscase study, 198–199compendial procedures for stability,
195–198General Information Chapter 1150
Pharmaceutical Stability, 195information on general notices and
requirements, 194parenteral, 198–199solid oral dosage form, 198
requirements for nasal spray and inhaledproducts, 340
results evaluation, 265–269specifications and data, 275–277
commercial specifications andextension of expiration dating, 277
expiry dating of clinical materials, 277refinement using stability studies,
275–277Stability chambers
calibration, 293–294excursions, 301–302monitoring and alarm system, 295photostability, 295–300
calibration, 299–300chamber, 297monitoring and alarms, 300options, 295–298
preventative maintenance andback-up, 300
qualification, 298–299preventative maintenance and chamber
back-up, 294qualification, 289–293
installation qualification, 289–290operation qualification, 290–291performance qualification, 291–293requalification, 293
reach-in chambers, 286–287size, 286–287specifications, 288walk-in chambers, 286–287
Stability guidelinesArabian Peninsula, 71, 75–76ASEAN member countries, 53–58Brazil, 58–63Caribbean islands, 86–87, 90Central America, 84–86, 89–90China, 63–67Eastern Mediterranean region, 70–82India, 67–70Indonesia, 53–54Middle East, 71, 78–79Northern and Eastern Africa, 71–74Panama, 84–86, 89–90Philippines, 54–55Saudi Arabia, 71, 77South Africa, 82–83South American countries, 63–64Southern Africa, 82–85Southern Asia, 71, 80of WHO, 5, 22, 51–53
Stability-indicating method (SIM)development and validation, 139–159FDA, EMEA guidelines and pharmacopeia,
144–145forced degradation studies, 141–151
acid and base hydrolysis of drugsubstance in solution, 148–149, 150
experimental approach to, 141–149guidelines and pharmacopeia, 144–145ICH guidelines, 142–143protocol for stress testing, 146reaction mechanism and degradation
pathway, 149stress testing conditions, 146–149timeline for conducting, 141, 146
HPLC method development, 151–158ICH guidelines, 142–143
Index 387
stress testingcombination drugs, 151conditions, 146–149degradants characterization, 151in forced degradation studies,
146–149low solubility drugs, 150polymorphism, 150protocol for, 146special considerations in, 150–151stereochemical stability, 150
Stability Operating Procedures (SOPs), 15,165, 177–178, 182, 264, 266,271–273, 279, 282, 288, 289–294,300, 302, 304–309
annual product review, 319bracketing, 314, 315–316development of, 304–309matrixing, 314, 316–319sample
destruction and disposition, 308–309inventory maintenance, 309pulling, 306–307testing turnaround, 307
stability protocols, 310–314contents, 310–311establishment, 310standard, 311–314
structure, 304study
activation, 306amendment, 308cancellation, 308completion, 308deviation, 308set-up, 305–306
training program, 307–308establishing laboratory controls, 310in-house training, 309new employee training, 310outside training, 310requirements, 309types, 309–310
Stability programcGMP requirements, 15critical regulatory requirements, 9–19expiration dating, 17laboratory controls, 17laboratory records, 18non-chromatographic methods, 202–219
appearance testing, 202–207content uniformity, 216–217density, 218
disintegration, 217dissolution, 219–221fill volume and delivery volume,
213–214FTIR spectroscopic testing, 207–208melting point, 218moisture testing, 208–210particulate matter in parenterals and
intravenous (IV) solutions, 218pH, 212–213residual solvents analysis, 211–212specific gravity, 218tablet and capsule physical tests,
215–216UV/Vis spectroscopy, 217weight variation, 213–214
for pharmaceutical products, 15–16reserve samples, 16–17testing and release for distribution, 17–18
Stability protocols, 310–314contents, 310–311establishment, 310–311stability requirements for changes in,
104–106standard, 311–314
Stability requirementsanalytical method changes, 107–108for changes to ANDA, 99–108changes to API, 103–104expiration date changes, 106–107formulation changes, 100–102manufacturing changes, 99–100packaging changes, 102–103specifications and analytical method
changes, 107–108stability protocol changes, 104–106
Stability studiesactive pharmaceutical ingredient,
11–12pull windows for, 306purpose, 140–141role in drug development process, 10–11special studies, 33–34
bulk stability, 33Freeze-Thaw studies, 34in-process testing, 33in-use testing, 34to support excursions, 34thermal studies, 34
to supportdrug registration, 13formulation development, 12marketed products, 13
388 Index
Stability studies (cont.)pre-clinical and clinical supplies of
drug, 12–13production and use of drug, 12–13
types, 11–13Stability testing
of biotech products, 25guidelines, 22–25ICH guidelines applicable to, 21–40for new dosage forms, 24–26probability of failure, 45–47
additional safety margins, 47built-in safety margins, 46risk factors, 45–46variability in loading and resistance, 47
program for pharmaceutical products,15–16
scientific principles of, 13–15Stability tests
for biologics, 362–363for nasal spray and inhaled products,
334–336Stereochemical stability, and stress
testing, 150Stokes’ Law, 256–257Storage conditions, for nasal spray and inhaled
products, 339Storage orientation, for drug-device
combination products, 345–346Stress stability
and solid-state physical change mechanism,249–251
testing of drug substances, 250Stress testing
combination drugs, 151conditions, 146–149degradants characterization, 151in forced degradation studies, 146–149low solubility drugs, 150parameters for drug substance and drug
product, 147polymorphism, 150protocol for, 146special considerations in, 150–151for stability-indicating method, 146–151stereochemical stability, 150
Supercritical fluid chromatography (SFC), 155Suppositories, 252Surface plasmon resonance, 355Suspensions drug, physical stability,
256–258System suitability criteria, for analytical
method validation, 173
TTablets, 252
drug physical stability, 254–255friability, 215hardness, 215–216tests for stability program, 204, 215–216
Tanzania, temperature fluctuationsin, 84
TaxusTMstent, 342Technology transfer, and analytical method
validation, 176Temperature
effects on pharmaceutical productshelf-life, 124–129
equations for, 48excursions and MKT, 39fluctuations
in Brazil, 59–60in China, 63–65and MKT, 36–39in Philippines, 54in Saudi Arabia, 77for South Africa, 83Tanzania, 84
Temperature cycling, for drug-devicecombination products, 346
Terahertz Pulsed Spectroscopy, 245, 249Testing conditions
for Central America and Panama,84–86, 89
humidity, 77, 79, 81temperature, 74, 76–77
Thermal dehydration process mechanism, 245Thermal microscopy, 249Thermal studies, 34Thin-layer chromatography (TLC), 155, 158Training program
establishing laboratory controls, 310in-house training, 309new employee training, 310outside training, 310requirements, 309under SOPs, 309types, 309–310
Transdermal patches, 252Transdermal products, 343–344Transportation studies, for drug-device
combination products, 346–347Triboelectric property, 249Two-needle technique, for stability
program, 214Type I variations, 97–98Type II variations, 98–99
Index 389
UUV/Vis spectroscopy, for stability
program, 217
VValidation of analytical method, see Analytical
method validationViadurTM leuprolide acetate implant, 343Vibrational spectroscopy
and equipment, 224–228equipment qualification, 234–236
design qualification, 234installation qualification, 234operational qualification, 235performance qualification,
234–236methods for quantitative analysis,
223–239method validation, 236–239MVA and chemometrics, 228–234
WWalk-in stability chambers, 286–287Water for injection (WFI), volume of, 206Water vapor sorption, 249Weight variation testing, for stability program,
213–214WHO Expert Advisory Panel on the
International Pharmacopoeia andPharmaceutical Preparations, 51
WHO Expert Committee on Specifications forPharmaceutical Preparations, 51
World Health Organization (WHO), 94classification of climatic zones, 45stability guidelines, 4, 22, 51–53
current status, 52–53development of, 51harmonization efforts, 51–52
XX-ray powder diffraction (XRPD),
244–246, 249