SPECIFICATIONOF DRUGSUBSTANCES ANDPRODUCTS
DevelopmentandValidationofAnalyticalMethods
SECONDEDITION
Editedby
ChristopherM.Riley
RileyandRabelConsultingServices,Inc.,Maryville,MO,UnitedStates
ThomasW.Rosanske
T.W.RosanskeConsulting,OverlandPark,KS,UnitedStates
GeorgeL.Reid
CardinalHealthRegulatorySciences,KansasCity,MO,UnitedStates
Elsevier
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Contributors
KentL.Amsberry CardinalHealthRegulatorySciences,OverlandPark,KS,UnitedStates
DanielW.Armstrong DepartmentofChemistry andBiochemistry,UniversityofTexasatArlington, Arlington,TX,UnitedStates
S.Baertschi BaertschiConsultingLLC,Carmel,IN, UnitedStates
JamesBergum BergumSTATS,LLC,Howell,NJ, UnitedStates
PingChen AlbanyMolecularResearch,Inc.,West Lafayette,IN,UnitedStates
A.M.Clarke Novartis,GDD/TRD/Chemical & AnalyticalDevelopment(CHAD),Novartis Campus,Basel,Switzerland
IanClegg BrukerBioSpin
JenniferE.Dally GlaxoSmithKline,KingofPrussia, PA,UnitedStates
VivianA.Gray V.A.GrayConsulting,Inc.,Hockessin,DE,UnitedStates
BrianL.He ChemicalandSyntheticDevelopment, Bristol-MyersSquibb,NewBrunswick,NJ,United States
QinC.Ji Bristol-MyersSquibb,Princeton,NJ, UnitedStates
E.Kikovska-Stojanovska ResearchandDevelopment,AlkaloidAD-Skopje,Skopje,Republicof NorthMacedonia(former);MerckHealthcare KGaA,GlobalRegulatoryAffairsCMC,Darmstadt, Germany(present)
RyanKlein TergusPharma,Durham,NC,United States
YinHwaLai CardinalHealthRegulatorySciences, OverlandPark,KS,UnitedStates
DavidK.Lloyd AnalyticalandBioanalyticalDevelopment,Bristol-MyersSquibb,NewBrunswick,NJ, UnitedStates
MyrnaA.Monck GlaxoSmithKline,KingofPrussia, PA,UnitedStates
KurtL.Moyer PineLakeLaboratories,Bristol,CT, UnitedStates
B.Olsen OlsenPharmaceuticalConsulting,Wake Forest,NC,UnitedStates
JohnD.Orr AssociatedAnalyticsLLC,Amesbury, MA,UnitedStates
LiPan PTCTherapeutics,SouthPlainfield,NJ, UnitedStates
ErnestParente CardinalHealthRegulatorySciences,OverlandPark,KS,UnitedStates
R.L.Phelps PharmAdvanceConsulting,Inc., Sequim,WA,UnitedStates
GeorgeL.Reid CardinalHealthRegulatorySciences,KansasCity,MO,UnitedStates
ChristopherM.Riley RileyandRabelConsulting Services,Inc.,Maryville,MO,UnitedStates
ThomasW.Rosanske T.W.RosanskeConsulting, OverlandPark,KS,UnitedStates
MichaelRuberto MaterialNeedsConsulting,Montvale,NJ,UnitedStates
JamesR.Scull ElementMaterialsTechnology,Santa FeSprings,CA,UnitedStates
EricB.Sheinin Sheinin & AssociatesLLC,North Potomac,MD,UnitedStates
PamelaA.Smith ImprovedPharma,WestLafayette,IN,UnitedStates
MohsenTalebi DepartmentofChemistryand Biochemistry,UniversityofTexasatArlington, Arlington,TX,UnitedStates
KailasThakker TergusPharma,Durham,NC, UnitedStates
PatrickA.Tishmack AlbanyMolecularResearch, Inc.,WestLafayette,IN,UnitedStates
LinnaWang Bristol-MyersSquibb,Princeton,NJ, UnitedStates
QinggangWang ChemicalandSyntheticDevelopment,Bristol-MyersSquibb,NewBrunswick,NJ, UnitedStates
HarryYang Non-ClinicalBiostatistics,Translational Sciences,MedImmune,LLC,Gaithersburg,MD, UnitedStates
LongYuan Bristol-MyersSquibb,Princeton,NJ, UnitedStates
1 Introduction
ChristopherM.Riley1,ThomasW.Rosanske2,GeorgeL.Reid3 1RileyandRabelConsultingServices,Inc.,Maryville,MO,UnitedStates; 2T.W.RosanskeConsulting, OverlandPark,KS,UnitedStates; 3CardinalHealthRegulatorySciences,KansasCity,MO, UnitedStates
OUTLINE
References6
Thepreviouseditionofthisbookwaspublishedin2014.1 Thegeneralframeworkofthat bookwasbasedonkeyqualityguidelines (Q1 Q11)2 26 publishedbytheInternational CouncilonHarmonisation(ICH)(thenreferred toasInternationalConferenceonHarmonization),alongwithregionalregulatoryguidelines andcompendialrequirements.Sincethen,revisionstosomepublishedICHguidelineshave occurred,andnewguidelinesrelatedmoreto thedrugdevelopmentprocessandlifecycle managementhavebeenadded(e.g.,ICH Q12 Q14)27 29 eitherintheformofdraftsor conceptpapers.
Thisbookeditionreferencesthenewand updatedICHguidelines,regulatoryguidance documents,andcompendialrequirementsas
thebasicframeworkforthetext.Theprimaryobjectivesofthisbookare(1)tocapturethemany regulatoryandtechnicaladvancesthathave occurredinthe fieldsincepublicationofthepreviousedition,(2)toprovideanupdatedcritical andcomprehensiveassessmentoftheapproachesusedtoidentifythekeyqualityattributesofadrugsubstanceordrugproductthat impactthesafety,efficacy,andmanufacturability,(3)toselectappropriateanalyticaltechniques basedonthesensitivity,accuracy,andprecision neededtoadequatelymeasureandcontrolthe identifiedqualityattributes,and(4)todetermine howtheanalyticalmethodsaredevelopedand validatedfortheirintendeduse.Newchapters, notincludedinthe firstedition,1 coveranalytical methodsintheclinicalphaseofdevelopment
(Chapter5),methodtransfer(Chapter6),process analyticaltechnology(Chapter7),mutagenicimpurities(Chapter12),drugreleasefortopical products(Chapter19),andbiotechnologyproducts(Chapters20and21).Thepreviousedition1 chaptershavebeenupdated.
TheICHQualityGuidelinesformthegeneral frameworkfortheapplicationofworldwide marketingsubmissionsandreviewsofnew drugproducts.Wherethequality (Q1 Q14)2 29 andrelevantkeymultidisciplinary(M4,M7 M10)30 34 ICHGuidelines fit intothegeneraldrugdevelopment,framework isshownin Fig.1.1.TheCommonTechnical Document(CTD,ICHM4)30 oritselectronic version(eCTD,ICHM8)isthegenerallyharmonizeddocumentmostwidelyusedbytheICH andmanynon-ICHcountriesforclinicaltrial andmarketingauthorizationapplications.The ICHQualityGuidelinesQ1 Q6describemost ofthegeneralrequirementsfortheanalytical contentoftheCTDandarethenfollowedbya seriesofguidelines(Q7 Q14)addressingsome
ofthekeyapproachestodrugdevelopment andlifecyclemanagementthatmayalsobe includedintheCTD.
AccordingtotheICHdefinition,thespecificationofanewdrugsubstanceoradrugproduct (Q6AandQ6B)containsthreeelements:(1)the qualityattributes(ortests),(2)referencestothe associatedmethods,and(3)theacceptance criteria.WhileICHguidelinesonspecifications (Q6)andmethodvalidation(Q2)describewhat informationregulatorsexpecttoseeinanew drugapplication,theyprovideverylittledetail onhowtheguidelinesaretobeimplemented atthetechnicallevel.TheabsenceofspecificdirectionontheimplementationoftheICHQualityGuidelinesalsoallowsforsponsor-tosponsordifferences,includingtheapplication ofnewandimprovedanalyticaltechnologies (suchasprocessanalyticaltechnology)targeted tomeasuringthecriticalqualityattributeswhich impactproductperformance.Inkeepingwith thespiritofthepreviouseditionofthisbook, thisversionisnotintendedasjustareviewof
• QUALITY (ANALYTICAL CONTENT)
• Stability (Q1)
• Validation (Q2)
• Impurities (Q3)
• Pharmacopeias (Q4)
• Biotechnology Products (Q5)
• Specifications (Q6)
• MULTIDISCIPLINARY
• Common Technical Document (CTD) (M4)
• Mutagenic Impurities (M7)
• Electronic Common Technical Document (eCTD) (M8)
• QUALITY (DRUG DEVELOPMENT/LIFE-CYCLE MANAGEMENT)
• GMPs for Active Pharmaceutical Ingredient (Q7)
• Pharmaceutical Development (Q8)
• Quality Risk Management (Q9)
• Pharmaceutical Quality System (Q10)
• Development/Manufacture of DS (Q11)
• Life Cycle Management (Q12)
• Continuous Manufacturing (Q13)
• Analytical Development (Q14)
existingregulatoryguidanceandindustrypractices.Rather,inadditiontodiscussingconventionalapproaches,eachchapterwilladdress currentandcriticalissuesandnovelapproaches. Theauthorshaveagainbeencarefullyselectedas beingformermembersoftheICHExpertWorkingGroupschargedwithdevelopingtheICH guidelinesand/orsubject-matterexpertsfrom industry,academia,andgovernmentlaboratories.Thisbookprovidesthereadernotonly withanunderstandingofindustrybestpractices butalsowithfuturedirections.
Thegeneralprinciplesofthespecification settingandmethodvalidationsprocessesare reviewedinChapter2andChapter3,respectively,andexploredingreaterdetailinsubsequentchapters.TheICHGuidelineonMethod Validation(Q2(R1))wasprimarilydeveloped withchromatographictechniquesinmindand thefollowingtestsinparticular:
• Identificationtests
• Quantitativetestsforimpuritiescontent
• Limittestsforthecontrolofimpurities
• Quantitativetestsoftheactivemoietyin samplesofdrugsubstanceanddrugproduct orotherselectedcomponentsinthedrug product(e.g.,preservatives,antioxidants).
Recently,ICHconstitutedanewExpert WorkingGroup,whichwilldevelopanewtopic Q14AnalyticalMethodDevelopmentaswellas expandQ2(R1)toincludethevalidationofnonchromatographicmethods.29 ThisQ14guideline, whendrafted,isexpectedtoapplytheconceptof QualitybyDesign(QbD)andanalyticallife-cyclemanagementtopharmaceuticalanalysis (AnalyticalQbD[AQbD]).TheconceptQbD wasintroducedintothedrugdevelopmentprocessthroughthemorerecentICHGuidelines (Q8 Q12),23 27 withtheprimaryaimof increasingtheunderstandingandtheknowledgebaseoftheprocessesforthemanufacturing ofdrugsubstancesandproducts.Contemporary thoughtsandtacticsforAQbDaredescribedin Chapter4andanalyticallife-cyclemanagement
inChapter10.Generalprocessconsiderations relatedtoanalyticalmethods(clinicalphase methodsandspeci fications,analyticalmethod transfer,andprocessanalyticaltechnology)are discussedinChapters5 7.Chapters8 23 discussspeci ficapplications(e.g.,elementalimpurities,solidstatecharacterization)andhow theprinciplesofmethodvalidationsetforthin Q2(R1)havebeenadaptedtothesenonchromatographictechniques.Chapter24pertainsto thedevelopmentandvalidationofbioanalytical methodsandChapter25discussesmicrobialand endotoxintestingmethods.
Inadditiontoprovidingthe “what” butnot the “how” tosetspeci ficationsandvalidate analyticalmethods,theICHQualityGuidelines (Q1 Q6)onlydefinewhatistobeprovidedfor productregistrationinanewdrugapplication. Theyexpresslyexcludewhatisexpectedinthe clinicalstagesofdrugdevelopmentsuchasan InvestigationalNewDrugApplication(INDin theUnitedStates).Therefore,acommontheme throughoutthebookishowthemethods, methodvalidations,andspecificationsevolve overthedruglifecycle(see Fig.1.2).
The “how” oftheearlierQ1 Q6Guidelines aretobeappliedisdescribedinlargepartinsubsequentguidelines(Q7 Q14).Forexample,16 attributeswereidenti fiedforapolymericexcipient,derivedfromanaturalproduct,andused insustainedreleaseproducttocontrolthepotentiallyvariableperformanceoftheexcipientinthe product.35 Theonlywaytomanagethe16attributesandachieveacceptableproductperformancewastounderstandthecontributionsof thevariousattributesandtheinteractionsbetweenthem(i.e.,eachphysicalandchemical characteristic).Byanalyticallymeasuringeach oftheattributesandthenusingstatistical/chemometricapproaches,itwaspossibletodefine a “designspace ” ofallparameterswhichcould delivertheoveralldesiredeffectofdrugrelease. Thesesamestatistical/chemometricapproaches canalsobeusedtobetterconnectmethodperformancerequirementswithrespecttocontrol
limitsforcriticalqualityattributesaswellasto monitorlong-termanalyticalmethodperformanceoverthemethod’slifecycle.Thisisan areacriticaltothedevelopmentandmaintenanceofanalyticalmethods.
Thus,thiseditionisintendedtobenotonlya reviewoftheICHGuidelinesrelatingtothe speci ficationandmethodvalidationofnew drugsbutalsotoprovideacriticalanalysisof theregulatoryguidelinesandacomprehensive treatmentofhowthoseguidelinesareapplied tothedevelopmentofnewdrugs.Itisintended
tobeanupdatededucationaltoolandareferencesourceforthoseinvolvedinthedevelopmentandregulationofnewdrugproducts.
References
1.Riley,C.M.;Rosanske,T.W.;Riley,S.R.;Eds. SpecificationofDrugSubstancesandProducts,Development andValidationofAnalyticalMethods; Elsevier,2014.
2.StabilityTestingofNewSubstancesandProducts (Q1A(R2)). TheInternationalCouncilonHarmonisationof TechnicalRequirementsforRegistrationofPharmaceuticals forHumanUse, SecondRevision,2003.
FIGURE1.2
3.StabilityTesting:PhotostabilityTestingofNewDrug SubstancesandProducts(Q1B). TheInternationalCouncil onHarmonisationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, 1996.
4.StabilityTesting:NewDosageForms(Q1C). TheInternationalCouncilonHarmonisationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse, 1997.
5.BracketingandMatrixingDesignforStabilityTesting: NewDrugSubstancesandProducts(Q1D). TheInternationalCouncilonHarmonisationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse, 2002.
6.EvaluationofStabilityData(Q1E). TheInternational CouncilonHarmonisationofTechnicalRequirementsfor RegistrationofPharmaceuticalsforHumanUse, 2003.
7.StabilityDataPackageforRegistrationApplicationsin ClimaticZonesIIIandIV(Q1F). TheInternationalCouncil onHarmonisationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, 2006.
8.ValidationofAnalytical Procedures:TextandMethodology(Q2(R1)). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationof PharmaceuticalsforHumanUse, FirstRevision,1996.
9.ImpuritiesinNewDrugsSubstances(Q3A(R2)). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse, SecondRevision,2006.
10.ImpuritiesinNewDrugsProducts(Q3B(R2)). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse, SecondRevision,2006.
11.Impurities:GuidelineforResidualSolvents(Q3C(R7)). TheInternationalCouncilonHarmonisationofTechnical RequirementsforRegistrationofPharmaceuticalsforHuman Use, SeventhRevision,2018.
12.Impurities:GuidelineforElementalImpurities (Q3D(R1)). TheInternationalCouncilonHarmonisationof TechnicalRequirementsforRegistrationofPharmaceuticals forHumanUse, SecondRevision,2019.
13.PharmacopeialHarmonisation(Q4A). TheInternational ConferenceonHarmonizationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse,in Development.Unpublished.
14.EvaluationandRecommendationofPharmacopeial TextsforUseintheICHRegions(Q4B)[andassociated Annexes]. TheInternationalCouncilonHarmonisationof TechnicalRequirementsforRegistrationofPharmaceuticals forHumanUse,2007and2010 2013
15.ViralSafetyEvaluationofBiotechnologyProducts DerivedfromCellLinesofHumanorAnimalOrigin (Q5A(R1)). TheInternationalCouncilonHarmonisationof TechnicalRequirementsforRegistrationofPharmaceuticals forHumanUse, FirstRevision,1999.
16.AnalysisoftheExpressionConstructinCellsUsedfor Productionofr-DNADerivedProteinProducts(Q5B). TheInternationalCouncilonHarmonisationofTechnical RequirementsforRegistrationofPharmaceuticalsforHuman Use, 1995.
17.StabilityTestingofBiotechnological/BiologicalProducts(Q5C). TheInternationalCouncilonHarmonisation ofTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse, 1995.
18.DerivationandCharacterisationofCellSubstratesUsed forProductionofBiotechnological/BiologicalProducts (Q5D). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsfor HumanUse, 1997.
19.ComparabilityofBiotechnological/BiologicalProducts SubjecttoChangesintheirManufacturingProcess (Q5E). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsfor HumanUse, 2004.
20.Specifications:TestProceduresandAcceptanceCriteria forNewDrugSubstancesandNewDrugProducts: ChemicalSubstances(Q6A). TheInternationalCouncil onHarmonisationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, 1999.
21.Specifications:TestProceduresandAcceptanceCriteria forBiotechnological/BiologicalProducts(Q6B). TheInternationalCouncilonHarmonisationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse, 1999.
22.GoodManufacturingacticeGuideforActivePharmaceuticalIngredients(Q7). TheInternationalCouncilon HarmonisationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, 2000.
23.PharmaceuticalDevelopment(Q8(R2)). TheInternational CouncilonHarmonisationofTechnicalRequirementsfor RegistrationofPharmaceuticalsforHumanUse, Second Revision,2009.
24.QualityRiskManagement(Q9). TheInternationalCouncil onHarmonisationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, SecondRevision,2005.
25.PharmaceuticalQualitySystem(Q10(R4)). TheInternationalCouncilonHarmonisationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse, Fourth Revision,2010.
26.DevelopmentandManufactureofDrugSubstances (Q11). TheInternationalCouncilonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsfor HumanUse, 2012.
27.TechnicalandRegulatoryConsiderationsforPharmaceuticalProductLifecycleManagement(Q12). TheInternationalCouncilonHarmonisationofTechnical RequirementsforRegistrationofPharmaceuticalsforHuman Use.DraftGuidance,2017.
28.ContinuousManufacturingofDrugSubstances andDrugProducts(Q13). TheInternationalCouncil onHarmonizationofTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse .ConceptPaper, 2018.
29.AnalyticalProcedureDevelopment(Q14). TheInternationalCouncilonHarmonizationofTechnicalRequirements forRegistrationofPharmaceuticalsforHumanUse ConceptPaper,2018.
30.TheCommonTechnicalDocumentfortheRegistration ofPharmaceuticalsforHumanUse:Quality M4Q(R1). TheInternationalCouncilonHarmonisationof TechnicalRequirementsforRegistrationofPharmaceuticals forHumanUse, FirstRevision,2002.
31.AssessmentandControlofDNAReactive(Mutagenic) ImpuritiesinPharmaceuticalstoLimitPotential CarcinogenicRisk(M7). TheInternationalCouncilon HarmonizationofTechnicalRequirementsforRegistration ofPharmaceuticalsforHumanUse, 2017.
32.ElectronicCommonTechnicalDocument(eCTD)(M8). TheInternationalCouncilonHarmonisationofTechnical RequirementsforRegistrationofPharmaceuticalsforHuman Use, 2016.
33.BiopharmaceuticsClassificationSystem-basedBiowavers(M9). TheInternationalCouncilonHarmonisation ofTechnicalRequirementsforRegistrationofPharmaceuticalsforHunanUse.DraftGuidance,2018.
34.BioanalyticalMethodValidation(M10). TheInternational CouncilofHarmonisationonTechnicalRequirementsfor RegistrationofPharmaceuticalsforHumanUse.Draft Guidance,2019.
35.Brown,B.;Caster,D.;Clarke,B.;Hopkins,S.; Llewelyn,J.;Martin,L.;Meehan,E.;Timko,R.; Yang,H. ExtendedReleaseFormulationsComprisingQuetiapineandMethodsforTheirManufacture, 2011.United StatesPatentApplication,US2011/0319383.
Generalprinciplesandregulatory
ChristopherM.Riley1,HarryYang2
1RileyandRabelConsultingServices,Inc.,Maryville,MO,UnitedStates; 2Non-ClinicalBiostatistics, TranslationalSciences,MedImmune,LLC,Gaithersburg,MD,UnitedStates
OUTLINE
2.1Introduction10
2.2Regulatoryrequirements11
2.2.1Internationalcouncilonharmonization ofthetechnicalrequirementsfor pharmaceuticalsforhumanuse11
2.2.1.1Universaltests14
2.2.1.2Specifictests17
2.2.2Compendialrequirements19
2.2.2.1Testingrequirements20
2.2.2.2USPgeneralchapters <1> to <5> 21
2.2.3Biotechnologyproducts (macromolecules)andbiological products24
2.2.4Regionaldifferences25
2.3Speci ficationsettingprocess27
2.3.1Identificationofcriticalqualityattributes27
2.3.2Considerationsinsettingacceptance criteria29
2.3.2.1Datasources29
2.3.2.2Frameofreference29
2.3.2.3Sourcesofvariation29
2.3.2.4Clinicalrelevance30
2.3.2.5Multivariatespecifications30
2.3.2.6Specificationsinearly development30
2.3.3Statisticaltoolsforsettingacceptable limits32
2.4Shelflifeandretestdate33
2.5Releaseandstabilityspeci fication35
2.6Referencestandards36
2.6.1Qualitativetests37
2.6.2Quantitativetests37
2.6.2.1Drugsubstance37
2.6.2.2Impurities38
2.6.3Pharmacopeialreferencestandards38
2.7Documentation39
2.Generalprinciplesandregulatoryconsiderations:speci
2.1Introduction
Thespeci fi cation a ofadrugsubstance(DS) (API b )ordrugproduct(DP)containstheattributes,analyticalmethods,andacceptance criteriawhicharedesignedtoensurethata productisacceptableforitsintendedapplication.However,conformancetothesetof criteriadescribedinthespeci fi cationalone doesnotassurethequality,safety,andef fi cacy ofapharmaceuticalproductbecausethe speci fi cationisonlypartoftheoverallcontrol strategyoftheDSandtheDPcontainedthe currentGoodManufacturingPractices(cGMPs) forhumanproductsandGoodLaboratory Practices(GLP)foranimalstudies.TheInternationalCouncilforHarmonisation(ICH)ofthe TechnicalRequirementsforPharmaceuticals forHumanUseGuidelinesonSpeci fi cations (Q6AandQ6B)states1 , 2 : “ Speci fi cationsareone partofatotalcontrolstrategyforthedrugsubstance anddrugproductdesignedtoensureproductqualityandconsistency.Otherpartsofthisstrategy includethoroughproductcharacterizationduring development,uponwhichspeci fi cationsarebased, andadherencetoGoodManufacturingPractices; e.g., suitablefacilities,avalidatedmanufacturing process,validatedtestprocedure,rawmaterial testing,in-processtesting,stabilitytesting,etc. Speci fi cationsarechosentocon fi rmthequalityof thedrugsubstanceanddrugproductratherthan toestablishfullcharacterizationandshouldfocus
onthosecharacteristicsfoundtobeusefulin ensuringthesafetyandef fi cacyofthedrugsubstanceanddrugproduct ”
Adistinctioncanbemadebetweenthe “releasespecification” (thetestsandacceptance criteria)thatapplyatthepointofreleaseofthe productintothemarketplace(ordistributionto theclinicalsiteforinvestigationaldrugs)and the “stabilityspeci fication ” (thetestsandacceptancecriteriathatapplyafterreleaseoftheproductuptotheexpirationdateoftheproduct). Certaintestsapplyonlyatrelease,andthe remainingtestsapplyatreleaseandthroughout theshelflifeoftheproduct.Morerestrictive acceptancecriteriamaybeappropriatefor certaintestsatreleasethanduringtheshelflife toallowforchangesintheproductduringstorage(suchasassay,impurities,anddissolution). Attributesthathavebeenshownduringdevelopmentnottochangewithtimeareonlytested atbatchrelease.
ThereisnoregulatoryrequirementtoestablishtheshelflifeoftheDS;insteaddevelopment studiesonthestabilityoftheDSareconducted toestablisharetestdateafterwhichabatchof DSmustbereanalyzed,andtheacceptance criteriametbeforethebatchcanbeusedto manufactureDP.Whilethereisnoregulatory requirementtoestablisharegulatoryshelflife oftheDS,aninternalshelflifemaybeestablished,beyondwhichtheDSmaynotbeused forthemanufactureofclinicalsuppliesor
a Theword “specification” inNDAsordrugsregisteredwithregulatoryauthoritiesissynonymouswiththeword “monograph” inapharmacopeia.
b TheInternationalCouncilontheHarmonization(ICH)oftheTechnicalRequirementsforPharmaceuticalsfor HumanUseusesthetermsdrugsubstanceandactivepharmaceuticalingredient(API)interchangeablytodescribe thepharmacologicallyactivecomponentinapharmaceuticalproduct.
commercialproducts.Whileamaximumshelf lifeof5yearsforaDSisnotuncommon,there isnoreasonthatexpiredDSorDPcannotbe usedinmethoddevelopmentstudies,method validation,andmethodtransfer,providedthe exceptionisappropriatelydocumented this avoidsthepossibilityout-of-specification(OOS) resultsbeinggeneratedonproductintheclinical orincommercialdistribution.Infact,theuseof agedsamplesofDSorDPindevelopment studiescanprovideusefulinformationtostudy thestabilityoftheDSandDPandtoestablish theretestdateorshelflife.
2.2Regulatoryrequirements
Theestablishmentofspecificationsforall componentsofapharmaceuticalproductforhumanoranimaluseisalegalrequirement,inall partsoftheworld,aspartoftheoverallcontrol strategycontainedwithinthecGMPs.Therequirementsforthetestingofanarticleforuse inanimalstudies(nonclinicalstudies)are coveredbytheGLPs.IntheUnitedStates,the legalrequirementsforcGMPsaredefinedin21 CFRPart210and211.3 21CFR211.160(a)states “Theestablishmentofany specifications,standards, samplingplans,testprocedures,orotherlaboratory controlmechanismsrequiredbythissubpart, includinganychangeinsuchspecifications,standards,samplingplans,testprocedures,orotherlaboratorycontrolmechanisms,shallbedraftedbythe appropriateorganizationalunitandreviewedand approvedbythequalitycontrolunit.Therequirementsinthissubpartshallbefollowedandshallbe documentedatthetimeofperformance.Anydeviationfromthewrittenspecifications,standards,samplingplans,testprocedures,orotherlaboratory controlmechanismsshallberecordedandjusti fied. ” IntheUnitedStates,thelegalrequirementsfor GLPsaredefinedin21CFRPart58.4 Testingof articlesfornonclinicalstudiesisdescribedin CFR2158.105(a): “Theidentity,strength,purity, andcompositionorothercharacteristicswhichwill
appropriatelydefinethetestorcontrolarticleshall bedeterminedforeachbatchandshallbedocumented ” WhiletheGLPsdonotexplicitlystate thatspeci ficationsarerequiredfornonclinical testarticles,speci ficationsareusuallyestablishedaspartoftheoverallcontrolstrategyin asimilarfashiontospeci ficationsforcGMPs. SimilarlegalrequirementsforcGMPsand GLPsexistinotherregionsoftheworld.
2.2.1Internationalcouncilon harmonizationofthetechnical requirementsforpharmaceuticalsfor humanuse
Thetechnicalrequirementsfortheworld registrationofnewpharmaceuticalproductsin theICHregions(EuropeanUnion[EU],Japan, andUnitedStates)aredefinedintheICHGuidelines,whicharedividedintothreesections,each coveringprincipleareasofdrugdevelopment, ef ficacy(E),quality(Q),andsafety(S),plusa fourthsectionthatdealswithmultidisciplinary topics(M)(see Section2.2.1).Thetechnicalrequirementsfortheinclusionofanewmonographofanapproveddruginaregional pharmacopeiaaredescribedinthegeneralchaptersoftheapplicablepharmacopeia(seealso Section2.2.2 andChapter23).
TheChemistry,Manufacturing,andControls (CMC)requirementsfortheregistrationofnew DSsandnewDPsarecoveredprimarilyinthe ICHQualityGuidelines(Q1 Q14).Themain ICHguidelinecoveringthespecificationofnew chemicalentities(NCEsor “smallmolecules”) isQ6A: “Specifications:TestProceduresandAcceptanceCriteriaforNewDrugSubstancesandNew DrugProducts:ChemicalSubstances. ”1 ThecorrespondingICHGuidelinecoveringbiotechnology productsandbiologicals(“macromolecules”)is Q6B2: “Specifications:TestProceduresandAcceptanceCriteriaforBiotechnological/BiologicalProducts. ” Additionalinformationonspeci fication settingcanbefoundinotherICHGuidelines
includingQ1A-F(stability),5 10 Q3 (impurities),11 14 andQ4(pharmacopeias). 15 17
ThelaterICHGuidelines,Q8,18 Q9,19 Q10,20 Q11,21 Q12,22 andQ13,23 alsohaveimportantimplicationsforspeci ficationsetting,especially withinthecontextoftheapplicationofQuality byDesign(QbD)toprocessoptimization/validationandformulationdevelopment,aswell astoanalyticalmethoddevelopmentandvalidation.TheQbDconcepts(inQ8,Q9,Q10,and Q11)andtheirapplicationtopharmaceutical analysis,AnalyticalQualitybyDesign(AQbD), riskassessment,andmethodlifecyclemanagementarediscussedindetailinChapter4as wellasinotherplacesthroughoutthisbook.In 2018,theICHSteeringCommitteeconveneda newExpertWorkingGroup(EWG),Q14,24 withtwoobjectives:todefinetherequirements foranalyticalproceduredevelopment(ideally focusingonAQbDprinciples)andtoexpand theICHmethodvalidationguideline,Q2(R2),25 toincludenonchromatographictechniques.
TheICHspecificationguidelinesdonotcover therequirementsforcertainmorespecialized productssuchastransdermalorinhalationproductsleavingavoid,whichis filledbyregional guidelinesandpharmacopeialrequirements.It shouldalsobenotedthatnotalltheICHquality guidelinesapplytotestarticlesinnonclinical studiesorclinicalsuppliesbecausetheyonlycover thetechnicalrequirementsforanewdrugapplication(NDA)(seeChapter5,Section5.6formoredetails).Nevertheless,theICHguidelinesdoprovide ausefulframeworkforthedevelopmentof nonclinicalandclinicalspecifications.
Oneofthecriticalqualityattributes(CQAs) thatplaysprominentlyinthedevelopmentofa speci ficationisimpuritiesbecauseofthepossible negativeeffecttheycanhaveonsafety.Therefore,theestablishmentofappropriateacceptance criteriarequirestheclosecollaborationofseveral disciplines,notjustanalyticaldevelopment,
c Formerlyknownasheavymetals. 2.Generalprinciplesandregulatoryconsiderations:speci
qualitycontrol,andqualityassurancebutalso nonclinicaldevelopment,clinicaldevelopment, formulationdevelopment,processchemistry, commercialmanufacturing,andregulatoryaffairs.Impuritiesarediscussedinmoredetailin Chapter11(AssayandImpurities),Chapter12 (GenotoxicImpurities),Chapter13(Residual Solvents),andChapter14(ElementalImpuritiesc).ThecontrolofDSimpuritiesisalsodiscussedinICHQ11Developmentand ManufactureofDrugSubstances(ChemicalEntitiesandBiotechnological/BiologicalEntities).21 AfulllistingofalltheICHqualityguidelines andrelevantmultidisciplinaryICHguidelines isgivenin Table2.1.
AccordingtoICHQ6A1 andQ6B,2 aspecification(singular)containsthreecomponents:alist oftests(orattributes),referencestotestmethods, andacceptancecriteria.TheICHspeci fication guidelineQ6Adistinguishesbetweenuniversal tests,whicharerequiredinanyspeci fication foranewDSorDP,andspecifictests,which shouldbeincluded,onacase-by-casebasis, dependingonthenatureoftheDSortheDP andtherouteofadministration.Theuniversal andspecifictestsforNCEsinICHQ6A1 are summarizedin Figs.2.1and2.2 forDSandDP, respectively.
Inadditiontoharmonizingthetechnicalrequirementsfortheregistrationofnewdrugsin theEU,theUnitedStates,andJapan,theICH Guidelinesattemptedtostandardizetheterminology,whichresultedinthereplacementof someofthetermsincommonusageatthe time.Theterminologyanddefinitionsinthe UnitedStatesPharmacopeia(USP)/National Formulary(NF),EuropeanPharmacopoeia(Ph. Eur.),andJapanesePharmacopoeia(JP), togetherwithmanyregionalpharmacopeias, havealsobeenstandardizedthroughtheICH Q4A16 andQ4B17 guidelines.Forexample,the term “ appearance ” hasbeenreplacedby
TABLE2.1 SummaryoftheICHQuality(Q)GuidelinesandthoseMultidisciplinaryGuidelines(M)Relevantto SpecificationSetting.
Numbera Titleb
Q1AStabilitytestingofnewsubstancesandproducts
Q1BPhotostabilityofnewsubstancesandproducts
Q1CStabilitytesting:newdosageforms
Q1DBracketingandmatrixingdesignforstabilitytesting:newsubstancesandproducts
Q1EEvaluationofstabilitydata
Q1FStabilitydatapackageforregistrationapplicationsinclimaticzonesIIIandIV
Q2(R1)Validationofanalyticalprocedures:textandmethodology
Q3A(R1)ImpuritiesinnewDSs
Q3B(R1)Impuritiesinnewdrugproducts
Q3C(R5)Impurities:guidelineforresidualsolvents
Q3DImpurities:elementalimpurities
Q4APharmacopeialharmonization
Q4BEvaluationandrecommendationofpharmacopeialtextsforuseinICHregions
Q5AViralSafetyevaluationofbiotechnologicalproductsfromcelllinesofhumanoranimalorigin
Q5BAnalysisoftheexpressionconstructincellsusedforproductionofr-DNAderivedproteinproducts
Q5CStabilitytestingofbiotechnological/biologicalproducts
Q5DDerivationandcharacterizationofcellsubstratesusedforproductionofbiotechnological/biologicalproducts
Q5EComparabilityofbiotechnological/biologicalproductssubjecttochangesintheirmanufacturingprocess
Q6ASpecifications:testproceduresandacceptancecriteriafornewsubstancesandnewdrugproducts:chemical substances
Q6BSpecifications:testproceduresandacceptancecriteriaforbiotechnological/biologicalproducts
Q7Goodmanufacturingpracticeguideforactivepharmaceuticalingredients
Q8(R2)Pharmaceuticaldevelopment
Q9Qualityriskmanagement
Q10(R4)Pharmaceuticalqualitysystem
Q11DevelopmentandmanufactureofDSs(Chemicalentitiesandbiotechnological/biologicalentities)
Q14Analyticalproceduredevelopment
M4Commontechnicaldocument
M7AssessmentandcontrolofDNAreactive(mutagenic)impuritiesinpharmaceuticalstolimitcarcinogenicrisk)
M8Electroniccommontechnicaldocument
a Thedesignationinparenthesesreferstothemostrecentrevision.
b See http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html forcopiesoftheGuidelinesandotherdetails.
FIGURE2.1 UniversalandspecifictestsforanewdrugsubstanceinICHQ6A. 2.Generalprinciplesandregulatoryconsiderations:speci
“description” and “heavymetals” hasbeen replacedby “elementalimpurities.” Theterm “relatedsubstances” haslargelydisappeared fromregulatorydocumentsandthemajorpharmacopeiasandreplacedby “impurities” inthe DSandDPbutstillpersistsinmanyinternal companydocuments.However,theuseofthe term-relatedsubstancesmayhavesomeutility indistinguishingimpuritiesstructurallyrelated totheDSfromotherstructurallyunrelatedimpurities,suchasresidualsolventsandcatalysts.
2.2.1.1Universaltests
Figs.2.1and2.2 showtheuniversaltestsfor bothnewDSsandDPs,respectively.
2.2.1.1.1Description
Description(formerlyappearance)isdefined inICHQ6A1 as “ . aqualitativestatementabout
thestate(e.g., solid,liquid)andcolorofthenew drugsubstance. ” Itisimportanttonotethatthe descriptionrelatestotheDSortheDPitself, nottotheprimarypackagingcontainer.The descriptionoftheDSshouldincludecolorand anyotherdistinguishingfeatures.ThedescriptionoftheDPshouldincludecolor,shape,size, physicalform(solid,semisolid,orliquid),and anyotherdistinguishingfeaturessuchasprinting,debossing,orembossing.Theguideline goesontostate “Ifanyofthesecharacteristics changeduringstorage,thischangeshouldbeinvestigatedandappropriateactiontaken. ”
2.2.1.1.2Identification
Identificationisaqualitativetesttoensurethe DSortheDPiswhatitisclaimedtobeonthelabel andthepackageinsert.Theidentificationtest
shouldbespecificfortheDSandcapableofunambiguouslydistinguishingbetweenDSandclosely relatedcompounds(suchimpurities)thatcould reasonablybeexpectedtobepresentinthesample (seeChapter8foramoredetaileddiscussionof descriptionandidentification).Organoleptic properties,suchasodorandtaste,areinappropriateandnolongerused.Thespecificityofthe identificationoftheDSintheDPshouldbe demonstratedbytheabsenceofinterference fromexcipients.Consequently,spectroscopic methodswithhighdegreeofspecificity(suchas FT-IR,NIR,orsolid-stateNMR)arepreferredfor theidentificationofNCEsbecauseoftheirability todistinguishdifferencesinfunctionalgroups andgeometricisomers.WhentheDSispredominantlyasingleenantiomer,achiralidentity test(suchaschiralchromatographyoroptical
FIGURE2.2 UniversalandspecifictestsforanewdrugproductinICHQ6A.
rotation)shouldbeincludedinthespecification todistinguishthelabeledenantiomericform fromtheunwantedenantiomerandtheracemic mixture.Aseparatechiralassaymaybeneeded todeterminetheleveloftheunwantedenantiomer.Alternatively,thechiralidentification testandthechiralassaymaybecombinedintoa singlemethod.Thechiralidentificationtestmay notbeneededinthespecificationoftheDPprovidedithasbeenshownduringdevelopment thatthedrugdoesnotconverttotheunwanted enantiomerduringmanufacturingorstorage.A moredetaileddiscussiononthedevelopment andvalidationofchiralidentificationtestsisprovidedinChapter16.Withappropriatevalidation, asinglespectroscopictechniquemaybesuitable fortheidentificationofthechemicalstructure andthephysicalform.
WhilechiralchromatographymaybeappropriatefortheidentificationofthedesiredenantiomerofNCEs,asinglechromatographic techniqueisnotconsideredsuf ficientlyspeci fic fortheidentificationofthedrugitself.Twochromatographic(orthogonal)procedures,which relyondifferentseparationmechanisms(e.g., reversed-phasehigh-performanceliquidchromatography[HPLC]andcapillaryelectrophoresis),differentnonspecificspectroscopictests techniquesorhyphenatedtechniquesinvolving thecombinationofchromatographyand nonspeci ficdetection(e.g.,HPLCwithdiode arraydetection)maybeappropriateifsuitably validated.
Whenthelabeleddrugisasalt,aspecifictest todistinguishtheindividualionsshouldbe includedinthespecificationfortheDS.Asingle identificationtestmaybeappropriateifthetechniqueiscapableofdistinguishingtheneutral formofthedrugfromthesalt(e.g.,FT-IR). AlthoughaDSmix-upshouldbeavoidedby compliancewiththecGMPs,someregulatory authoritiesmayrequireanidentificationtest forthecounterionintheDP.Acounterionassay mayalsobeneededintheDPifdisproportionationofthesalts,followedbylossofavolatile acid(orbase),hasnotbeenruledoutduring development.
2.2.1.1.3Assay
Assayisaquantitativetestmethodusedto determinethecontent,concentration,orthepurityofthedrugintheDSortheDP.Ideally, theassaymethodshouldbestability-indicating andspecificfortheDS.Undercertaincircumstances,theuseofanonspecificassaymethod oramethodthatisnotstability-indicating(e.g., titrationorUV-visiblespectrophotometry)may bejustified ICHQ6A1 3.2.1.cstates “[i]ncases
whereuseofanon-specificassayisjustified,other supportinganalyticalproceduresshouldbeusedto achieveoverallspecificity.Forexample,wheretitrationisadoptedtoassaythedrugsubstance,thecombinationoftheassayandasuitabletestforimpurities shouldbeused. ” Thespecification,development, andvalidationofmethodsforassayandimpuritiesarediscussedinmoredetailinChapters 9 11,respectively.Ifthedrugisasalt,anassay forthecounterionisusuallyusedindevelopmentandmaybenecessaryforthecommercial productifthesaltissusceptibletodisproportionationandthecounterionisvolatile.Replacement ofthecounterionassaywithanidentificationtest forthecounterionmaybejustifiedifthedrug doesnotdisproportionate,thecounterionisnot volatile,orboth.
2.2.1.1.4Impurities
Impuritiesarecompoundsorelementsthat areknowntobepresentorlikelytobepresent intheDSorDPintracequantities.Theriskof othercontaminantsbeingpresentinNCEsor productsisminimizedbytheuseofothercontrol strategiesinthecGMPsandGLPs.However, certaincontaminantsinbiotechnologyproducts, suchasfermentationby-products,maybeunavoidableandarecontrolledduring manufacturingandqualitycontrolofthe final product.Theimpuritiesguidelinesarecontained infourseparatedocuments:ICHQ3A(R2) “ImpuritiesinNewDrugSubstances,”11 ICH Q3B(R2) “ImpuritiesinNewDrugProducts,”12 ICHQ3C(R8) “Impurities:ResidualSolvents, ”13 andICHQ3D “GuidelineforElemental Impurities.”d14 ICHQ3AandQ3B,originally releasedinMarch1994,weredevelopedbythe sameExpertWorkingGroup(EWG)inan attempttodevelopconsistencybetweentherequirementsforDSandDP.Combiningthetwo
d TheICHprocessexpandedtheconceptoftestingfortracelevelsofimpuritiestoincludeallpotentiallytoxicelements,notjust “heavymetals” thetermwhichhasbeenreplacedbytheterm “elementalimpurities” inmostinternationalguidelines,regionalguidelines,andpharmacopeias.
guidelinesunderoneEWGachievedoneofits statedobjectivesofdefiningtheidentification, quali fication,andreportingrequirementsofimpuritiesarisingfromthemanufacture,processing,andstorageoftheDS(Q3A(R2))11 andDP (Q3B(R2)).12 BothICHQ3AandQ3Bhavebeen updatedtwice,inOctober1999andFebruary 2002,toprovideclarificationandaddressinconsistenciesbetweenthetwoguidelines.Although ICHQ3A(R2)11 andQ3B(R2)12 coverimpurities structurallyrelatedtotheDSitself,theterm “relatedsubstances” isdisappearingfromcommonusagebecauseitisnotusedintheICH guidelinesandhasbeenreplacedinthepharmacopeiasbytheterm “impurities.” Otherterms, suchas “organicimpurities” or “ordinaryimpurities,” arealsoinoccasionalusage.
Impuritiesarisingduringthemanufacture, processing,andstorageoftheDSaredefined inICHQ3A(R2)11 andincludestartingmaterials, by-products,intermediates,degradationproducts,reagents,ligands,andcatalysts.TheICH Q3B(R2)12 definesimpuritiesintheDPasdegradationproductsoftheDSintheDP.Accordingly,impuritiescarriedoverintotheDPdo nothavetobemonitoredintheDP,unless theyarealsodegradationproducts.Thisdoes notmeanthatDSimpuritiescarriedoverinto theDPcanbeignored thespeci ficityofthe DPimpuritymethodshouldbevalidatedto showthatDSimpurities,aswellasexcipients, donotinterferewiththedeterminationofdegradantsorwiththedrugitself.Theprincipleofnot requiringthecontroloftheDSimpuritiesinthe DPextendstoresidualsolvents(ICH Q3C(R8)) 13 andelementalimpurities(ICH Q3D),14 providedariskassessment(seeICH Q9,ref.19)isconductedtoconfirmtheyare notintroducedduringprocessingoftheDPor fromothersourcessuchasexcipients,equipment,andprocessingsolvents.TheICHGuidelinesQ3A(R2)11 andQ3B(R2)12 recognize “unusuallytoxic” impurities,suchasmutagens andneurotoxinsmayrequirespecialattention butprovidenospeci ficrecommendations, first
leadingtothedevelopmentofaEuropean Guideline,anindustrywhitepaper,andthena multidisciplinaryICHGuidelineM7(R1)26 “AssessmentandControlofDNAReactive(Mutagenic)ImpuritiesinPharmaceuticalstoLimitPotentialCarcinogenicRisk” (discussedinmoredetail inChapter12).TheICHguidelinesQ3A(R2)11 andQ3B(R2)12 arediscussedindetailinChapter 11.Residualsolvents(Q3C(R8))13 andelemental impurities(Q3D)14 intheDSandtheDPare coveredindetailinChapters13and14,respectively.Decisiontrees#1and#2inICHQ6A1 provideguidanceonthesettingofacceptance criteriaforimpuritiesintheDSandDP, respectively.
2.2.1.2Specifictests
Thespeci fictestsanduniversaltests(Section 2.2.1.1)arepartoftheoverallcontrolstrategy toensurethedrugissafe,iseffective,andperformsasexpected,deliveringtheprescribed doseofthedrugeitherdirectlytositeofaction (e.g.,topicalorpulmonaryproducts)ortothe siteofabsorption(e.g.,oralproductsandinjectables)inaconsistentandpredictablefashion. TheICHguidelinesonspecifications(Q6A)1 dividethespecifictestsintothoserequiredfor DS(Fig.2.1)andDP(Fig.2.2).
2.2.1.2.1Drugsubstance
ThespecifictestsforNCEs(Fig.2.1)aredeterminedbythechemicalstructure(including chirality),physicalform(particlesize,polymorphicforms),andhygroscopicity(watercontent) oftheDS.Otherdistinguishingphysicochemical properties,suchasmeltingpointormelting range,pH(ofanaqueoussolution),andrefractiveindex,mayalsobeuseful.Atestfor elementalimpurities(ICHQ3D)14 mayalsobe necessary,particularlyifmetalcatalystsare usedinthemanufactureoftheDS.Decisiontrees #3,#4,and#5inICHQ6A1 provideguidanceon thesettingofacceptancecriteriaforparticlesize, polymorphism,andchirality,respectively.The typeofmicrobialtestingrequireddependson
theintendedapplicationoftheDS themethods aredescribedintheapplicablepharmacopeia (harmonizedthroughICHQ4A16 andQ4B17). Microbiologicalattributes(MicrobialEnumeration(USP <61>)27 andTestsforSpecifiedMicroorganisms(USP <62>))28 arerequiredforany DSintendedfornonsterileproducts.Decision tree#6providesfurtherguidanceonsettingthe microbialqualityattributesoftheDS.Testing forSterility(USP <71>)29 andBacterial Endotoxins(USP <85>)30 orPyrogens (USP <151>)31 arerequiredforDSintended forsterileproducts(injectablesandophthalmic products).Therequirementsforsterileproducts arediscussedindetailinChapter25.
2.2.1.2.2Drugproduct
Asdiscussedpreviously,thepurposesofthe product-speci fictestsaretoensurethattheproductperformsasexpectedandthepatientreceives areproducibledoseoftheprescribeddrugthatis deliveredeithertothesiteofactionortothesite ofabsorption.TheDP-speci fictestsaredivided intooralproductsandparenteralproducts,and thesectiononoralproductsisfurtherdivided insolidandliquiddosageforms(Fig.2.2).One oftheprimaryobjectivesofthecontrolofall dosageformsistoensurethatthedrugis releasedfromtheformulationinaconsistent fashion,maintainingthedose-to-doseand batch-to-batchvariabilitywithinappropriate speci fiedlimits.Thedoseoftheactiveingredient shouldbewithinspeci fiedlimitsofthelabel claimandismeasuredbytheassay,whichis anaveragevalueoftheconcentrationofthe drugacrossthebatch.Forunitdosageforms, suchastabletsandcapsules,thewithin-batch variabilityisassessedbydeterminingtheuniformityofdosageunits,typicallyusingthesame analyticalmethodusedfortheassay.Uniformity ofdosageunitsisonlytestedatreleaseforsolid dosageformsbecauseitisunlikelythatthe activeingredientcanmigratefromonedosage unittothenext.
Forliquidorsemisoliddosageforms,uniformityoftheactiveingredientacrossthebatchis assessedinprocessandatreleasebytestinga predeterminednumberofindividualcontainers. Testingthedistributionoftheactiveingredient withinsinglecontaineratreleaseandonstability maybeappropriateifthepotentialexistsfor segregationoftheformulation,ormigrationof thedrug,duringpackagingoruponstorage.Solutionformulations,bydefinition,areconsideredtobehomogeneousandtheassessmentof redistributionoftheactiveingredientduring storageisusuallyunnecessary(inadequatemixingshouldbedetectedbyappropriatein-process testing).Toensurethattheproductremains withinspeci ficationthroughoutitsshelflife, antimicrobialpreservatives,antioxidants,and otherexcipients(suchasbuffers)maybeadded tocontrolthestabilityoftheproduct.Inthese cases,specifictestssuchaspH,antioxidant content,andpreservativecontentmaybe appropriate.
Ingeneral,moretestsarerequiredforliquid productsthanforsoliddosageforms.Measurementofrheologicalpropertiesofsemisolidsandliquidsmayberequiredifthe deliveryofthedugtotheintendedsiteof actionisaffectedbytheviscosityofthe product.Redispersibilitytestingisrequired forsuspensionsandemulsions,andreconstitutiontimeisrequiredforproductsthatare manufacturedinconcentratedform(eithera solidoraliquid)andmixedwithadiluent beforedosing.
AswithDS,microbiologicalattributes(MicrobialEnumeration(USP <61>)27 andTestsfor SpecifiedMicroorganisms(USP <62>))28 (Staphylococcusaureus, Pseudomonasaeruginosa, Escherichiacoli, Salmonellaentericasubspecies,and Candidaalbicans)arerequiredfornonsterile products,andtestingforSterility(USP <71>)29 andBacterialEndotoxins(USP <85>)30 orPyrogens(USP <151>)31 isrequiredforsterileproducts(parenteralandophthalmicproducts)(see alsoChapter25).Osmolalitytestingisrequired
forisotonicproductssuchasparenteralproducts andophthalmicpreparations.
Oneofthemostchallengingtestsforsolid dosageforms(bothoralproductsandimplants) isdissolution,whichisdesignedtoensurethat theactiveingredientisreleasedfromthedosage formandsubsequentlydissolvedintheextracellular fluidsorclosetothesiteofabsorption. (Note:forwater-soluble,high-permeability drugs,adisintegrationtestmaybejustified insteadofadissolutiontest.)Whileitisdesirablethattherateandextentofdrugabsorption ispredictablefromthedissolution(invitro/ invivocorrelation,IVIVC),thisisoftendiffi cult toachieve,particularlywhendrugabsorptionis controlledbybiologicalmembranepermeability ratherthantherateofdissolutionofthedrugin gastrointestinaltract.Evenintheabsenceofan IVIVC,theinclusionofadiscriminatingdissolutiontest,whichiscapableofdetectingbatch-tobatchvariabilityandchangesduringstorage inthespecification,isessentialtoensurethe reproducibilityofasoliddosage.Disintegration ofasoliddosageform(orerosionofmatrixtablets)isaprerequisitetothedissolutionofthe activeingredientinasoliddosageformand changesindisintegrationratemaybepredictive ofchangesintherateofdissolution.Therefore, disintegrationofsoliddosageforms,together withfriabilityandhardness,isusually measuredasin-processcontrolstoallowany adjustmentofprocessparametersduringa manufacturingrun.
Thespeci fictestsrequiredformore complexdosageforms,suchastransdermal deliverysystems(TDS),topicals,andinhalationproducts,arenotcoveredbyICHQ6A. ComplexTDSoftenrequirespecialized equipmenttoassessthequalityandperformanceoftheproduct,whicharediscussed indetailinthevariouspharmacopeiaandin FDAGuidances.Thetestsandregulatory requirementsfortopicalproductsarealso summarizedin Section2.2.2 anddiscussedin detailinChapter19.
2.2.2Compendialrequirements
Whilethereisnoregulatoryrequirementfor theregistrationofanewpharmaceuticalto followthetestproceduresdescribedinthegeneralchaptersofapharmacopeia,therearesignificantadvantagestousingcompendialmethods whenpossible.Inparticular,thecompendial methodshavestoodthetesttime,andmostof thekeymethodshavebeenharmonizedinthe majorpharmacopeias,includingUSP,Ph.Eur., andJP.Therefore,reviewingchemistsand field inspectorsarefamiliarwiththedetailsofmost compendialprocedures.Consequently,thecompendialtestsdonothavetobedescribedindetail inthemarketingapplicationandtheydonot havetobeupdatedwhentheproceduresor acceptancecriteriaarechanged,providedthe applicationstatesthattheproductistestedaccordingtocurrentcompendialmethods,meets theacceptancecriteriainthepharmacopeia, andisnotsignificantlymodified.Therefore,it maybeinadvisabletoreproduceageneralchapterortheacceptancecriteriainthepharmacopeia inanNDAbecausechangesinthegeneralchaptermayresultinuseofawrongmethodorthe wrongacceptancecriteria.However,anysignificantmodificationsofacompendialtestordifferencebetweenlistedacceptancecriteriaand thosebeingusedshouldbejustifiedintheapplication.Therequirementsforthevalidation,or verificationofcompendialmethods,described inthepharmacopeialgeneralchaptersarediscussedindetailinChapter23andareusually lessthanthoserequiredforthevalidationofa newnonpharmacopeialmethod,whicharesubjecttothefullrequirementsofICHQ2(R2).25 GeneralChapter <1225> oftheUSPstates “[t] estproceduresforassessmentofthequalitylevelsof pharmaceuticalarticlesaresubjecttovariousrequirements.Accordingto Section501 oftheFederalFood, Drug,andCosmeticAct,assaysandspecificationsin monographsoftheUSP NFconstitutelegalstandards.TheCurrentGoodManufacturingPractice regulations[21CFR211.194(a)]requirethattest
2.Generalprinciplesandregulatoryconsiderations:speci
methods,whichareusedforassessingcomplianceof pharmaceuticalarticleswithestablishedspecifications,mustmeetproperstandardsofaccuracyand reliability.Also,accordingtotheseregulations[21 CFR211.194(a)2],usersofanalyticalmethods describedinUSP NFarenotrequiredtovalidate theaccuracyandreliabilityofthesemethods,but merelyverifytheirsuitabilityunderactualconditions ofuse.RecognizingthelegalstatusofUSPandNF standards,itisessential,therefore,thatproposals foradoptionofneworrevisedcompendialanalytical proceduresbesupportedbysufficientlaboratory datatodocumenttheirvalidity.Thetextofthisinformationchapterharmonizes,totheextentpossible, withtheInternationalCouncilforHarmonisation (ICH)tripartiteguidelineValidationofAnalytical ProceduresandtheMethodologyextensiontext, whichareconcernedwithanalyticalprocedures includedaspartofregistrationapplicationssubmittedwithintheEC,Japan,andtheUSA ”23
ThesestatementsintheUSPimplythatnew methodstobeincludedinaUSPmonograph thatarenotcoveredbyageneralchaptermust bevalidatedaccordingtotheGeneral Chapter <1225>, 32 whichcoversessentiallythe samerequirementsasICHQ2(R2).25 Methods alreadylistedinacompendialmonographdo nothavetobevalidatedbutsimplyverified whenusedforthe firsttimeinaparticularlaboratoryaccordingtoGeneralChapter <1226>, 25 providedtheyareusedfortheparticularlisted product.ItisimportanttonotethatGeneral Chapters <1225>32 and <1226>33 relateto USPmethodsforneworexistingdrugsspeci fied byaUSPmonograph.Additionalverificationor validationofamethoddescribedintheUSPmay berequiredtodemonstratethatthemethodis suitablefortheanalysisofnewDSorDP. Furthermore,itmaybeunreasonabletoexpect thatamethod(especiallyHPLCmethods)for thetestingofaparticularDPorDSlistedina pharmacopeialmonographwillbesuitablefor theanalysisofanewdrugdeliverysystemcontainingalistedDS(an “olddruginanewproduct”).Therefore,ananalyticalmethoddescribed
inapharmacopeialmonographmaybeauseful startingpointforthedevelopmentofamethod fortheanalysisofanewdosageformandthe establishmentofacceptancecriteria.Therequirementsforthedevelopment,verification,and validationofmethodsinapharmacopeiaorproposedmethodsforinclusioninapharmacopeia arediscussedinmoredetailinChapters3and 23,aswellasinvariousotherplacesthroughout thisbook.
2.2.2.1Testingrequirements
Althoughtheattributeslistedinthevarious generalchaptersofthepharmacopeiasapply onlytotherequirementsfortheinclusionofa newmonograph,theseattributescanprovide veryusefulreferencesforthedevelopmentof specificationsofnewDSsandnewDPs,particularlywherenationalorinternationalguidelines areinadequateorabsent.Furthermore,somedifferencesbetweencompendial,national,andinternationalguidelinesexistforcertaintypesof productsandsponsorsofNDAsarealwaysrecommendedtoseekadvicefromregulatoryauthoritiestocon firmthesuitabilityofa proposedspeci ficationbefore filing.TheUSP buildsonthetaxonomyintroducedinICH Q6A,1 whichdividesthespeci ficationsofDS andDPintouniversaltestsandspeci fictests. TheuniversalDStestsintheUSParethesame asthoseinICHQ6A1:description,assay,identification,andimpurities.TheUSPalsoseparates theattributesrequiredforinclusionofanew DPmonographintouniversaltests(required forallDPs)andspecifictests,whichdependon thetypeofproduct,therouteofadministration, orboth.TheUSPalsodistinguishesbetween qualitytestsandperformancetests,alsoaccordingtothetypeofdosageform,therouteof administration,orboth.TheUSPclassi fication ofdosageformsissummarizedin Fig.2.3.The universalqualitytests,thespecificqualitytests, andthespeci ficperformancetestsaredescribed indetailinthe first fivegeneralchaptersofthe USPandaresummarizedin Fig.2.4 2.10.
FIGURE2.3 Dosageformsdefinedinthe first fivegeneralchaptersoftheUSP.
2.2.2.2USPgeneralchapters <1> to <5>
The first fiveUSPgeneralchaptersclassify DPsaccordingtotheirrouteofadministration asInjectionsandImplants(<1>),34 OralProducts(<2>),35 TopicalandTransdermalProducts (<3>),36 MucosalProducts(<4>),37 orInhalationProducts(<5>)38 andaresummarizedin Fig.2.3.GeneralChapter <1> InjectionsandImplants34 doesnotlistdescription(whichmaybe anoversight)butlistssevenuniversaltests,in
additiontoidentifi cation,assay,andimpurities, aswellasanumberofteststhatarespeci ficto thetypeofproductorrouteofadministration (Fig.2.4).Thespecifi ctestsfororalproducts (<2>)35 aredividedintosolidsandliquids (Fig.2.5).GeneralChapter <3>36 dividesthe speci fictestsintothosethatapplytoalltopical andTDSandthosethatapplyadditionallyto TDS(Fig.2.6).Thetestingrequirementsfor topicalproductsarediscussedinmoredetail inChapter19.GeneralChapter <4>37 divides
2.Generalprinciplesandregulatoryconsiderations:specificationsandshelflifesetting
Injections/Implants <1>
Universal Tests
Impurities
Foreign and Particulate Matter1
Sterility2 Bacterial Endotoxins3
Specific Tests
Product
Other Products14
Uniformity of Dosage Units8
Vehicles and Added Substances9
Antimicrobial Effectiveness10
Water Content11 Aluminum Content12
Container Content4 Packaging5
Container-Closure Integrity6 Labeling7
DPsforapplicationtomucousmembranes intosevencategoriesaccordingtothesiteof administration:optic,ophthalmic,nasal, oropharyngeal,urethral,vaginal,andrectal (Fig.2.7).GeneralChapter <5>38 dividesthe specifictestsforinhalationproductsintosix
Completeness and Clarity of Solution13
FIGURE2.4 UniversalandspecifictestsforinjectableproductsandimplantsinUSP <1>
categoriesaccordingtothetypeofdosage form:inhalationaerosols,inhalationsolutions, inhalationsuspensions,solutionsordrug forinhalationsolution(nebulizationproducts), inhalationsprays,andinhalationpowder(see Fig.2.8).Thespeci fictestsfornasalproducts
I.Introduction
aredividedintothreecategories:sprays,solutions,andpowders(Fig.2.9).
Oneoftheseveralcomplications,andpotential areasofconfusion,intheclassificationandtesting requirementsofnasalproductsandinhalation products,arisesfromthefactthattheUSPrequirementsfornasalspraysaredescribedinGeneralChapterUSP <4>30 andtherequirementsfor inhalationproductsaredescribedinUSP <5>, buttheFDAguidelinesforthesetypesofproductsarecontainedinthesamedocument: “GuidanceforIndustry:NasalSpraysandInhalation Solution,SuspensionandSprayProducts Chemistry,ManufacturingandControlsDocumentation. ”39
Asdiscussedpreviously,theperformance testsareintendedtodemonstratethattheprescribeddoseoftheactiveingredientintheDP isdeliveredataconsistentpredictablerateeither directlytothesiteofactionortothesiteofabsorption.TheperformancetestsintheUSPfor oral,topical,transdermal,nasal,andinhalation productsaresummarizedin Fig.2.10.Although theUSPrecognizesthatsystemicdrugdelivery mayoccurintentionallyorunintentionallyfrom drugsdeliveredtothemucosalmembranes, therearenospeci ficperformancetestsdescribed inGeneralChapter <4>. 37 Similarly,thereare noperformancetestsforparentalproductslisted
FIGURE2.5 UniversalandspecifictestsfororalproductsinUSP <2>
FIGURE2.6 UniversalandspecifictestsfortopicalandtransdermalproductsinUSP <3>
inGeneralChapter <1>, 34 despitethefactthat manyinjectableproducts,suchasimplantsand subcutaneousorintramuscularinjections,are intendedforcontrolledorsustaineddelivery. (Oneexceptiontothisisparenteralemulsions, whicharetestedforglobulesize(USP <729>), whichmayaffectreleaserateofthedrugfrom theemulsion.)Inthesecases,appropriate invitroreleaseratetestsshouldbeincludedin thespeci fication.
2.2.3Biotechnologyproducts (macromolecules)andbiologicalproducts
Abasicprincipleofmolecularpharmacology isthatadrugmustbepresentinsolutionatthe siteofactiontoexertitsbiologicalactivity.For smallmolecules(alsoknownas “ chemical
entities ” ),thepharmacologicalactivityisdeterminedbythechemicalstructure(includingany speci fi cstereochemicalarrangements).Forlarge molecules,producedbybiotechnologyorbiologicalprocesses,pharmacologicactivitydependsnotonlyonthechemicalstructurebut alsoontheconformationalstructureandposttranslationalmodifi cations.Therefore,thespeci fi ctestsdescribedinICHQ6B 2 maybe requiredinadditionto,orinsteadof,those describedinQ6A1 toprovideacompletespecifi cationofabiotechnologicalproduct.Asa consequenceoftheneedtospecifytheconformationalandposttranslationalcharacteristics, thenumberandcomplexityofthetestsinthe speci fi cationofbiotechnologyproductsmay begreaterthanwhatisrequiredforaNCE. Forexample,morethanonetestisusually requiredfortheidenti fi cationofabiotech-
