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List of Abbreviations Acronym Definition ACN Acetonitrile ACVA azobis-cyan valeric acid AFM atomic force microscope AIBN 2,2-azobisisobutyronitrile AMPD azobis methyl propionamidine dihydrochloride ANDA Abbreviated New Drug Application ANVISA Agˆ encia Nacional de Vigilˆ ancia Sanit´ aria API Active Pharmaceutical Ingredient AR & D Analytical Research & Development ASEAN Association of South East Asian Nations ASTM American Society for Testing and Materials ATR Attenuated total reflectance BA Bioavailability BE Bioequivalence BLA Biologics License Application CAPA Corrective and Preventive Actions CBE Changes Being Effected CBE-30 Changes Being Effected – 30 Days CBER Center for Biologics Evaluation and Research CDER Center for Drug Evaluation & Research CDRH Center for Devices and Radiological Health CE Capillary Electrophoresis CE Conformit´ e Europ´ eenne CFR Code of Federal Regulations cGMPs current Good Manufacturing Practices CHMP Committee for Medicinal Products for Human Use CI confidence interval CMC Chemistry, Manufacturing & Controls COA Certificate of Analysis CQA Critical Quality Attribute CR Child Resistant CRH Critical relative Humidity 371

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Page 1: List of Abbreviations - Home - Springer978-0-387-85… ·  · 2017-08-27List of Abbreviations Acronym Definition ... CDER Center for Drug Evaluation & Research ... PAS Prior Approval

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

Page 2: List of Abbreviations - Home - Springer978-0-387-85… ·  · 2017-08-27List of Abbreviations Acronym Definition ... CDER Center for Drug Evaluation & Research ... PAS Prior Approval

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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