ICH guidelines in biopharmaceutics b.pharm

Ich guidelines

1. ICH-GUIDELINES OF ICH-Q S E M
GNYANA RANJAN PARIDA
Assistant Professor
SoPLS, CUTM

2. Outline
–ICH
–Mission
–Need to Harmonize
–Structure
–Observers
–Process of Harmonization
–Guidelines Q S E M
–Regulatory Requirements of Following countries:
•EU
•MHRA
•TGA
•ROW

3. WhatisICH?
•TheInternationalCouncilforHarmonizationof
TechnicalRequirementsforPharmaceuticalsfor
HumanUse(ICH)isuniqueinbringingtogether
theregulatoryauthoritiesandpharmaceutical
industrytodiscussscientificandtechnicalaspects
ofdrugregistration.ICHwascreatedinApril1990.
ICHGuidelines
•TheICHtopicsaredividedintofourcategoriesand
ICHtopiccodesareassignedaccordingtothese
categories.
–QualityGuidelines
–SafetyGuidelines
–EfficacyGuidelines
–MultiDisciplinaryGuidelines

4. InternationalConferenceonHarmonization
•Itisajointinitiativeinvolvingregulators&industry
asequalpartnersinthescientific&technical
discussionofthetestingprocedurewhichare
requiredtoensureandassesstheQuality,Safety,&
efficacyofmedicines.
Mission
•Tomakerecommendationstowardsachieving
greaterharmonizationintheinterpretationand
applicationoftechnicalguidelinesand
requirementsforpharmaceuticalproduct
registration,therebyreducingduplicatingof
testingcarriesoutduringtheresearchand
developmentofnewHumanMedicines.

5. •HarmonizationachievementsintheQualityarea
includepivotalmilestonessuchastheconduct
ofstabilitystudies,definingrelevantthresholds
forimpuritiestestingandamoreflexible
approachtopharmaceuticalqualitybasedon
GoodManufacturingPractice(GMP)risk
management.
•ICHhasproducedacomprehensivesetofsafety
guidelinestouncoverpotentialriskslike
carcinogenicity,genotoxicityandreprotoxicity.
•Arecentbreakthroughhasbeenanon-clinical
testingstrategyforassessingtheQTinterval
prolongationliability.

6. •TheworkcarriedoutbyICHundertheEfficacy
headingisconcernedwiththedesign,conduct,
safetyandreportingofclinicaltrials.
•Italsocoversnoveltypesofmedicinesderivedfrom
biotechnologicalprocessesandtheuseof
pharmaco-genetics/genomicstechniquestoproduce
bettertargetedmedicines.
•Thosearethecross-cuttingtopicswhichdonotfit
uniquelyintooneoftheQuality,SafetyandEfficacy
categories.
•ItincludestheICHmedicalterminology(MedDRA),
theCommonTechnicalDocument(CTD)andthe
developmentofElectronicStandardsfortheTransfer
ofRegulatoryInformation(ESTRI).

7. NeedtoHarmonize
•Realizationwasdrivenbytragedies,suchasthatwith
thalidomideinEuropeinthe1960s.
•The1960sand1970ssawarapidincreaseinlaws,
regulationsandguidelinesforreportingandevaluating
thedataonQuality,SafetyandEfficacyofnewMedicinal
products.
•Divergenceintechnicalrequirementsfromcountryto
country.
•StructureRegulatoryBodyIndustryEuropeanunion
MinistryofHealth,Labor&welfare,Japanan(MHLW)US
Food&DrugAssociation(USFDA)EuropeanFederationof
PharmaceuticalIndustriesAssociations(EFPIA)Japan
PharmaceuticalAssociation(JPMA)Pharmaceutical
Research&ManufacturersofAmerica(PhRMA).

8. Observers
•WHO,EFTA(EuropeanFreeTradeAssociation),Canada,Austrila–Non
votingmembers
•IFPMA(InternationalfederationsofPharmaceuticalManufactures
Association)representative
ProcessofHarmonization
•ICHharmonizationactivitiesfallinto4categories:
1.FormalICHprocedure:NewtopicforHarmonization
2.Q&AProcedure:Clarificationonexistingguideline
3.RevisionProcedure
4.MaintenanceProcedure
TheGuidelines–QSEM
–Quality(Q1-Q11)
–Chemical&PharmaceuticalQA
–Safety(S1-S10,M3)
–Dealingwithin-vitro&in-vivopreclinicaltesting
–Efficacy(E1-E16ExceptE13)
–Clinicalstudyinhumanbeings
–Multidisciplinary(M1-M8)
–Terminology,electronicstandards,commondocuments

9. Quality
–Q1-Stability
–Q2-AnalyticalValidation
–Q3-Impurities
–Q4-Pharmacopoeias
–Q5-QualityofBiotechnologicalProducts
–Q6-Specification
–Q7-GoodManufacturingPractice
–Q8-PharmaceuticalDevelopment
–Q9-QualityRiskManagement
–Q10-PharmaceuticalQualitySystem
Safety
•S1-CarcinogenicityStudies
•S2-Geno-toxicityStudies
•S3-Toxico-kineticsandPharmacokinetics
•S4-ToxicityTesting
•S5-Reproductivetoxicology
•S6-BiotechnologicalProduct
•S7-pharmacologyStudies
•S8-Imuno-toxicologyStudies
•S9-NonclinicalevaluationforanticancerPharmaceutical
•S10-PhotosafetyEvaluation

10. Efficacy
–E1&E2-ClinicalSafety
–E3-ClinicalStudyReports
–E4-Dose-responseStudies
–E5-EthnicFactors
–E6-GoodClinicalPractice
–E7,E8,E9,E10,E11-ClinicalTrials
–E12-GuidelinesforClinicalEvaluationbytherapeuticCategory
–E14-ClinicalEvaluation
–E15&E16-Pharmacogenomics
Multidisciplinary
–M1-MedDRATerminology
–M2-ElectronicStandards
–M3-Non-clinicalSafetyStudies
–M4-CTD
–M5-Dataelements&StandardsforDrugdictionaries
–M6-GeneTherapy
–M7-Genotoxicimpurities
–M8-eCTD

11. Regulatory Requirements Of Different Countries
EuropeanUnion
•Intergovernmentalpoliticalandeconomicunionof28
Europeancountrieshavinginternalsinglemarketthrough
thestandardizedsystemoflaws.
•Establishedunderthenamein1992bythetreatyon
EuropeanUnion.
•EuropeanMedicineAgency(EMA)isadecentralized
agencyoftheEuropeanUnion.
•EMAprotectspublicandanimalhealthbyensuringthatall
medicinesavailableontheEUmarketaresafe,effectiveof
highquality.
•Theagencyisresponsibleforthescientificevaluation,
supervisionandsafetymonitoringofthemedicines
developedbypharmaceuticalcompaniesfortheuseinEU.
•EMAandthememberstatecooperateshareexpertisein
theassessmentofnewmedicinesandofnewsafety
information.

12. TheRoleofEMA:
•EMAplaysanimportantroleintheregulationofmedicinesin
theEU.
•Onthebasisofscientificassessmentscarriedout.Itgrants
andrefuses,changesandsuspendsmarketingauthorizations
formedicinethathavebeensubmittedviathecentralized
procedure.
•TheEuropeancommissioncanalsotakeactionconcerning
otheraspectsofmedicineregulations:
•RightofInitiative-Itcanproposenewlegislationfor
pharmaceuticalsector;
•Implementation-itcanadoptimplementingmeasuresas
wellasoverseethecorrectapplicationofEUlawon
pharmaceuticals;
•Globaloutreach:itensureappropriatecollaborationwith
relevantinternationalpartnersandpromotestheEU
regulatorysystemglobally.

13. MHRA
•MedicineandHealthcareProductsRegulatoryAgencyisan
ExecutiveagencyoftheDepartmentoftheHealthofUnited
Kingdom.
•MHRAwassetupinApril,2003bringingtogetherthefunction
ofmedicineControlagency(MCA)andtheMedicalDevice
Agency(MDA).
•MHRAisresponsibleforensuringthatmedicinesandmedical
deviceswork,andareacceptablysafe.
•MHRAfunctionswhenthecompanywantstostartclinicaltrials
inpatients.
RoleofMHRA
–Licensing
–Safetyandefficacymonitoring
–Enforcementoflaws
–Regulationsofclinicaltrials
–ProvidinginformationtopublicandHealthProfessionals
–MHRAdoesnotregulatedietarysupplements,veterinaryproducts
andcosmetics.

14. TGA
•TherapeuticGoodsAdministrationistheregulatory
bodyfortherapeuticgoodinAustralia.
•TGAisresponsibleforconductingassessmentand
monitoringactivitiestoensurethattherapeutic
goodsavailableinAustraliaareanacceptable
standard.
•TheobjectivesofTherapeuticGoodsAct1989,
Whichcameintoeffecton15thFeb1991isto
provideanationalframeworkfortheregulationof
therapeuticgoodsinAustraliatoensurequality,
safetyandefficacyofthemedicinesandensure
quality,safetyandperformancesofmedical
devices.

15. •EssentiallyTGmustbeenteredonAustralianRegisterof
Therapeuticsgoods(ARTG)beforesuppliedinAustralia.
•ARTGiscomputerdatabaseofinformationofTG
•AustraliaManufactureallmedicineslicensedunderpart4of
theTGact1989.
•OnceapprovalformarketinginAustralia,ARTGcanbe
identifiedbyAUSTR(forregisteredMedicines)orAUSTL(for
listedmedicine)thatappearsonpackagingofthemedicines.
•ROW(Restoftheworld):dividedtheworldin5regions(ASIA,
EmergingEurope/Turkey/Israel,LatinAmerica,Middle
East/Africa,Russia/CIS)
•Keyfunctions:
–1.Productregistration
–2.Regulationofdrugmanufacturing,importationanddistribution
–3.Adversedrugreactionmonitoring
–4.Licensingofpremises,personandpractices.
–5.Maingoaloftheagencyistoguaranteethesafety,efficacy,and
qualityoftheavailabledrugproduct.

16. QUALITY GUIDELINES (Q)
•HarmonizationachievementsintheQualityareaincludepivotalmilestones
suchastheconductofstabilitystudies,definingrelevantthresholdsfor
impuritiestestingandamoreflexibleapproachtopharmaceuticalquality
basedonGoodManufacturingPractice(GMP)riskmanagement
QUALITYGUIDELINES(Q)
•Q1A-Q1F(Stability)
•Q2(AnalyticalValidation)
•Q3A-Q3D(Impurities)
•Q4-Q4B(Pharmacopoeias)
•Q5A-Q5E(QualityofBiotechnologicalProducts)
•Q6A-Q6B(Specifications)
•Q7(GoodManufacturingPractice)
•Q8(PharmaceuticalDevelopment)
•Q9(QualityRiskManagement)
•Q10(PharmaceuticalQualitySystem)
•Q11(DevelopmentandManufactureofDrugSubstances)
•Q12(LifecycleManagement)
•Q13(ContinuousManufacturingofDrugSubstancesandDrugProducts)
•Q14(ANALYTICALPROCEDUREDEVELOPMENT)

17. Q1A--Q1F(STABILITY)
•Q1A(R2)-StabilityTestingofNewDrugSubstancesand
Products
•Q1B-StabilityTesting:PhotostabilityTestingofNewDrug
SubstancesandProducts
•Q1C-StabilityTestingforNewDosageForms
•Q1D-BracketingandMatrixingDesignsforStability
TestingofNewDrugSubstancesandProducts
•Q1E-EvaluationofStabilityData
•Q1F-StabilityDataPackageforRegistrationApplications
inClimaticZonesIIIandIV
Q2(ANALYTICALVALIDATION)
•Q2(R1)-ValidationofAnalyticalProcedures:Textand
Methodology
•Q2(R2)/Q14-AnalyticalProcedureDevelopmentand
RevisionofQ2(R1)AnalyticalValidation

18. Q3A-Q3D(IMPURITIES)
•Q3A(R2)-ImpuritiesinNewDrugSubstances
•Q3B(R2)-ImpuritiesinNewDrugProducts
•Q3C(R7)-Impurities:GuidelineforResidual
Solvents
•Q3C(R8)-Impurities:GuidelineforResidual
Solvents
•Q3D(R1)-GuidelineforElementalImpurities
•Q3D(R2)-RevisionofQ3D(R1)forcutaneousand
transdermalproducts
•Q3D-TrainingImplementationofGuidelinefor
ElementalImpurities

19. SAFETY GUIDELINES (S)
•ICHhasproducedacomprehensivesetofsafetyGuidelinestouncover
potentialriskslikecarcinogenicity,genotoxicityandreprotoxicity.
•Arecentbreakthroughhasbeenanon-clinicaltestingstrategyfor
assessingtheQTintervalprolongationliability(thesinglemostimportant
causeofdrugwithdrawalsinrecentyears)
SAFETYGUIDELINES(S)
•S1A-S1C(CarcinogenicityStudies)
•S2(GenotoxicityStudies)
•S3A-S3B(ToxicokineticsandPharmacokinetics)
•S4(ToxicityTesting)
•S5(ReproductiveToxicology)
•S6(BiotechnologicalProducts)
•S7A-S7B(PharmacologyStudies)
•S8(ImmunotoxicologyStudies)
•S9(NonclinicalEvaluationforAnticancerPharmaceuticals)
•S10(PhotosafetyEvaluation)
•S11(Nonclinical PaediatricSafety)

20. S1A-S1C(CARCINOGENICITYSTUDIES)
•S1(R1)-RodentCarcinogenicityStudiesforHumanPharmaceuticals
•S1A-NeedforCarcinogenicityStudiesofPharmaceuticals
•S1B-TestingforCarcinogenicityofPharmaceuticals
•S1C(R2)-DoseSelectionforCarcinogenicityStudiesofPharmaceuticals
•S2(R1)-GuidanceonGenotoxicityTestingandDataInterpretationfor
PharmaceuticalsIntendedforHumanUseS2(GenotoxicityStudies)
S3A-S3B(TOXICOKINETICSANDPHARMACOKINETICS)
•S3A-NoteforGuidanceonToxicokinetics:TheAssessmentofSystemic
ExposureinToxicityStudies.
•S3AQ&As-QuestionsandAnswers:NoteforGuidanceonToxicokinetics:The
AssessmentofSystemicExposure-FocusonMicrosampling
•S3B-Pharmacokinetics:GuidanceforRepeatedDoseTissueDistribution
Studies
S4-DurationofChronicToxicityTestinginAnimals
•S4(ToxicityTesting)(RodentandNonRodentToxicityTesting)
S5(REPRODUCTIVETOXICOLOGY)
•S5(R2)-DetectionofToxicitytoReproductionforMedicinalProducts&Toxicity
toMaleFertility
•S5(R3)-RevisionofS5GuidelineonDetectionofToxicitytoReproductionfor
HumanPharmaceuticals

21. •S6(R1)-PreclinicalSafetyEvaluationofBiotechnology-Derived
PharmaceuticalsS6(BiotechnologicalProducts)
S7A-S7B(PHARMACOLOGYSTUDIES)
•S7A-SafetyPharmacologyStudiesforHumanPharmaceuticals
•S7B-TheNon-ClinicalEvaluationofthePotentialforDelayed
VentricularRepolarization(QTIntervalProlongation)byHuman
Pharmaceuticals.
•S8-ImmunotoxicityStudiesforHumanPharmaceuticalsS8
(ImmunotoxicologyStudies)
S9(NON-CLINICALEVALUATIONFORANTICANCERPHARMACEUTICALS)
•S9-Non-clinicalEvaluationforAnticancerPharmaceuticals
•S9Q&As-QuestionsandAnswers:NonclinicalEvaluationfor
AnticancerPharmaceuticals
•S10-PhotosafetyEvaluationofPharmaceuticals
•S11(NON-CLINICALPAEDIATRICSAFETY)
•S11-Non-clinicalSafetyTestinginSupportofDevelopmentof
PediatricMedicines

22. EFFICACY GUIDELINES (E)
•TheworkcarriedoutbyICHundertheEfficacy
headingisconcernedwiththedesign,conduct,
safetyandreportingofclinicaltrials.
•Italsocoversnoveltypesofmedicinesderived
frombiotechnologicalprocessesandtheuseof
pharmacogenetics/genomicstechniquesto
producebettertargetedmedicines.

23. EFFICACYGUIDELINES(E)
•E1(ClinicalSafetyforDrugsusedinLong-TermTreatment)
•E2A-E2F(Pharmacovigilance)
•E3(ClinicalStudyReports)
•E4(Dose-ResponseStudies)
•E5(EthnicFactors)
•E6(GoodClinicalPractice)
•E7(ClinicalTrialsinGeriatricPopulation)
•E8(GeneralConsiderationsforClinicalTrials)
•E9(StatisticalPrinciplesforClinicalTrials)
•E10(ChoiceofControlGroupinClinicalTrials)
•E11-E11A(ClinicalTrialsinPediatricPopulation)
•E12(ClinicalEvaluationbyTherapeuticCategory)
•E14(ClinicalEvaluationofQT)
•E15(DefinitionsinPharmacogenetics/Pharmacogenomics)
•E16(QualificationofGenomicBiomarkers)
•E17(Multi-RegionalClinicalTrials)
•E18(GenomicSampling)
•E19(SafetyDataCollection)
•E20(AdaptiveClinicalTrials)

24. E1(CLINICALSAFETYFORDRUGSUSEDINLONG-TERM
TREATMENT)
–E1-TheExtentofPopulationExposuretoAssessClinicalSafetyfor
DrugsIntendedforLong-TermTreatmentofNon-LifeThreatening
Conditions
E2A-E2F(PHARMACOVIGILANCE)
–E2A-ClinicalSafetyDataManagement:DefinitionsandStandards
forExpeditedReporting.
–E2B(R3)-ClinicalSafetyDataManagement:DataElementsfor
TransmissionofIndividualCaseSafetyReports.
–E2B(R3)Q&As-Implementation:ElectronicTransmissionof
IndividualCaseSafetyReports.
–E2C(R2)-PeriodicBenefit-RiskEvaluationReport.
–E2C(R2)Q&As-Questions&Answers:PeriodicBenefit-Risk
EvaluationReport.
–E2D-Post-ApprovalSafetyDataManagement:Definitionsand
StandardsforExpeditedReporting.
–E2E-PharmacovigilancePlanning.
–E2F-DevelopmentSafetyUpdateReport.

25. E3(CLINICALSTUDYREPORTS)
•E3-StructureandContentofClinicalStudyReports.
•E3Q&AsR1-Questions&Answers:StructureandContentofClinical
StudyReports.
•E4-Dose-ResponseInformationtoSupportDrugRegistration
E4(Dose-ResponseStudies)
E5(ETHNICFACTORS)
•E5(R1)-EthnicFactorsintheAcceptabilityofForeignClinicalData
•E5Q&As(R1)-Questions&Answers:EthnicFactorsintheAcceptability
ofForeignClinicalData
E6(R2)-GoodClinicalPractice(GCP)
•E6(GoodClinicalPractice)
E7(CLINICALTRIALSINGERIATRICPOPULATION)
•E7-StudiesinSupportofSpecialPopulations:Geriatrics.
•E7Q&As-Questions&Answers:StudiesinSupportofSpecial
Populations:Geriatrics.
E8-GeneralConsiderationsforClinicalTrials
•E8(R1)-RevisiononGeneralConsiderationsforClinicalTrials.
•E8(GeneralConsiderationsforClinicalTrials)

26. E9(STATISTICALPRINCIPLESFORCLINICALTRIALS)
•E9-StatisticalPrinciplesforClinicalTrials
•E9(R1)-Addendum:StatisticalPrinciplesforClinical
Trials
E10-ChoiceofControlGroupandRelatedIssuesin
ClinicalTrials
E11-E11A(CLINICALTRIALSINPEDIATRIC
POPULATION)
•E11(R1)-Addendum:ClinicalInvestigationof
MedicinalProductsinthePediatricPopulation
•E11A-PediatricExtrapolation
E12-PrinciplesforClinicalEvaluationofNew
AntihypertensiveDrugs
•E12(ClinicalEvaluationbyTherapeuticCategory)

27. •36.E14(CLINICALEVALUATIONOFQT)36AshwiniK.
BawankuleE14-TheClinicalEvaluationofQT/QTc
IntervalProlongationandProarrhythmicPotentialfor
Non-AntiarrhythmicDrugsE14Q&As(R3)-Questions
&Answers:TheClinicalEvaluationofQT/QTcInterval
ProlongationandProarrhythmicPotentialforNon-
AntiarrhythmicDrugsE14/S7BQ&As-Questions&
Answers:Clinicalandnon-ClinicalEvaluationofQT/QTc
IntervalProlongationandProarrhythmicPotential
E15-DefinitionsforGenomicBiomarkers,
Pharmacogenomics,Pharmacogenetics,GenomicData
andSampleCodingCategoriesE15(Definitionsin
Pharmacogenetics/Pharmacogenomics)

28. E16(QUALIFICATIONOFGENOMICBIOMARKERS)
•E16-BiomarkersRelatedtoDrugor
BiotechnologyProductDevelopment:Context,
StructureandFormatofQualification
Submissions.
•E17-Generalprinciplesforplanninganddesign
ofMulti-RegionalClinicalTrials.
•E18-GenomicSamplingandManagementof
GenomicData.
E19(SAFETYDATACOLLECTION)
•E19-OptimizationofSafetyDataCollection
•E20(AdaptiveClinicalTrials)

29. MULTIDISCIPLINARY GUIDELINES (M)
•Thosearethecross-cuttingtopicswhichdonot
fituniquelyintooneoftheQuality,Safetyand
Efficacycategories.
•ItincludestheICHmedicalterminology
(MedDRA),theCommonTechnicalDocument
(CTD)andthedevelopmentofElectronic
StandardsfortheTransferofRegulatory
Information(ESTRI).

30. •MULTIDISCIPLINARYGUIDELINES(M)
•M1(MedDRATerminology)
•M2(ElectronicStandards)
•M3(NonclinicalSafetyStudies)
•M4(CommonTechnicalDocument)
•M5(DataElementsandStandardsforDrugDictionaries)
•M6(GeneTherapy)
•M7(Mutagenicimpurities)
•M8(ElectronicCommonTechnicalDocumenti.e.,eCTD)
•M9(BiopharmaceuticsClassificationSystem-basedBio-
waivers)
•M10(Bio-analyticalMethodValidation)
•M11(ClinicalelectronicStructuredHarmonizedProtocol
i.e.,CeSHarP)
•M12(DrugInteractionStudies)

31. •M1(MedDRATERMINOLOGY)
•MedDRA:MedicalDictionaryforRegulatory
Activities
•ESTRI:ElectronicStandardsfortheTransferof
RegulatoryInformation
•M3(R2)-GuidanceonNon-clinicalSafetyStudies
fortheConductofHumanClinicalTrialsand
MarketingAuthorizationforPharmaceuticals.
•M3(R2)Q&AsR2-Questions&Answers:Guidance
onNon-ClinicalSafetyStudiesfortheConductof
HumanClinicalTrialsandMarketingAuthorization
forPharmaceuticals.
•M2(ElectronicStandards)
•M3(Non-clinicalSafetyStudies)

32. •M4(COMMONTECHNICALDOCUMENT)
–CTD:TheCommonTechnicalDocument
•M5(DataElementsandStandardsforDrug
Dictionaries)
•M6-VirusandGeneTherapyVectorSheddingand
Transmission
•M7(MUTAGENICIMPURITIES)
–M7(R1)-AssessmentandControlofDNAReactive
(Mutagenic)ImpuritiesinPharmaceuticalstoLimit
PotentialCarcinogenicRisk
–M7(R2)-AssessmentandControlofDNAReactive
(Mutagenic)ImpuritiesinPharmaceuticalstoLimit
PotentialCarcinogenicRisk.
–ElectronicCommonTechnicalDocument(eCTD)
•M8(ElectronicCommonTechnicalDocument)