GUIDELINES ON SIMILAR BIOLOGICS - ableindia.in on Similar... · Government of India Department of...
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GUIDELINES ON SIMILAR BIOLOGICS
Regulatory Requirements forMarketing Authorization in India
2016
GovernmentofIndia
Department of BiotechnologyMinistryofScience&Technology
Central Drugs Standard Control Organiza�onMinistryofHealth&FamilyWelfare
GovernmentofIndia
Department of BiotechnologyMinistryofScience&Technology
Central Drugs Standard Control Organiza�onMinistryofHealth&FamilyWelfare
Guidelines on Similar Biologics:RegulatoryRequirementsfor
Marke�ngAuthoriza�oninIndia
12016
Guidelines on Similar Biologics: Regulatory Requirements for Marke�ng Authoriza�on in India
Effec�ve 15th August 2016
2
Content
Message
1.Introduc�on
2.Background&Objec�ves
3.ApplicableRegula�onsandGuidelines
4.CompetentAuthori�es
5.Scope
6.PrinciplesforDevelopmentofSimilarBiologics
6.1Selec�onofReferenceBiologic
6.2ManufacturingProcess
6.3QualityBasedConsidera�onofSimilarBiologics
6.4QualityComparabilityStudy
7.DataRequirementsforPreclinicalStudies
7.1PrerequisitebeforeConduc�ngPreclinicalStudies
7.2PreclinicalStudies(PharmacodynamicandToxicologyStudies)
7.3ImmuneResponsesinAnimals
8.DataRequirementsforClinicalTrialApplica�on
8.1Pharmacokine�c(PK)studies
8.2Pharmacodynamics(PD)studies
8.3ConfirmatorySafetyandEfficacyStudy
8.4SafetyandImmunogenicitydata
8.5Extrapola�onofEfficacyandSafetyDatatoOtherIndica�ons
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9.DataRequirementsforMarketAuthoriza�onApplica�on ...................................................30
Foreword .....................................................................................................................................5
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11.Applica�onForms
12.ArchivingofData/Reten�onofSamples
13.Glossary
14.References
Annexure I
Acknowledgement
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Annexure II .................................................................................................................................42
10.Post-MarketDataforSimilarBiologics
10.1PharmacovigilancePlan
10.2AdverseDrugReac�on(ADR)Repor�ng
10.3PostMarke�ngStudies(PhaseIV)
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Guidelines on Similar Biologics:
Regulatory Requirements for Marke�ng Authoriza�on in India.
1. Introduc�on
The“GuidelinesonSimilarBiologics”preparedbyCentralDrugsStandardControlOrganiza�on
(CDSCO)andtheDepartmentofBiotechnology(DBT)laydowntheregulatorypathwayfora
SimilarBiologicclaimingtobeSimilartoanalreadyauthorizedReferenceBiologic.
ASimilarBiologicproductisthatwhichissimilarintermsofquality,safetyandefficacytoan
approvedReferenceBiologicalproductbasedoncomparability.
Theseguidelinesaddresstheregulatorypathwayregardingmanufacturingprocessand
safety,efficacyandqualityaspectsforSimilarBiologics.
Theseguidelinesalsoaddressthepre-marketregulatoryrequirementsincluding
comparabilityexerciseforquality,preclinicalandclinicalstudiesandpostmarketregulatory
requirementsforSimilarBiologics.
Theseguidelinesarefortheguidanceofallstakeholdersandarenotmeanttosubs�tuteor
rephrasetheRulesmadeunderDrugsandCosme�csAct,1940oranyotherrelevantActs
andaresubjecttobeinginconformitywiththeDrugsandCosme�csActandRulesasmaybe
amendedfrom�meto�me.
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2. Background & Objec�ves
CDSCOisthena�onalregulatoryauthorityinIndiathatevaluatessafety,efficacyandquality
ofdrugsinthecountry.DBTthroughReviewCommi�eeonGene�cManipula�on(RCGM)is
responsibleforoverseeingthedevelopmentandpreclinicalevalua�onofrecombinantDNA
derivedproducts.
Presently,severalorganiza�onsareac�velyengagedinmanufacturingandmarke�ngSimilar
BiologicsinIndia.Sofar,theseSimilarBiologicswereapprovedbyRCGMandCDSCOusingan
abbreviatedversionofthepathwayapplicabletonewdrugsonacasebycasebasis.Since
thereareseveralsuchproductsunderdevelopmentinIndia,bothregulatoryagencies
consideredtheneedtopublishaclearregulatorypathwayoutliningtherequirementsto
ensurecomparablesafety,efficacyandqualityofaSimilarBiologictothereferenceBiologic.
Basedondemonstra�onofsimilarityinthecompara�veassessment,aSimilarBiologicmay
requirereducedpreclinicalandclinicaldatapackageaspartofsubmissionformarket
authoriza�on.
The objec�ve of this document is to provide guidelines to applicants to enable them to
understandandcomplywiththeregulatoryrequirementsformarketauthoriza�onofSimilar
BiologicsinIndia.
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3. Applicable Regula�ons and Guidelines
TheSimilarBiologicsareregulatedaspertheDrugsandCosme�csAct,1940,theDrugsand
Cosme�csRules,1945(asamendedfrom�meto�me)andRulesforthemanufacture,use,
import,exportandstorageofhazardousmicroorganisms/gene�callyengineeredorganisms
orcells,1989(Rules,1989)no�fiedundertheEnvironment(Protec�on)Act,1986.Various
applicableguidelinesareasfollows:
· RecombinantDNASafetyGuidelines,1990.
· Guidelinesforgenera�ngpreclinicalandclinicaldataforrDNAvaccines,diagnos�csand
otherBiologicals,1999.
· CDSCOguidanceforindustry,2008:
o SubmissionofClinicalTrialApplica�onforEvalua�ngSafetyandEfficacy
o RequirementforpermissionofNewDrugApproval
o PostapprovalchangesinBiologicalproducts:Quality,SafetyandEfficacy
Documents
o Prepara�onofQualityInforma�onforDrugSubmissionforNewDrug
Approval:Biotechnological/BiologicalProducts
· GuidelinesandHandbookforIns�tu�onalBiosafetyCommi�ees(IBSCs),2011.
· GuidelinesonSimilarBiologics:RegulatoryRequirementsforMarke�ngauthoriza�onin
India2012.
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4. Competent Authori�es
Thecompetentauthori�esinvolvedintheapprovalprocessareasfollows:
Ins�tu�onal BioSafety Commi�ee (IBSC)
IBSCisrequiredtobecons�tutedbyanypersonincludingresearchins�tu�onshandling
hazardousmicroorganismsand/orgene�callyengineeredorganisms.IBSCisresponsiblefor
ensuringbiosafetyon-site,alongwithini�alreviewofapplica�onstoberecommendedto
RCGM.IBSCisalsoassignedwiththeresponsibilitytoreviewandauthorizefirmforexchange
ofaforesaidorganismsforthepurposeofresearch.
1Review Commi�ee on Gene�c Manipula�on (RCGM)
RCGMisfunc�oningfromtheDepartmentofBiotechnology(DBT),MinistryofScienceand
Technology,GovernmentofIndia.InthecontextofSimilarBiologics,RCGMisresponsiblefor
authorizingtheconductofresearchanddevelopment,exchangeofgene�callyengineered
cellbanksforthepurposeofresearchanddevelopmentandreviewofdatauptopreclinical
evalua�on.
1Gene�c Engineering Appraisal Commi�ee (GEAC)
GEACfunc�onsundertheMinistryofEnvironmentandForests(MoEF)asstatutorybodyfor
reviewofapplica�onsandapprovalofac�vi�eswherefinaldrugproductcontainsgene�cally
modifiedorganisms/livingmodifiedorganisms.
1( RCGM and GEAC are statutory commi�ees set up as per provisions of Rules, 1989)
2Central Drugs Standard Control Organiza�on (CDSCO)
CDSCO,headedbytheDrugControllerGeneralofIndia(DCGI)istheapexregulatorybodyunder
MinistryofHealth&FamilyWelfare(MoHFW),GovernmentofIndia,whichisresponsiblefor
theapprovalofclinicaltrialsaswellasnewdrugs.InthecontextofSimilarBiologics,CDSCOis
responsibleforclinicaltrialapproval(alsograntspermissionforimportofdrugsforclinicaltrial
andexportofclinicalsamplesforbiochemicalandimmunologicalanalysis)andpermissionfor
manufacturingandmarke�ng.
ZonalofficesofCDSCOareresponsibleforauthorizingimportofdrugsforexamina�on,testand
analysisforresearchanddevelopment.
2( CDSCO func�ons as per the provisions of the Drugs and Cosme�cs Act 1940).
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5. Scope
TheseguidelinesapplytoSimilarBiologicsthatcontainwellcharacterizedproteinsastheir
ac�vesubstance,derivedthroughmodernbiotechnologicalmethodssuchasuseof
recombinantDNAtechnology.Thedemonstra�onofsimilaritydependsupondetailedand
comprehensiveproductcharacteriza�on,preclinicalandclinicalstudiescarriedoutin
comparisonwithaReferenceBiologic.
SimilarBiologicscanonlybedevelopedagainsttheReferenceBiologicthathasbeenapproved
usingacompletedatapackageinIndia.IncasetheReferenceBiologicisnotauthorizedinIndia,
itshouldhavebeenapproved/licensedandmarketedinanICH(TheInterna�onalCouncilfor
Harmonisa�onofTechnicalRequirementsforPharmaceu�calsforHumanUse)country.
AnyproductcanbeconsideredasaSimilarBiologic,only if it isproventobeSimilarusing
extensivequalitycharacteriza�onagainsttheReferenceBiologic.Furtherproductdevelopment
shouldonlybeconsideredoncethesimilarityoftheSimilarBiologicisdemonstratedinquality
toaReferenceBiologic.
TheseguidelinesareapplicableforSimilarBiologicstobedevelopedinIndiaorimportedinto
the country for marke�ng authoriza�on. Detailed regulatory pathways for indigenously
developedandimportedproducts³aregiveninAnnexureI.
3( Adopted from Report of the Task Force on Recombinant Pharma, 2005, chaired by Dr R.A. Mashelkar, DG, CSIR)
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6. Principles for Development of Similar Biologics
SimilarBiologicsaredevelopedthroughasequen�alprocesstodemonstratetheSimilarity
byextensivecharacteriza�onstudiesrevealingthemolecularandqualitya�ributeswith
regardtotheReferenceBiologic.
Althoughtheextentofpreclinicalandclinicalevalua�onoftheSimilarBiologicislikelytobeless
than that required for theReferenceBiologic, it is essen�al that the tes�ngof the Similar
Biologicbesufficienttoensurethattheproductmeetsacceptablelevelsofsafety,efficacyand
qualitytoensurepublichealthinaccordancewithinterna�onalguidelines(WHO2013).
Generally, abbreviated data requirements are only possible for preclinical and /or clinical
components of the development program but not for the quality components by
demonstra�onofcomparabilityofproduct(SimilarityestablishedtotheReferenceBiologic).
Iden�fica�onofanysignificantdifferencesinsafety,efficacyandqualitystudieswouldmeanthe
needforamoreextensivepreclinicalandclinicalevalua�onandtheproductwillnotqualifyasa
SimilarBiologic.
IncasetheReferenceBiologicisusedformorethanoneindica�on,theSimilarBiologicalso
qualifiesforalltheindica�onsonlyifitisjus�fiedandifmeetsthecondi�onssetforthinthe
sec�on “Extrapola�on of Efficacy and Safety Data to other Indica�ons”. Jus�fica�on for
extrapola�onofindica�onshallbebasedoncomparabilityinquality,preclinicalandclinical
studies,availableliteraturedataandwhetherornotthesamemechanismofac�onisinvolved
inspecificindica�ons.
6.1 Selec�on of Reference Biologic
ReferenceBiologicisaninnovator'sproductapproveda�erevalua�onofcompletedossieris
cri�calforthedevelopmentofSimilarBiologic.
TheReferenceBiologichastobeusedinallthecomparabilityexerciseswithrespecttoquality,
preclinicalandclinicalconsidera�ons.Thefollowingfactorsshouldbeconsideredforselec�on
oftheReferenceBiologic:
• TheReferenceBiologic shouldbe licensed/approved in Indiaor ICHcountriesand
shouldbetheinnovator'sproduct.TheReferenceBiologicshouldbelicensedbasedona
full safety, efficacy and quality data. Therefore another Similar Biologic cannot be
consideredasachoiceforReferenceBiologic.
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• IncasetheReferenceBiologicisnotmarketedinIndia,theReferenceBiologicshould
havebeenlicensedinanyICHcountries.TheReferenceBiologicproductcanbeimported
fordevelopingtheSimilarBiologicforquality,pre-clinicalandclinicalcomparability.
• ThesameReferenceBiologicshouldbeusedthroughoutthestudiessuppor�ngthe
safety,efficacyandqualityoftheproduct(i.e.inthedevelopmentProgrammeforthe
SimilarBiologic).
• Thedosageform,strengthandrouteofadministra�onoftheSimilarBiologicshouldbe
thesameasthatoftheReferenceBiologic.
• The ac�ve drug substance (ac�ve ingredient) of the reference biologic and that of
SimilarBiologicmustshowntobesimilar.
TheacceptanceofaninnovatorproductasaReferenceBiologicforevalua�onofSimilarBiologic
doesnotimplyapprovalforitsuseinIndia.
6.2 Manufacturing Process
The Similar Biologics manufacturer should develop the manufacturing process to yield a
comparablequalityproductintermsofiden�ty,purityandpotencytotheReferenceBiologic.
ThemanufacturingprocessforSimilarBiologicsshouldbevalidatedanddemonstratedtobe
highlyconsistentandrobust.Ifthehostcelllineusedfortheproduc�onofReferenceBiologicis
disclosed, it is desired to use the same host cell line for manufacturing Similar Biologics.
Alterna�velyanycelllinethatisadequatelycharacterizedandappropriateforintendedusecan
beusedtodevelopaSimilarBiologic,withappropriatejus�fica�oninordertominimizethe
poten�al for significant changes in quality a�ributes (QAs) of the product and to avoid
introduc�onofcertaintypesofprocessrelatedimpuri�esthatcouldimpactclinicaloutcomes
and immunogenicity. For the establishment and characteriza�on of the cell banks, the
guidelinesissuedbytheICHviz.Q5A⁴,Q5B⁵andQ5D⁶shouldbereferredforguidance.
4ICHQ5A(R1): Viral Safety Evalua�on of Biotechnology products derived from cell lines of Human or Animal Origin
5ICHQ5B: Quality of Biotechnological Products: Analysis of the expression construct in cells used for produc�on of R-DNA
derived protein products
6ICH Q5D: Deriva�on and characteriza�on of cell substrates used for produc�on of Biotechnological/Biological products)
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Thedata requirements for reviewofmanufacturingprocessatpreclinical submissionstage
include a complete descrip�on of the manufacturing process from development and
characteriza�onofcellbanks,stabilityofclone,cellculture/fermenta�on,harvest,excipients,
formula�on,purifica�on,primarypackaginginterac�ons(ifdifferentfromReferenceBiologic),
etc.andtheconsequencesonproductcharacteris�csasindicatedbelow:
6.2.1 Molecular Biology Considera�ons
Thedetailsregardinghostcellcultures(includingviralclearance),vectors,genesequences,
promotersetc.usedintheproduc�onofSimilarBiologicsshouldbeprovidedwith
appropriatedrawings/figures.Thedetailofpost-transla�onalmodifica�ons(glycosyla�on,
oxida�on,deamida�on,phosphoryla�onetc.),ifanyshouldbeexplained.
6.2.2 Upstream Process Development
· Upstreamprocessshouldbedescribedindetailincludingmediacomponentsusedfor
cellgrowth.
· At least three batches of reproducible fermenta�on data at pilot scale (batch size
adequatetogiveenoughpurifiedproducttogeneratepreclinicaldata).
· Upstreamprocessshouldbewellcontrolledandmonitored.
· Details of upstream process kine�cs data from consistency batches indica�ng cell
growth, product forma�on, pH, temperature, dissolved oxygen, major nutrient
consump�onpa�ernandagita�onrate.
· Concentra�ontobedefinedintermsofproduct/litre,yieldandvolumetricproduc�vity.
· Data to verify that the specificprotein yield (amountofproteinperunit cellmass)
remainsconstantforallupstreambatches.
· Demonstratethattheoverallproduc�vityisreproducibleandscalable.
6.2.3 Downstream Process Development
· Detaildescrip�onofthemethodsfollowedforthecellharves�ngandextrac�onofthe
protein.
· Stepsinvolvedinpurifica�onofprotein.
· Batchsizeforproteinpurifica�on.
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· Descrip�onofeachunitopera�onstepduringpurifica�onandrecoveryofproteinalong
withquan�ta�verecoveryofproductateachstage.
· Describethequalityoftherefoldedproteinifthestar�ngmaterialisaggregatedorfrom
inclusionbodiesandincludedetailsoftherefoldingprocess,specificac�vityatdifferent
doses,doseresponsecurve,stabilitydataandconfirma�onofsolubilityandabsenceof
aggrega�on.
· Consistency of recovery in three consecu�ve batches of purifica�on from three
independentbatchesofcellculture/fermenta�on.
· Describeposttransla�onalvaria�on,ifany.
· Detailsofremovalofimpuri�eslikeproductrelatedvariants&impuri�es,andhostcell&
processrelatedimpuri�esconsideredtoposeariskofImmunogenicity(EMEA1997).
· Virusclearancevalida�onstudies.
Forclinicaltrialapplica�on,addi�onalrequirementsareapplicableasperCDSCOguidelines.A
well-defined manufacturing process with its associated process controls assures that an
acceptableproductisproducedonconsistentbasisinaccordancewithGoodManufacturing
Prac�ce(GMP).Dataforsubmissionshouldinclude:
• Detaileddescrip�onofthedrugsubstanceanddrugproductprocesses
• Cri�calandkeyQualityA�ributesoftheproduct
• Manufacturingprocesscontrols
• Cri�calprocessparameters
• Stabilitydata
• ComparabilityofproductmanufacturedatclinicalscaleagainstReferenceBiologic
• Datafromconsistencybatchesand/orprocessvalida�onbatchesasapplicable.
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6.3 Quality Based Considera�ons for Similar Biologics
6.3.1 Analy�cal Methods
Theanaly�calmethodsshouldbechosenforestablishingproductcomparabilityasperthecri�cal
qualitya�ributesoftheproduct.Forcertaina�ributes(e.g.productaggrega�on)itiscustomaryto
usemul�ple,orthogonalmethods for characteriza�on.Extensive stateof theartanaly�cal
methodsshouldbeappliedtodetecteven“slightdifferences”inallrelevantqualitya�ributes.
IndianPharmacopoeiamonographshouldbefollowed,ifavailable.
Themeasurementofqualitya�ributesincharacteriza�onshouldentailtheuseofappropriately
qualifiedassays,whicharereproducibleandreliable.Themethodsusedtomeasurequality
a�ributesforbatchrelease,stabilitystudiesandin-processcontrolsshouldbevalidatedin
accordancewithICHguidelines(ICHQ2⁷,Q5C⁸,Q6B⁹),asappropriate.
Thecharacteriza�onstudiesshouldincludesamplesoftheapplicant'sr-DNAderivedproduct,
ReferenceBiologicascontrol,knownposi�vestandardandnega�vecontrol,whereverrelevant.
Toensurethesta�s�calanalysis,eachquan�ta�veexperimentshouldbedoneatleastthree
�mesanddatashouldberepresentedintermsofmeanandstandarddevia�on.Appropriate
sta�s�cal significance should be represented throughout the characteriza�on data.
PhysicochemicalandBiologicalcharacteriza�onmethodstobeusedforr-DNAderivedproducts
aregiveninAnnexureII.ItmaybenotedthatthisAnnexureIIissugges�vebutnotlimitedtothe
specifiedmethodandtherequirementsmayvaryoncasebycase.
6.3.2 Product Characteriza�on
Characteriza�on studies for SimilarBiologics includephysicochemical proper�es, Biological
ac�vity, immunological proper�es, func�onal assays, purity (process and product-related
impuri�es etc.), contamina�on, strength and content. Principles outlined in the ICH Q6B
guideline should be followed. Indian Pharmacopoeia Monograph should be followed, if
available.
7( ICH Q2(R1): Valida�on of Analy�cal Procedures: Text and Methodology8ICH Q5C: Stability tes�ng of Biotechnological/Biological Products
9ICHQ6B: Specifica�ons: test Procedures and Acceptance criteria for Biotechnological/Biological Products)
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i. Structural and Physicochemical Proper�es: Theanalysisofphysicochemicalcharacteris�c
shouldincludedetermina�onofprimaryandhigherorderstructureofthedrugsubstanceand
theproductalongwithothersignificantphysicochemicalproper�es.Thetargetaminoacid
sequenceoftheSimilarBiologicshouldbeconfirmedandisexpectedtobethesameasforthe
Reference Biologic. Analy�cal methods that are used (including Biological and func�onal
assays) should have acceptable precision and accuracy. In cases, where post transla�onal
modifica�onsaretakingplace,thesemodifica�onsneedtobeiden�fiedandquan�fied.Incase
any significant differences are found, these should be scien�fically jus�fied and cri�cally
examinedinpreclinicalstudiesandclinicaltrials.
ii. Biological Ac�vity: Biologicalproductsmayhavemul�plebiologicalac�vi�es.Insuchcases,
appropriatebiological assayswill be required to characterize theac�vity andestablish the
product'smechanismofac�onandclinicaleffects(inunitsofac�vity).Thedatafrombiological
assayswillsupplementthephysicochemicalcharacteriza�onoftheproductasdescribedinthe
sec�on 6.3.1. Biological assays should be validated against an interna�onal or na�onal
Referencestandard,whereavailableandappropriate.Ifnosuchstandardsareavailable,an
internalReferencestandardmustbeestablishedaspertheICHguidelines.Ifthemethodsof
bioassay(s)aredocumentedinthespecifica�on,test(s)canbeconductedaccordingly.
iii. Immunological Proper�es: ThemanufacturingprocessofSimilarBiologicsisknowntoaffect
the levelofprocess related impuri�esandpost transla�onalmodifica�onsof theproduct.
These characteris�csmay affect the immunogenicity of the product. Hence evalua�on by
characteriza�on (an�body or an�body-derived product); comparison to Reference Biologic
withrespecttospecificity,affinity,bindingstrengthandFcfunc�on;andevalua�onbyanimal
studiesshouldbeperformed.
iv. Purity and Impuri�es: Characteriza�on of a Similar Biologic requires evalua�on of the
followingviaacombina�onofanaly�calprocedures:
DifferencesobservedinthepurityandimpurityprofilesoftheSimilarBiologicrela�vetothe
ReferenceBiologicshouldbeevaluatedtoassesstheirpoten�alimpactonsafetyandefficacy.
WheretheSimilarBiologicexhibitsdifferentimpuri�es,thoseimpuri�esshouldbeiden�fied
andcharacterizedwhenpossible.Dependingontypeandamountoftheimpurity,conductof
preclinicalandclinicalstudieswillhelptoconfirmthatthereisnoadverseimpactonsafetyand
efficacyoftheSimilarBiologic.
• Productrelatedvariants(e.g.,glycoforms,isomersetc.)
• Productrelatedimpuri�es(e.g.,aggregated,oxidizedordeamidatedproduct)
• Hostcellrelatedimpuri�es(e.g.,hostcellprotein,hostcellDNAetc.)
• Processrelatedimpuri�es(residualmediacomponents,resinleachatesetc.)
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6.3.3 Specifica�ons
Specifica�onsofSimilarBiologics(fordrugsubstanceanddrugproduct)areestablishedaround
quality a�ributes (QAs) with the intent of ensuring consistency in product quality and
comparabilitytoReferenceBiologicaccordingtorelevantguideline(ICHQ6B).Methodsused
forse�ngspecifica�onsmayormaynotbethesameastheanaly�calmethodsusedforproduct
characteriza�onandforestablishingproductcomparability.Acceptancelimitsshouldbeset
basedonReferenceBiologicdataanddatafromsufficientnumberofbatchesfrompreclinicalor
clinicalbatches,whichmustbeinlinewithinterna�onalnorms.
6.3.4 Stability
Theshelf-lifeandstoragecondi�onofdrugsubstanceanddrugproductshouldbeassigned
basedonreal-�mestabilitystudies.Stabilitystudiesondrugsubstanceanddrugproductshould
becarriedoutusingcontainersandcondi�onsthatarerepresenta�veoftheactualstorage
containersandcondi�ons,accordingtorelevantguidelines(e.g.ICHQ1A(R2),ICHQ5C,WHO
TRS822).Side-bysideacceleratedandstressedstabilitystudiescomparingtheSimilarBiologic
to theReferenceBiologicwill beof value in determining the Similarityof theproducts by
showingcomparabledegrada�onprofiles.
6.4 Quality Comparability Study
The quality comparison between Similar Biologic and Reference Biologic is essen�al. The
applicantshouldsubmitafullqualitydossierasperCDSCOguidanceforindustry,2008including
theresultsofcomparabilityexercisefortheSimilarBiologicwiththeReferenceBiologicbefore
the applicant proposes to take the Similar Biologic to clinical development. First three
consecu�vestandardizedbatcheswhichhavebeenusedtodemonstrateconsistencyofthe
manufacturingprocessshouldbeused.
Head-to-headcharacteriza�onstudiesarerequiredtocomparetheSimilarBiologicandthe
ReferenceBiologic at ac�vedrugproduct level. It is required to assure that themolecular
structureofac�vedrugsubstancepresentintheSimilarBiologiciscomparabletoac�vedrug
substancepresent inReferenceBiologic.However, incaseswhere the requiredanalysesof
qualitya�ributesoftheac�vesubstanceoftheReferenceBiologiccanbemadeatthefinished
productstage,tes�ngoftheisolatedac�veingredientmaynotbeneeded.Differencesbetween
theSimilarBiologicandtheReferenceBiologicshouldbeevaluatedfortheirpoten�alimpacton
safety and efficacy of the Similar Biologic and addi�onal characteriza�on studies may be
necessary.
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MinordifferencesbetweenSimilarBiologicandreferenceBiologicineachqualitycomponent
maybethere.However,appropriatedatashouldbesubmi�edtoverifythatthesedifferences
donotimpactonthesafetyandefficacy.
Thequality comparisonbetween theSimilarBiologicand the referenceBiologic shouldbe
governedbyQualityA�ributes(QAs),whichemploystate-of-the-arthighresolu�onanaly�cal
techniquesandmethodsthataresensi�veenoughtodetectthepossibili�esofchangestothe
product.Fromtheperspec�veofestablishingSimilarity,QualityA�ributesofaSimilarBiologic
may be considered in two categories; Cri�cal Quality A�ributes (CQA) and Key Quality
A�ributes(KQA):
1)Cri�calQualityA�ributes(CQA)arethoseQualityA�ributeswhichhavedirectimpactonthe
clinicalsafetyorefficacy.Alla�ributesthatdirectlyimpacttheknownmechanism(s)ofac�onof
themolecule fall in this category. CQAsmust be controlled within limits that need to be
establishedbasedontheReferenceBiologic.
2) KeyQualityA�ributes(KQA)arethoseQualityA�ributeswhicharenotknowntoimpact
clinicalsafetyandefficacybutareconsideredrelevantfromaproductandprocessconsistency
perspec�ve.A�ributesthatdonotimpacttheknownmechanism(s)ofac�onofthemolecule
fallinthiscategory.KQAsmustnecessarilybecontrolledwithinacceptablelimits;howeverit
mayacceptabletohaveslightdifferencesincomparisontotheReferenceBiologic.
Thelistofrou�neanaly�calteststobeincludedforacomprehensivequalitycomparability
exerciseofCri�calandKeyQualityA�ributesisgiveninAnnexure-II.
Thisisintendedasguidance,andproposesaframeworktoestablishanaly�calsimilaritythat
incorporatesmolecularstructure,func�onandheterogeneity.Itmaybenotedthatisonly
indica�veandaspecificdetermina�onwillneedtobemadeforeachbiologicmolecule.
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7. Data Requirements for Preclinical Studies
7.1 Prerequisite before Conduc�ng Preclinical Studies
TheapplicanthastocomplywiththeRCGMrequirementslikedemonstra�onofconsistencyof
theprocessandproduct,productcharacteriza�onandproductspecifica�ons.Theapplicant
should submit the data generated along with the following basic clinical informa�on and
preclinicalstudyprotocolstoRCGMforobtainingpermission.Thetoxicologystudiesshouldbe
ini�ateda�ertheapprovalofRCGM.Thebasicinforma�onabouttheReferenceBiologicand
SimilarBiologicmayincludethefollowing:
Basic informa�on about the Reference Biologic
• Informa�onaboutthedrug,routeofadministra�on,absorp�onandelimina�onrate,
therapeu�cindex,dose,vehicle,modeofadministra�on,doseresponseetc.
• Bioequivalencerange,ifavailable.
• Tissue-specificlocaliza�on,ifavailable.
• AvailabletoxicitydataonReferenceBiologic.
• Modeofac�on.
Basic informa�on about the Similar Biologics
• Known/proposedclinicaluse
• Targetpopula�on(Age,sex,pregnancy,lacta�ng,childrenetc.)
• Dosage(frequencyandintervals)–units
• Route/alternateroutesofadministra�on
• Finalformula�on+adjuvants,addi�vesetc.-Toxicologydataofadjuvants
• Diluents
• Presenta�one.g.prefilledsyringe,cartridge,vial
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The applica�on to RCGM should be accompanied by approval of Ins�tu�onal BioSafety
Commi�ee(IBSC)ofthedeveloper(copyoftheminutesshouldbesubmi�ed),andapprovalof
Ins�tu�onalAnimalEthicsCommi�ee(IAEC), ifavailable.Theapplicantshouldalsoprovide
detailsoftheproposedsiteforconductoftoxicitytes�ngandpersonneltobeinvolvede.g.
study director, principal inves�gator, pathologist, other Inves�gators and quality assurance
officeratthesite.StatusofGLPcer�fica�onofproposedfacilityshouldalsobeprovided.
7.2 Preclinical Studies (Pharmacodynamic and Toxicology Studies)
Thepreclinicalstudiesshouldbeconductedpriortotheini�a�onofanyclinicalstudies.These
preclinicalstudiesshouldbecompara�veinnatureanddesignedtodetectdifferencesifany,
betweentheSimilarBiologicandReferenceBiologic.Thepreclinicalstudydesignmayvary
dependingupontheclinicalparameterssuchastherapeu�cindex,thetypeandnumberof
indica�onsapplied.
Theapproachadoptedshouldbefullyjus�fiedinthepreclinicaloverview.Preclinicalstudies
shouldbeconductedwiththefinalformula�onoftheSimilarBiologicintendedforclinicaluse
andfortheReferenceBiologicunlessotherwisejus�fied.Thedosageform,dose,strengthand
routeofadministra�onoftheSimilarBiologicshouldbethesameasthatoftheReference
Biologicandincaseofanydifferencesintheseparameters,itshouldbejus�fied.Thefollowing
studiesarerequiredforpreclinicalevalua�on:
7.2.1 Pharmacodynamic Studies
i. In vitro studies: Comparability of Similar Biologic and Reference Biologic should be
established by in vitro cell based bioassay (e.g. cell prolifera�on assays /cytotoxicity /
neutralizing/receptorbindingassays).
ii. In vivo studies: In vivo evalua�on of Biological/ pharmacodynamic ac�vity may be
dispensable if in vitroassaysareavailable,whichareknowntoreliablyreflecttheclinically
relevantpharmacodynamicac�vityoftheReferenceBiologic.Incaseswherethein-vitroassays
donotreflectthepharmacodynamics,In vivostudiesshouldbeperformedasapplicable.
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Guidelines on Similar Biologics: Regulatory Requirements for Marke�ng Authoriza�on in India
7.2.2 Toxicological Studies
Incaseofin vivo toxicitystudies,atleastonerepeatdosetoxicitystudyinapharmacologically
relevantspeciesisrequiredtobeconductedwithanintendedrouteofadministra�on.
Regardingtheanimalmodelstobeused,theapplicantshouldprovidethescien�ficjus�fica�on
forthechoiceofanimalmodel(s)basedonthedataavailableinscien�ficliterature.However,if
the pharmacologically relevant animal species is not available and has been appropriately
jus�fied,toxicitystudiesneedtobeundertakeneitherinrodentornon-rodentspeciesasper
requirementsofScheduleYwithduepermissionfromRCGM.
Regarding route of administra�on either in pharmacologically relevant animal model or
pharmacologically non-relevantmodel the route of administra�onwould include only the
intendedrouteasperscheduleY.
Thedura�onofthestudywouldbegenerallynotlessthan28dayswith14daysrecoveryperiod.
Howeverthedura�onmayvarydependingonthedosageandotherparametersoncasebycase
basis.
Thedose shouldbecalculatedbasedon the therapeu�cdoseof theReferenceBiologic. If
requiredapilotdoseresponsestudyshouldbeconductedpriortoini�a�ngthetoxicitystudies.
Generallytherewouldbethreelevelsofdoses(viz.low,mediumandhigh)usedintheanimal
toxicologystudiescorrespondingto1X,2Xand5Xofhumanequivalentdoseorhighertestdose
forrepeated-dosetoxicitystudies.InthetoxicitystudytheSimilarBiologicshouldbecompared
withReferenceBiologicatleastat1Xofhumanequivalentdose(HED).Anydifferenceinthe
levelsofdosesshouldbejus�fiedandapprovedpriortothestudies.Regardingthescheduleof
administra�on,thetherapeu�cschedulesmaybeusedasthebasis.
Dependingontherouteofadministra�on,localtoleranceshouldbeevaluated.Thisevalua�on,
iffeasiblemaybeperformedasapartofabovemen�onedrepeated-dosetoxicitystudy.
Accordingly,thestudygroupsofanimalsinrepeated-dosetoxicitytes�ngwillconsistof:
i. HistoricalControl(Op�onal)
ii. VehicleControl
iii. VehicleControlforrecoverygroup
22
iv. Formula�onwithoutprotein(forvaccines)ifmul�pleadjuvants-eachtobechecked
independently
v. 1XSimilarBiologicforstudydura�on(lowestdose)
vi. 1XReferenceBiologicforstudydura�on
vii. 2XMediumdoseSimilarBiologic
viii. 5XHighdoseSimilarBiologic
ix. SimilarBiologicwitharecoverygroupgoingbeyondtheendofstudyperiodfor7to14
days
Theprotocolsandthestudyreportsshouldprovidecompletedetailsofvariousstepsinthe
toxicitytes�ngasindicatedbelow:
• Procedurespriortoeuthanasiae.g.blooddrawing,bodyweight,etc.
• Eventsimmediatelya�ereuthanasia,necropsy,gross–descrip�on,organweightsand
organssampledforhistopathology.
• Biochemicalparameters–Equipmentandmethodsused-unitsofmeasurementand
expression.
• Haematologyproceduresandparameters–methodtobeused(automatedormanual).
• Sta�s�calmethodsused.
• Bonemarroweitherexaminedasanaspirate/smearoronhistopathologysec�on.
Incaseofhistopathologicalobserva�ons,theapplicantsshouldconsiderthefollowingpoints:
• Everyobserva�onconsideredasdevia�onfromdescribednormalhistologyneedstobe
documented and the incidence of each of these in the different groups should be
denoted.
• Whether sucha feature is significantornot canbedecidedon reviewof sta�s�cal
significanceordoseresponseorifitiswithinoroutsidethenormalrangeofvaluesin
caseofbiochemicalandhaematologicalobserva�ons.
• Ifallorgansfromallanimalswerenotexaminede.g. in5animalsonly4liverswere
examined,thereasonforthe1livernotbeingexaminedshouldbedocumented.
• Incaseofprematuredeathormorbiditytheproposedcourseofac�onistobeincluded
intheprotocol.2016
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Othertoxicitystudies,includingsafetypharmacology,reproduc�vetoxicity,mutagenicityand
carcinogenicitystudiesarenotgenerallyrequiredforevalua�onofaSimilarBiologicunless
warrantedbytheresultsfromtherepeated-dosetoxicologicalstudies.
Thefinalreportofthestudyshouldreflectalltheaspectsapprovedintheprotocolandthe
followingaddi�onalsec�ons/documents:
• RCGMapprovalofprotocolandtestcentre
• IBSCapprovalofreport
• IAECapprovalforanimaluseandfortheprocedures
• QAstatement
• Signaturesofstudydirectorandallinves�gatorswhowereinvolvedinthestudy
• Allqualityanaly�calreportsonthetestmaterialandvehicle
• Animalfeedandanimalhealthcer�fica�ons.
Protocoldevia�onsifany
• Discussionontheresults.
• Individualanimaldata,summarydataandanyotherdatalikecomputeranalysisoutputs
etc.
• Conclusion.
7.3 Immune Responses in Animals
An�body response to the Similar Biologic should be compared to that generated by the
referenceBiologic in suitable animalmodel. The test serum samples should be tested for
reac�ontohostcellproteins.
For evalua�ng immune toxicity of the Similar Biologic under study, the results of local
tolerance(partofrepeatdoseorstandalonetest)shouldbeanalyzedwiththeobserva�ons
regarding immunogenicity in sub-chronic study. Therefore, the immunogenicity tes�ng
shouldbe includedaspartof the sub-chronic repeated-dose studywhiledeveloping the
protocols.
Theotherparametersforevalua�ngimmunetoxicityincludeimmunecomplexesintargeted
�ssuesmaybeconsideredwhileevalua�nghistopathologyobserva�ons,etc.A�ercomple�on
ofpreclinicalstudiesthereportsaresubmi�edtoRCGMforreviewandconsidera�on.
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Othertoxicitystudies,includingsafetypharmacology,reproduc�vetoxicity,mutagenicityand
carcinogenicitystudiesarenotgenerallyrequiredforevalua�onofaSimilarBiologicunless
warrantedbytheresultsfromtherepeated-dosetoxicologicalstudies.
Based on the successful evalua�on of preclinical study reports including demonstra�on of
consistencyoftheprocessandproduct,productcharacteriza�on,productspecifica�onsand
comparisonofsimilarbiologicstoreferenceBiologic,RCGMwillrecommendtheDCG(I)toallow
thesponsortoconductappropriatephaseofclinicaltrialaspertheCDSCOrequirements.The
applicantmaysubmitparallelapplica�ontoRCGMandofficeofDCG(I)seekingapprovalto
conductclinicaltrial.However,officeofDCG(I)shallcompletethescru�nyofapplica�onand
issuepermission,onlya�erRCGMclearancewasreceived.
8. Data Requirements for Clinical Trial Applica�on
Besidestheinforma�onsubmi�edinthepreclinicalapplica�on,theapplicanthastosubmit
applica�onforconductofclinicaltrialaspertheCDSCOguidanceforindustry,2008.Thequality
data submi�ed should indicate that there are no differences in Cri�cal Quality A�ributes
(CQAs),and thatallKeyQualityA�ributes (KQAs)arewell controlled inorder toallowthe
ini�a�onofclinicalevalua�on.
8.1 Pharmacokine�c (PK) Studies
The PK data should support the subsequent Phase III clinical development given that the
purportedSimilarBiologicwouldbeestablishedtobesimilarastheReferenceBiologicproduct.
A�ercomple�onofextensivecharacteriza�oncomparabilityonqualitya�ributes,aPKstudyof
theSimilarBiologicincomparisonwiththeReferenceBiologicproductmaybeperformedinan
appropriatenumberof:
a. NormalHealthyVolunteers(NHV)and/or
b. Pa�ents
Thedesignofcompara�vepharmacokine�cstudiesshouldtakethefollowingfactors
intoconsidera�on.
· Halflife
· LinearityofPKparameters
· Endogenouslevelsanddiurnalvaria�onsofSimilarBiologicunderstudy(where
applicable)
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· Condi�onsanddiseasestobetreated
· Route(s)ofadministra�on,and
· Indica�ons
Appropriatedesignconsidera�onsinclude:
· Singledose,compara�ve,PKstudies
· Parallelarmor
· Crossover
· Mul�pledose,compara�veparallelarmsteadystatePKstudies
Insequen�aldevelopmentapproach,theNormalHealthyVolunteers(NHV)studyisperformed
beforethePhaseIIIsafetyandefficacystudy.
8.1.1 Single Dose Compara�ve PK Studies
Dosage in thePKstudy shouldbewithin the therapeu�cdose rangeof referenceBiologic.
Appropriatera�onalefordoseselec�onshouldbeprovided.Therouteofadministra�onshould
betheonewherethesensi�vitytodetectdifferencesisthelargest.Samplesizeshouldhave
sta�s�calra�onale(i.e.sta�s�callyjus�fied)andcomparabilitylimitsshouldbedefinedand
jus�fiedpriortoconduc�ngthestudy.
Theanaly�calmethodshouldbevalidatedtohavesa�sfactoryspecificity,sensi�vityandarange
ofqualifica�onwithadequateaccuracyandprecision.Itshouldhavecapabilitytodetectand
follow the �me course of the Similar Biologic (the parentmolecule and / or degrada�on
products)inacomplexBiologicalmatrixthatcontainsmanyotherproteins.
Differences in elimina�on kine�cs between Similar Biologic and reference Biologic e.g.
clearance and elimina�on half-life should be explored. Similarity in terms of absorp�on /
bioavailabilityshouldnotbetheonlyparametersofinterest.
AparallelarmdesignstudyismoreappropriateforSimilarBiologicswithalonghalf-lifeorfor
proteinsforwhichforma�onofan�bodiesislikelyorifstudyisbeingdoneinpa�ents.Incaseof
shorthalf-life,crossoverdesignmaybeconsideredwithascien�ficjus�fica�on.
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8.1.2 Mul�ple Dose Compara�ve PK Studies
Mul�ple-dose, compara�ve,parallel arm steady statePK studies are required for a Similar
Biologicthatisusedinamul�pledoseregimen,wheremarkedlyhigherorlowerconcentra�ons
areexpectedatsteadystatethanthatexpectedfromsingledosedataPKmeasurements,and
where�me-dependenceanddose-dependenceofPKparameterscannotberuledout.Incase
mul�-dosecompara�vePKstudiesarenotdoneadequatejus�fica�onshouldbeprovided.
8.2 Pharmacodynamic Studies
As required for the PK studies in the Similar Biologic clinical development program, the
pharmacodynamic(PD)studiesshouldalsobecompara�veinnature.Compara�ve,parallelarm
orcross-over,PDstudyinmostrelevantpopula�on(pa�entsorhealthyvolunteers)isrequired
fordetec�ngdifferencesbetweenSimilarBiologicandReferenceBiologic. IfaPDmarker is
available in healthy volunteers, PD in healthy volunteers can be done, unless considered
unethicalduetoexpectedadverseeventsandtoxicitye.g.oncologydrugs.
Compara�vePDstudiesarerecommendedwhenthePDproper�esoftheReferenceBiologic
arewell characterizedwith at least onePDmarker validated for a clinical outcomeof the
molecule.Therela�onshipbetweendose/exposure,therelevantPDmarker(s)andresponse/
efficacyoftheReferenceBiologicshouldbewellestablishedandusedtojus�fythedesign.The
acceptancerangesforthedemonstra�onofSimilarityinPDparametersshouldbepredefined
and appropriately jus�fied. The parameters inves�gated in PD studies should be clinically
relevantandsurrogatemarkersshouldbeclinicallyvalidated.PDstudiesmaybecombinedwith
PKstudies,inwhichcasethePK/PDrela�onshipshouldbecharacterized.IfPDmarkerisnot
availableandthePKcanbedoneinpa�entsthenthePKstudycanbecombinedwithphaseIII
clinicalstudy.ThePDstudycanalsobeapartofPhaseIIIclinicaltrialswhereverapplicable.
8.3 Confirmatory Safety and Efficacy Study
Theestablishmentofin-vitro,pre-clinicalandPK/PDSimilarityasdescribedinearliersec�onis
important as robust, high quality processes, a comprehensive quality comparison and
compara�vepreclinicalandPK/PDstudieshelpindemonstra�ngtheSimilarityoftheSimilar
Biologicsinthesese�ngs.
Inordertoeliminateanyresidualrisk,acompara�vephaseIIIclinicaltrialmayalsoberequired
toestablishthecomparabilitywithrespecttoclinicalsafetyandefficacy.Onlyinexcep�onal
cases i.e. if there are no residual uncertain�es le� a�er comparing Similar Biologic and
ReferenceBiologicattheanaly�cal,non-clinicalandPK/PDlevel,anaddi�onalcompara�ve
safetyandefficacytrialisnotneeded.
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Informa�on to establish compara�ve safety and efficacy in relevant pa�ent popula�on is
mandatoryforallSimilarBiologics.Compara�veclinicaltrialsarecri�caltodemonstratethe
similarityinsafetyandefficacyprofilesbetweentheSimilarBiologicandReferenceBiologicwith
fewexcep�ons(e.g.recombinanthumansolubleinsulinproductsforwhichonlycompara�ve
clinicalsafetystudyisrequired).Thestudyshouldbeconductedinasensi�veandhomogenous
pa�entpopula�onwithappropriatesensi�veprimaryendpointsasperrequirementofaPhase
IIIclinicaltrial.Thedesignofthestudiesandtheclinicalcomparabilityoftheprimaryefficacy
endpointsareimportantandshouldbegivencarefulconsidera�onandshouldbescien�fically
jus�fiedonclinicalgrounds.Equivalence,non-inferiorityorcomparabilityPhaseIIIclinicaltrials
may be conducted based on comparability established during physicochemical
characteriza�on,preclinicalandPK/PDstudies,a�erapprovalofdesignandprotocolbyCDSCO.
However,thecomparabilityPhaseIIIclinicaltrialsintendedforseekingmarke�ngapprovalof
SimilarBiologicsfallingunderthecategoryofnewdrugsasperDrugsandCosme�csRules,1945
shall be conducted in accordancewith the Indian Good Clinical Prac�ce (GCP) guidelines,
generallyinnotlessthanhundredevaluablepa�entsintestarmtoevaluatethesafety,efficacy
andcomparability.BasedontheresultsofsuchClinicaltrials,themarke�ngapprovalmaybe
consideredifsafety,efficacyandcomparabilityareestablished.Further,PhaseIVclinicaltrials
mayberequiredtobeconducted,generallyinmorethantwohundredpa�entsincon�nua�on
ofcomparabilityclinicaltrials.
Thenature,severityandfrequencyofadverseeventsshouldbecomparedbetweentheSimilar
BiologicandReferenceBiologicandshouldalsobebasedonsafetydataandeffortsmadeto
ensure that compara�ve clinical studies have a sufficient number of pa�ents treated for
acceptableperiodof�meinordertoallowdetec�onofsignificantdifferencesinsafetybetween
SimilarBiologicandReferenceBiologicaspertheprotocol.
Oneormoreadequatelypowered,randomized,parallelgroup,blindedconfirmatoryclinical
safetyandefficacytrialsaredesirablebasedonthecomparabilityestablishedduringpreclinical
andPK/PDstudies.MorethanonesafetyandefficacystudymayberequiredandtheSimilar
Biologicwillbetreatedasa“stand-aloneproduct”iftheSimilarBiologicisnotcomparableto
ReferenceBiologic inpreclinicalevalua�onsconductedand/orthePK/PDstudieshavenot
demonstratedcomparability.
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8.3.1 Waiver of safety and efficacy study
Theconfirmatoryclinicalsafetyandefficacystudycanbewaivedifallthebelowmen�oned
condi�onsaremet:
i. Structural and func�onal comparability of Similar Biologic and Reference
Biologiccanbecharacterizedtoahighdegreeofconfidencebyphysicochemical
andin vitrotechniques.
ii. The Similar Biologic is comparable to Reference Biologic in all preclinical
evalua�onsconducted.
iii. PK / PD study has demonstrated comparability of PDmarkers validated for
clinicaloutcomeandhaspreferen�allybeendoneinanin-pa�ent se�ngwith
safety measurement (including meaningful immunogenicity assessment) for
adequateperiodjus�fiedbytheapplicantandefficacy/PDmeasurements.
iv. A comprehensivepost-marke�ng riskmanagementplanhasbeenpresented
thatwill gatheraddi�onal safetydatawitha specificemphasisongathering
immunogenicitydata.
The confirmatory clinical safety and efficacy study cannot be waived especially for large
molecularweightbiologicslikeMonoclonalan�bodies.Incase,thesafetyandefficacystudyis
waivedalltheindica�onsapprovedforreferenceproductmaybegrantedbasedoncomparable
quality,non-clinicalaswellasconvincingPK/PDdata.
WhereverthephaseIIItrialiswaived,theimmunogenicityshouldhavebeengatheredinthe
PK/PDstudyandwillalsoneedtobegeneratedduringpost-approvalPhaseIVstudy.
TheconfirmatoryclinicalsafetyandefficacystudycannotbewaivedifthereisnoreliablePD
markervalidatedforclinicaloutcome.
8.3.2 Non-compara�ve safety and efficacy study
ForaproductwhichisfoundSimilarinpre-clinical,in-vitrocharacteriza�onhavingestablished
PKmethods and a PDmarker that is surrogate of efficacy, the residual risk is significantly
reducedinthePhaseIstudyifequivalenceisdemonstratedforbothPKandPD.PhaseIIIclinical
trialsofsuchaSimilarBiologicsproductmaybewaivedasnotedaboveor,whereconsidered
necessary,anappropriatesinglearmstudyinatleast100evaluablesubjectsmaybecarriedout
inthemostsensi�veindica�ontoaddressanyresidualuncertainty.
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8.4 Safety and Immunogenicity Data
Bothpre-approvalandpost-approvalassessmentofsafety isdesiredtobeconductedfora
SimilarBiologic.Regardingpre-approvalsafetyassessment,compara�vepre-approvalsafety
dataincludingtheimmunogenicitydataisrequiredforallSimilarBiologicsincludingthosefor
whichconfirmatoryclinicaltrialshavebeenwaived.Thispre-approvalsafetydataisprimarily
intendedtoprovideassuranceoftheabsenceofanyunexpectedsafetyconcerns.Compara�ve
safetydatabasedonadequatepa�entexposure(bothnumbersand�me)must,inconjunc�on
with the published data on the Reference Biologic provide assurance of absence of any
unexpected safety concerns and in conjunc�on with the proposed non-compara�ve
post-marke�ngstudyprovideacomprehensiveapproach to theevalua�onofsafetyof the
SimilarBiologic.Postapprovalsafetydatarequirementsareelaboratedinsec�on10.3.
FromasafetyandImmunogenicityperspec�ve,ifthefirmconductspre-approvalstudiesthat
includedmorethan100pa�entsontheproposedSimilarBiologicdrug,thenumberofpa�ents
inphaseIVstudycanbemodifiedaccordinglysothatthesafetydata(frombothPhaseIIIandIV)
isderivedfromaminimumof300pa�entstreatedwiththeSimilarBiologics.
8.5 Extrapola�on of Efficacy and Safety Data to Other Indica�ons
Extrapola�onofthesafetyandefficacydataofapar�cularclinicalindica�on(forwhichclinical
studieshasbeendone)ofaSimilarBiologic tootherclinical indica�onsmaybepossible if
followingcondi�onsaremet:
• SimilaritywithrespecttoqualityhasbeenproventoReferenceBiologic.
• SimilaritywithrespecttopreclinicalassessmenthasbeenproventoReferenceBiologic.
• Clinicalsafetyandefficacyisproveninoneindica�on.
• Mechanismofac�onissameforotherclinicalindica�ons.
• Involvedreceptor(s)aresameforotherclinicalindica�ons.
• However,newindica�onsnotmen�onedbyinnovatorwillneedstobecoveredbya
separateapplica�on.
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9. Data Requirements for Market Authoriza�on Applica�on
The applicant should submit applica�on for market authoriza�on as per CDSCO guidance
documentforindustry,2008.Forcaseswherecommercialmanufacturingisperformedeitherat
adifferentscaleand/orwithadifferentprocessascomparedtothatusedformanufacturing
phase III clinical trial batches, then informa�on on comparability of quality needs to be
addi�onallysubmi�edwithappropriatejus�fica�onandwillbedealtwithonacasetocase
basis.
10. Post-Market Data for Similar Biologics
ItisimportanttoestablishaformalRiskManagementPlantomonitoranddetectbothknown
inherentsafetyconcernsandpoten�alunknownsafetysignalsthatmayarisefromtheSimilar
Biologicsinceauthoriza�onisbasedonareducedpreclinicalandclinicaldatapackage.Therisk
managementplanshouldconsistofthefollowing:
10.1 Pharmacovigilance Plan
TheclinicalstudiesdoneonSimilarBiologicspriortomarketauthoriza�onarelimitedinnature
so the rare adverse events are unlikely to be encountered. Hence comprehensive
pharmacovigilanceplanshouldbepreparedbymanufacturertofurtherevaluatetheclinical
safetyinalltheapprovedindica�onsinthepostmarke�ngphase.Thepharmacovigilanceplan
shouldincludethesubmissionofperiodicsafetyupdatereports(PSURs).ThePSURsshallbe
submi�edevery sixmonths for thefirst two years a�er approval of the SimilarBiologic is
grantedtotheapplicant.ForsubsequenttwoyearsthePSURsneedtobesubmi�edannuallyto
DCGIofficeaspertheScheduleY.
10.2 Adverse Drug Reac�on (ADR) Repor�ng
All cases involvingseriousunexpectedadverse reac�onsmustbe reported to the licensing
authorityasperScheduleY.
10.3 Post Marke�ng Studies (Phase IV Study)
Finally,inordertofurtherreducetheresidualriskoftheSimilarBiologics,addi�onalsafetydata
mayneed tobecollecteda�ermarketapproval throughapre-definedsinglearmstudyof
generally,morethan200evaluablepa�entsandcomparedtohistoricaldataoftheReference
Biologic.Thestudyshouldbecompletedpreferablywithin2yearsofthemarke�ngpermission/
manufacturinglicenseunlessotherwisejus�fied.
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Theprimaryaimofthepostmarke�ngphaseIVstudyissafetyandhencefollowingparameters
shouldbeconsideredforthepostmarke�ngphaseIVstudyprotocol:
• Primaryendpoint:Safety
• Secondaryendpoint:EfficacyandImmunogenicity
ThephaseIVprotocolshouldbesubmi�edalongwithmarke�ngauthoriza�onapplica�onfor
approval.
TheclinicalstudiesdoneonSimilarBiologicspriortomarketauthoriza�onarelimitedinnature
sopostmarke�ngstudiesshouldbeconductedandthereportsbesubmi�edtoDCGI.Theplan
ofpostmarketstudiesshouldbecapturedinPharmacovigilanceplanandupdateonthestudies
shouldbesubmi�edtotheCDSCO.
Regarding post-marke�ng safety and immunogenicity study at least one non- compara�ve
post-marke�ngclinicalstudywithfocusonsafetyandimmunogenicity(oncasebycasebasis)
shouldbeperformed.ThisstudymustbedesignedtoconfirmthattheSimilarBiologicdoesnot
haveanyconcernswithregardtothetherapeu�cconsequencesofunwantedimmunogenicity.
Itisnotmandatorytocarryoutaddi�onalnon-compara�veimmunogenicitystudiesinpost
marke�ngstudies,ifimmunogenicityisevaluatedinclinicalstudies.Theimmunogenicityofthe
SimilarBiologicsshouldbeevaluatedusingappropriatelydesignedstudieswithstate-of-the-art
methods,takingintoconsidera�onthepoten�alimpactonbothsafetyandefficacy.
Ra�onaleonthestrategyfortes�ngimmunogenicityshouldbeprovided.
Assay methods should be validated and should be able to characterize an�body content
(concentra�onor�ter)aswellasthetypeofan�bodiesformed.
Ofmost concern are those an�bodies that have poten�ally serious impact on safety and
efficacy,suchasneutralizingan�bodiesandan�bodieswithcrossreac�vity.Whenneutralizing
an�bodiesaredetectedinpa�entsinclinicalstudies(eitherinpre-approvalclinicalstudiesor
post-approvalclinicalstudies),theimpactofthean�bodiesonthePK/PDparametersofthe
SimilarBiologicsshouldbeanalyzed,wherethedataisavailable.Furthermore,anassessment
oftheimpactoftheneutralizingan�bodiesandcross-reac�ngan�bodies(ifapplicable)onthe
overallsafetyandefficacyoftheSimilarBiologicsshouldbeconducted.
Excep�ons:
In the case of Similar Biologics that can be evaluated for rare diseases, the clinical trial
popula�onsizecanbe reducedasper the rarityandseverityof thediseaseaswellas the
limita�onofaccesstotherapeu�cop�ons.
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11. Applica�on Forms
Variousapplica�onformsforsubmi�ngrequesttoregulatoryagenciesareasunder:
The applicant should comply with the established pharmacopoeia requirements while tes�ng
the excipients and as well as Biological product for which monograph is available in Indian
Pharmacopoeia. Refer Drugs and Cosme�c Act, 1940 and Rules 1945 for the applica�on format.
Stage Agency involved Applica�on Approval
ManufacturingLicensefortest,analysisandexamina�on(A�erCDSCONOC)
Form30 Form29
FormC1
Form28DForm27D
StateFDA
RCGM
StateFDA/CDSCO(countersignature)
Form11Form12CDSCO-zonalImportlicensefortest,analysisandexamina�on
FormB1/B3/B5/B7
RCGMCellbankimport/export/transfer/received
FormC5aRCGMSubmissionofPreclinicalstudyreport
Form44 CTPermissionLe�er
CDSCOClinicalTrial
Form45A/46A(bulkproduct)andForm5/46(Finishedproduct)
Form44(separateforDSandDP)
CDSCOImport/Manufacturingandmarke�ngpermission
ManufacturingLicense
Form41/Form45
Form40(withscheduleDIandDII)/Form44
CDSCORegistra�oncer�ficateforimport
Form10Form8&9CDSCOMarke�ngpermission/Licenseforimportedproduct
CarryingoutResearchandDevelopment
FormC3aRCGMPreclinicalstudiespermission
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12. Archiving of Data / Reten�on of Samples:
ThemanufacturershouldestablishtheSOPfordataarchivalaswellassamplereten�on.The
applicantshouldarchiveallthedata(quality,preclinicalandclinicaldocumenta�on)foraperiod
of at least five years a�ermarke�ng approval by competent authority in India. Important
samplessuchastestsubstance,vehicle,plasma/serum,�ssues,paraffinblocks,microscope
slides,electronicmaterial,etc., shouldberetained�ll theperiodofexpiry.Thedesignated
authority,whichwillbe responsible forarchivingandcanbeapproached for inspec�onor
retrievalifrequired,shouldbeindicatedinthedataarchivalandsamplereten�onSOP.
13. Glossary
Thedefini�onsgivenbelowapplytothetermsusedinthisguideline.Theymayhavedifferent
meaningsinothercontexts.
a. Comparability exercise: ComparisonofaSimilarBiologicwithaReferenceBiologicwiththe
goaltoestablishSimilarityinsafety,efficacyandquality.
b. Drug: Drugincludes(asdefinedinDrugsandCosme�csAct,1940).
i. allmedicinesfor internalorexternaluseofhumanbeingsoranimalsandall
substancesintendedtobeusedfororinthediagnosis,treatment,mi�ga�onor
preven�onofanydiseaseordisorder inhumanbeingsoranimals, including
prepara�onsappliedonhumanbodyforthepurposeofrepellinginsectslike
mosquitoes;
ii. such substances (other than food) intended to affect the structure or any
func�onofhumanbodyorintendedtobeusedforthedestruc�onof(vermin)or
insectswhichcausediseaseinhumanbeingsoranimals,asmaybespecified
from�me to �meby the Central Government by no�fica�on in theOfficial
Gaze�e;
iii. All substances intended for use as components of a drug including empty
gela�necapsules;and
iv. Suchdevicesintendedforinternalorexternaluseinthediagnosis,treatment,
mi�ga�onorpreven�onofdiseaseordisorderinhumanbeingsoranimals,as
maybespecifiedfrom�meto�mebytheCentralGovernmentbyno�fica�onin
theOfficialGaze�e,a�erconsulta�onwiththeBoard.
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c. Drug substance
Anysubstanceormixtureofsubstances intendedtobeused in themanufactureofadrug
(medicinal) product and that, when used in the produc�on of a drug, becomes an ac�ve
ingredient of the drug product. Such substances are intended to furnish pharmacological
ac�vityorotherdirecteffect inthediagnosis,cure,mi�ga�on,treatment,orpreven�onof
diseaseortoaffectthestructureandfunc�onofthebody.
d. Drug product
Thedosageforminthefinalimmediatepackagingintendedformarke�ng.Apharmaceu�cal
producttypethatcontainsadrugsubstance,generallyinassocia�onwithexcipients.
e. Gene�c engineering
The techniquebywhichheritablematerial,whichdoesnotusuallyoccurorwillnotoccur
naturally in the organismor cell concerned, generated outside the organismor the cell is
insertedintosaidcellororganism.Itshallalsomeantheforma�onofnewcombina�onsof
gene�cmaterialby incorpora�onofacell intoahostcell,wheretheyoccurnaturally (self
cloning)aswellasmodifica�onofanorganismorinacellbydele�onandremovalofpartsofthe
heritablematerial(Rules,1989).
f. Immunogenicity
Theabilityofasubstancetotriggeranimmuneresponseorreac�on(e.g.,developmentof
specifican�bodies,Tcellresponse,allergicoranaphylac�creac�on).
g. Impurity
Anycomponentpresentinthedrugsubstanceordrugproductthatisnotthedesiredproduct,a
product-relatedsubstance,orexcipientincludingbuffercomponents.Itmaybeeitherprocess-
orproduct-related.
h. Manufacture
“Manufacture”inrela�ontoanydrugincludesanyprocessorpartofaprocessforproducing,
altering, ornamen�ng, finishing, packing, labelling, breaking up or otherwise trea�ng or
adop�nganydrugwithaviewtoitssaleordistribu�onbutdoesnotincludethecompounding
ordispensingintheordinarycourseofretailbusiness;and“tomanufacture”shallbeconstrued
accordingly.
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i. Pharmacovigilance
Thescienceandac�vi�esrela�ngtothedetec�on,assessment,understandingandpreven�on
ofadverseeffectsoranyotherdrugrelatedproblems.
j. Reference Biologic
A Reference Biologic is used as the comparator for comparability studieswith the Similar
Biologic in order to show Similarity in terms of safety, efficacy and quality. The Reference
Biologicshouldbelicensed/approvedinIndiaorICHcountriesandshouldbetheinnovator's
product.TheReferenceBiologicshouldbelicensedbasedonafullsafety,efficacyandquality
data. Therefore another Similar Biologic cannot be considered as a choice for Reference
Biologic.
k. Similar
Absenceofarelevantdifferenceintheparameterofinterest.
l. Similar Biologic
ASimilarBiologicproductisthatwhichissimilarintermsofquality,safetyandefficacytoan
approvedReferenceBiologicalproductbasedoncomparability.
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14. References
I. EMA guideline on Similar Biological medicinal products, London, 2014
(CHMP/437/04Rev1)
II. EMA Guideline on Similar Biological medicinal products containing biotechnology-
derived proteins as ac�ve substance: non-clinical and clinical issues, London, 2014
(EMEA/CHMP/BMWP/42832/2005Rev1)
III. EMA guideline on Similar Biological medicinal products containing biotechnology
derived proteins as ac�ve substance: non-clinical and clinical issues. London, 2006
(CHMP/BMWP/42832)
IV. EMAguidelineonimmunogenicityassessmentofbiotechnology-derivedtherapeu�c
proteinsLondon,2007(CHMP/BMWP/14327)
V. ICHguidelineonpreclinicalsafetyevalua�onofbiotechnology-derivedpharmaceu�cals
(S6),1997andaddendum,2011
VI. GuidelineforSafetyStudyofBiologicalProducts,(KFDA,2010)
VII.WorldHealthOrganiza�on(WHO)GuidelinesonEvalua�onofSimilarBiotherapeu�c
Products(SBP),2009
VIII.WorldHealthOrganiza�on(WHO),Guidelinesonthequality,safetyandefficacyof
bio-therapeu�cproteinproductspreparedbyrecombinantDNAtechnology,2013
IX. EMA-DNAandHostcellproteinimpuri�esrou�netes�ngversusvalida�onstudies,
1997
X. ICHQ1A(R2)-StabilityTes�ngofNewDrugSubstancesandProducts,2003
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Annexure 1:
Protocols on Regulatory Pathway for Recombinant Pharma Products Adopted from
MashelkarReport.
PROTOCOL – IIndigenous product development, manufacture and marke�ng of pharmaceu�cal products
derived from LMOs but the end product is not a LMOs
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PROTOCOL – IIIndigenous product development, manufacture and marke�ng pharmaceu�cal products
where the end product is a LMO
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PROTOCOL – IIIImport and marke�ng of Pharma Products in Finished Formula�ons where the End
Product is a LMO
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PROTOCOL – IVImport and marke�ng of Pharma Products in Bulk for making Finished Formula�on
where the End Product is a LMO
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PROTOCOL – VImport and marke�ng of Pharma Products derived from LMOs in bulk and/or Finished
Formula�ons where the end product is not a LMO
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Annexure II:
Cri�cal Quality A�ributes (CQA) and Key Quality A�ributes (KQA)
A. Physicochemical and biological characteriza�on of nucleic acid based recombinant
products (Vector for expression of recombinant protein, siRNA/ snRNA etc.)
Physico-chemical Characteriza�on Biological Characteriza�on
Structure of ac�ve substance
Iden�ty analysis:
• Sequence(Toproveifthebasessequencesameasreferencebiologic).(CQA)
For Secondary Structure analysis:
• Restric�onmapfor>1000bp(To check if secondary structure is same as reference biologic). (CQA)
• CDspectrumfrom190to800nm.(CQA)
• Absorp�on spectrum from 190 to 800nm.(CQA)
Isoforms of ac�ve substance
• Gelelectrophoresis(agarose/acrylamide/ureapage).(CQA)
• Southern/Northernblot/Hybridiza�ontothetargetsequence.(CQA)
Product related variants and impuri�es
Depending on % content, ac�vity level andunderstanding its poten�al for undesirableac�vity/immunogenicitywouldenabletojus�fyitsimpactonsafetyandefficacy.
• Es�ma�on of RNA and DNA usingnanodroporreagent.(KQA)
• PurityonHPLC(To check if any impuri�es are there).(KQA)
• Tmprofile.(KQA)
Func�onal& Biological ac�vity
Datafromin-vitro and/ or in-vivo potencyassaysreflec�ngthemechanismofac�onofthedrug.
• Expressionpa�ern inactual targethostcell.(To compare efficiency of expression of similar biologic with reference biologic in the target cell). (CQA)
• Expression pa�ern in closest animalspecies upon administra�on(alongwithvehicleasnega�vecontrol)(To compare efficiency of expression of similar biologic with reference biologic in the target cell when administered in whole animal, this will evaluate the efficiency of vector loca�on and promoter ac�vity in target cell).(CQA)
• Kine�cs of expression during thep roposed therapeu�c per iod o fprotec�on (To compare half-life with reference biologics). (CQA)
Efficacy (in vitro / in vivo)
• Efficacyinappropriatedisease/infec�onmodelin vitro and/orin vivo).(CQA)
• Absence of interference of markerenzyme/an�bio�c, if any (To compare therapeu�c interference and toxicity due to a marker in the similar biologic with that of reference biologic). (CQA)
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Process related impuri�es
Someprocessrelatedimpuri�esmaynotimpactbiological ac�vity. Robust process controls toacceptablelimitswouldenabletojus�fyitslowimpactonsafety.
• Absence of interference of markerenzyme/an�bio�c.(KQA)
Vector for expression of siRNA/ snRNA etc.
• Expressionpa�ern inactual targethostcell(To compare efficiency of expression of similar biologic with reference biologic in the target cell). (CQA)
• Expression pa�ern in closest animalspeciesuponadministra�on(alongwithvehicleasnega�vecontrol)(To compare efficiency of expression of similar biologic with reference biologic in the target cell when administered in whole animal, this will evaluate the efficiency of vector loca�on and promoter ac�vity in target cell). (CQA)
• Kine�cs of expression during thep roposed therapeu�c per iod o fprotec�on (To compare half-life of the similar biologic with reference biologic). (CQA)
• Efficacyinappropriatedisease/infec�onmodelin vitro and/orin vivo (To compare therapeu�c ac�vity of the similar biologic with reference biologic). (CQA)
• Absenceofinterferenceofmarkerenzyme/an�bio�cifany(To compare therapeu�c interference and toxicity due to a marker in the similar biologic with that of reference biologic). (CQA)
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B. Physicochemical and biological characteriza�on of recombinant therapeu�c Proteins:
Physico-chemical Characteriza�on Biological Characteriza�on
Structure of ac�ve substance
For Primary Structure analysis:
• Aminoacidsequence(fullaswellasNand/orCterminal)(CQA)
• IntactMassassessmentbyLC-ESI-MS/MALDI-TOFMS(CQA)
• Pep�demap(CQA)
For Secondary Structure analysis:
• FarUVCircularDichroismSpectrum/FTIRAnalysis(CQA)
• Tryp�cPep�deMap-1Dand2D(To check if secondary structure is conserved)(CQA)
• Sul�ydrylgroups(s)anddisulphidebridges(To check if secondary structure is conserved)(CQA)
For Ter�ary Structure analysis:
• Fluorescencespectrum(CQA)
• NearUVCircularDichroism(CQA)
• UV-VISspectroscopy(CQA)
Isoforms of ac�ve substance:
I so fo rms gene rated by g l ycosy l a�on ;phosphoryla�on; acetyla�on; myristoyla�on;PEGyla�on (if applicable), esterifica�on (ifapplicable)aggregatesandclippedproducts;NorCterminaltrunca�onormodifica�on;chargevariants and non-polar variants are known toinfluence the target binding or other receptorbinding ac�vity and therefore can have directimpactonthefunc�on.
Func�onal& Biological ac�vity
Datafromin-vitro and / or in-vivo potencyassaysreflec�ngthemechanismofac�onofthedrug,receptor binding analysis can be consideredstrongly suppor�ve forestablishingcomparablesafetyandefficacy for theSimilarBiologicsandReferenceBiologic:
• ReceptorBindingAssay(CQA)
• In-vitrobioassay
• Biologicalac�vityinactualtargethostcell(at least one highly prevalent Indianvariant /isolate should be used)(to compare ac�vity of similar biologic with reference biologic in the target cell) (CQA)
Biological ac�vity in closest animalspecies(iffeasible)uponadministra�on(alongwith vehicle as nega�ve control)(at least one highly prevalent Indianvariant /isolate should be used) (To compare ac�vity of similar biologic with reference biologic in the target cell when administered in whole animal, this will evaluate the efficiency of vector / an�body loca�on and promoter ac�vity in target cell)(CQA)
• Kine�csofbiologicalac�vityduring thep roposed therapeu�c per iod o fprotec�on(atleastonehighlyprevalentIndianvariant / isolate shouldbeused)(To compare half-life of the similar biologic with reference biologic). (CQA)
• Efficacyinappropriatedisease/infec�onmodelin vitro and/orin vivo (ifavailable)(prolifera�on/cytotoxicity/neutralizing)(To compare therapeu�c interference and toxicity due to a marker in the similar biologic with that of reference biologic). (CQA)
• In-vivo bioassay(if available)(KQA)
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• Glycoformsandothermodifica�onslikeP h o s p h o r y l a � o n , a c e t y l a � o n ,myrsitoyla�on,PEGyla�on,esterifica�onbyHPLC&MALDI-TOF(CQA)
• Isoforms and charge variants by Iso-electricfocusing(KQA)
• N-terminalsequenceconfirma�on(CQA)
• C-Terminalsequenceconfirma�on(CQA)
• Ionexchangechromatographyforcharge
• heterogeneity(KQA)
Host and Process related impuri�es
Hostcellproteins,HostcellDNA,proteinAandLeachableetc.,maynotimpactbiologicalac�vity.Robust process controls to acceptable limitswouldenabletojus�fyitslowimpactonsafety.ThesetestsfallunderthecategoryofKQAs.
• Hostcellproteinanalysis(KQA)
• HostcellDNAanalysis(KQA)
• Pyrogencontent(KQA)
Drug Product characteris�cs
Thefollowingqualitya�ributesneedtobetestedtocharacterizethedrugproduct.
• Proteincontent(CQA),
• Appearance(KQA)
• pH(KQA)
• Osmolarity(KQA)
• Composi�onof keyexcipients includingstabilizer(if formula�on is same) (KQA)
• Visible/subvisiblepar�cles,(KQA)
• Pyrogencontent(KQA)
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C. Physicochemical and biological characteriza�on of recombinant mAbs:
Physico-chemical Characteriza�on Biological Characteriza�on
Structure of ac�ve substance
For Primary Structure analysis:
• Aminoacidsequence(fullaswellasNand/orCterminal)(CQA)
• IntactMassassessmentbyLC-ESI-MS/MALDI-TOFMS(CQA)
• Pep�demap(CQA)
For Secondary Structure analysis:
• FarUVCircularDichroismSpectrum/FTIRAnalysis(CQA)
• Tryp�cPep�deMap-1Dand2D(To check if secondary structure is conserved)(CQA)
• Sul�ydrylgroups(s)anddisulphidebridges(To check if secondary structure is conserved)(CQA)
For Ter�ary Structure analysis:
• Fluorescencespectrum(CQA)
• NearUVCircularDichroism(CQA)
• UV-VISspectroscopy(CQA)
Func�onal& Biological ac�vity
Datafromin-vitro and / or in-vivo potencyassaysreflec�ngthemechanismofac�onofthedrug,receptor binding analysis and Fc-receptor andC1q binding assays (for monoclonal an�bodieswitheffectorfunc�on)canbeconsideredstronglysuppor�ve for establishing comparable safetyand efficacy for the Similar Biologics andReferenceBiologic:
• ReceptorBindingAssay(CQA)
• In-vitrobioassay
• Apoptosisassay,(if applicable)(KQA)
• NeonatalReceptor(FcRn)BindingAssay (CQA)
• For mAbs with effector func�on (formAbs having established effectorfunc�ons)thefollowingqualitya�ributesshouldbeconsideredasCQA.
a. Receptorbindingbioassay(FcRs)
b. CDCassay
c. ADCCassay
• NeutralizingBiologicalac�vityinactualtarget host cell (at least one highlyprevalentIndianvariant/isolateshouldbeused)(to compare ac�vity of similar biologic with reference biologic in the target cell) (CQA)
• Neutralizing Biological ac�vity inclosestanimalspecies(iffeasible)uponadministra�on (along with vehicle asnega�ve control) (at least one highlyprevalentIndianvariant/isolateshouldbeused)(To compare ac�vity of similar biologic with reference biologic in the target cell when administered in whole animal, this will evaluate the efficiency of vector /an�body loca�on and promoter ac�vity in target cell )(CQA)
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Isoforms of ac�ve substance:
I s o fo rms gene ra ted by g l y co sy l a�on ;phosphoryla�on; acetyla�on; myristoyla�on,esterifica�on (if applicable) aggregates andclippedproducts;NorC terminal trunca�onormodifica�on; charge variants and non-polarvariantsareknowntoinfluencethetargetbindingorotherreceptorbindingac�vityandthereforecanhavedirectimpactonthefunc�on.
• Glycoformsandothermodifica�onslikeP h o s p h o r y l a � o n , a c e t y l a � o n ,myrsitoyla�on,esterifica�onbyHPLC&MALDI-TOF(CQA)
• Isoforms and charge variants by Iso-electricfocusing(KQA)
• N-terminalsequenceconfirma�on(CQA)
• C-Terminalsequenceconfirma�on(CQA)
• Ionexchangechromatographyforchargeheterogeneity(KQA)
Product related variants and impuri�es
Depending on % content, ac�vity level andunderstanding its poten�al for undesirableac�vity / immunogenicity would enable us tojus�fyitsimpactonsafetyandefficacy
• RP-HPLC(KQA)
• SE-HPLC(CQA)
• IE-HPLC(KQA)
• WesternBlot(CQA)
• SDSPAGE/CE–SDS(KQA)
• IEF/CE-IEF(KQA)
• Light and heavy chain separa�on (To check an�genic recogni�on mo�f) (KQA)
• HelixtoCoilTransi�onProfile(To verify if the prepara�on is stable and impuri�es or isoforms are affec�ng the stability) (KQA)
• Kine�csofneutralizingbiologicalac�vityduringtheproposedtherapeu�cperiodof protec�on (at least one highlyprevalentIndianvariant/isolateshouldbe used) (To compare half-life of the similar biologic with reference biologic). (CQA)
• Efficacyinappropriatedisease/infec�onmodelin vitro and/orin vivo (ifavailable)(prolifera�on/cytotoxicity/neutralizing)(To compare therapeu�c interference and toxicity due to a marker in the similar biologic with that of reference biologic). (CQA)
• In-vivo bioassay(if available)(KQA)
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Host and Process related impuri�es
Hostcellproteins,HostcellDNA,proteinAandLeachableetc.,maynotimpactbiologicalac�vity.Robust process controls to acceptable limitswouldenabletojus�fyitslowimpactonsafety.ThesetestsfallunderthecategoryofKQAs.
• Hostcellproteinanalysis(KQA)
• HostcellDNAanalysis(KQA)
• ResidualProteinA(ifapplicable)(KQA)
• Pyrogencontent(KQA)
Drug Product characteris�cs
Thefollowingqualitya�ributesneedtobetestedtocharacterizethedrugproduct.
• Proteincontent(CQA)
• Appearance(KQA)
• pH(KQA)
• Osmolarity(KQA)
• Composi�on of keyexcipients includingstabilizer(if formula�on is same) (KQA)
Visible/subvisiblepar�cles,(KQA)
Pyrogencontent(KQA)
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D. Physicochemical and biological characteriza�on of recombinant therapeu�c Enzymes.
Physico-chemical Characteriza�on Biological Characteriza�on
Structure of ac�ve substance
For Primary Structure analysis:
• Amino acid sequence (full aswell as Nterminal)(CQA)
• IntactMass assessment by LC-ESI-MS /MALDI-TOFMS(CQA)
• Pep�demap(CQA)
For Secondary Structure analysis:
• Circular Dichroism Spectrum/ FTIRAnalysis(CQA)
• Tryp�cPep�deMap-1Dand2D(To check if secondary
• structure is conserved)(CQA)
For Ter�ary Structure analysis:
• Fluorescencespectrum(CQA)
• NearUV-CircularDichroism(CQA)
• UV-VISspectroscopy(CQA)
Isoforms of ac�ve substance
I s o fo rms gene ra ted by g l y co sy l a�on ;phosphoryla�on; acetyla�on; myristoyla�on;aggregatesandclippedproducts;NorCterminalt r un ca�on o r mod i fi ca�on ; C hem i ca lmodifica�onsareknowntoinfluencethetarget(substrate) binding ac�vity and therefore canhavedirectimpactonthefunc�on.
• N-terminalsequenceconfirma�on(CQA)
• C-terminalsequence(CQA)
• Glycosyla�on(CQA)
• Phosphoryla�on(CQA)
• Myristoyla�on,ifany(CQA)
• Pegyla�on, esterifica�on (if applicable)(CQA)
Func�on & Biological ac�vity
Datafromin-vitro and/ or in-vivo potencyassaysreflec�ngthemechanismofac�onofthedrug,receptorbindinganalysiscanbe
considered strongly suppor�ve for establishingcomparable safety and efficacy for the SimilarBiologicsandReferenceBiologic:
• Enzymeac�vityingelassayinpresenceofchromogenic substrate (To check ac�vity). (CQA)
• Kmwithnaturalsubstrate(CQA)
• Kiwithknowninhibitors(CQA)
• Biologicalac�vityinactualtargethostcell(to compare ac�vity of enzyme in similar biologic with reference biologic in the target cell) (CQA)
• Biological ac�vity in closest animalspeciesuponadministra�on(alongwithvehicleasnega�vecontrol)(To compare ac�vity of similar biologic with reference b io log ic in the target ce l l when administered in whole animal, this will evaluate the efficiency of vector loca�on and promoter ac�vity in target cell )(CQA)
• Kine�csofbiological ac�vityduring thep roposed therapeu�c per iod o fprotec�on (To compare half-life of the similar biologic with reference biologic). (CQA)
• Efficacyinappropriatedisease/infec�onmodelin vitro and/orin vivo (ifavailable)(prolifera�on/cytotoxicity/neutralizing)(To compare therapeu�c interference and toxicity due to a marker in the similar biologic with that of reference biologic). (CQA)
• Apoptosisassay,(if applicable)(KQA)
In-vivo bioassay (if available) (KQA)
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Product related variants and impuri�es
Depending on % content, ac�vity level andunderstanding its poten�al for undesirableac�vity / immunogenicity would enable us tojus�fyitsimpactonsafetyandefficacy
• RP-HPLC (KQA)
• SE-HPLC(CQA)
• IE-HPLC(KQA)
• WesternBlot(CQA)
• SDSPAGE/CE–SDS (KQA)
• IEF/CE-IEF(KQA)
• Light and heavy chain separa�on (To check an�genic recogni�on mo�f) (KQA)
• HelixtoCoilTransi�onProfile(To verify if the prepara�on is stable and impuri�es or isoforms are affec�ng the stability) (KQA)
Process related impuri�es
Hostcellproteins,HostcellDNA,proteinAandLeachable etc., may not impact biologicalac�vity. Robust process controls to acceptablelimitswouldenabletojus�fyitslowimpactonsafety.
• Hostcellproteinanalysis(KQA)
• HostcellDNAanalysis(KQA)
• ResidualProteinA(ifapplicable)(KQA)
• Pyrogencontent(KQA)
Drug product characteris�cs
Thefollowingqualitya�ributesneedtobetestedtocharacterizethedrugproduct.
• Proteincontent(CQA),
• Appearance(KQA)
• pH(KQA)
• Osmolarity(KQA)
• Quan�ta�ve composi�on of KQAexcipients including stabil izer ( ifformula�onissame)(KQA)
• Visible/subvisiblepar�cles(KQA)
• Pyrogencontent(KQA)
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Acknowledgement:
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Guidelines on Similar Biologics: Regulatory Requirements for Marke�ng Authoriza�on in India
Theseguidelineswerepreparedbythetaskforcecons�tutedbyCentralDrugsStandardControl
Organiza�on(CDSCO),DirectorateGeneralofHealthServices,MinistryofHealthandFamily
Welfare,Govt.ofIndiaandtheexpertsfromsub-commi�eeofReviewCommi�eeofGene�c
Manipula�on(RCGM)ofDepartmentofBiotechnology(DBT),MinistryofScience&Technology,
Govt.ofIndiabyrevisingtheearlierguidelinesonSimilarBiologicspublishedinyear2012.
· Chairperson: Dr. G.N. Singh, Drugs Controller General (lndia), Central Drugs Standard
ControlOrganiza�on(CDSCO),NewDelhi-110002
·� Co-chairperson: Dr. S. R. Rao, Adviser, Department of Biotechnology (DBT),Ministry of
Science&Technology,Govt.ofIndia,NewDelhi-110003
·� Scien�sts fromDepartmentofBiotechnology(DBT)
·� Scien�stsfromNa�onalIns�tuteofBiologicals(NIB),Noida
·� Scien�stsfromotherpremierins�tu�onsincludingIndianPharmacopeiaCommission(IPC)
andotherlaboratories
· Representa�ves from Organisa�on of Pharmaceu�cal Producers of India (OPPI),
Associa�onof Biotechnology Led Enterprises (ABLE), Federa�onof Indian Chambers of
Commerce&Industry(FICCI),Confedera�onofIndianIndustry(CII),AssociatedChambers
ofCommerceofIndia(ASSOCHAM),IndianPharmaceu�calAssocia�on(IPA),IndianDrug
Manufacturers'Associa�on(IDMA)andotherassocia�ons
·� All par�cipantswhocontributedonwebbasedconsulta�on
·� Regulatory officialsofBiologicalDivision(SimilarBiologics),CDSCO(HQ),NewDelhi
·� Coordinators:Dr.V.G.Somani,JointDrugsController(India)&Dr.A.Ramkishan,Deputy
DrugsController(India),BiologicalDivision,CDSCO(HQ),NewDelhi.
CDSCO and DBT sincerely acknowledge the contribu�on of:
52
Central Drugs Standard Control Organiza�on
DirectorateGeneralofHealthServices
MinistryofHealthandFamilyWelfare
GovernmentofIndia,FDABhavan,ITO,KotlaRoad,NewDelhi-110002
Department of Biotechnology,
MinistryofScience&Technology,
Block-2,CGOComplex,LodiRoad,
NewDelhi-110003
For further informa�on please contact:
2016
Guidelines on Similar Biologics: Regulatory Requirements for Marke�ng Authoriza�on in India
Department of BiotechnologyMinistryofScience&Technology
Central Drugs Standard Control Organiza�onMinistryofHealth&FamilyWelfare
GovernmentofIndiaFDABhavan,ITO,KotlaRoad,
NewDelhi-110002Phone:91-11-23216367(CDSCO)/23236975
Fax:91-11-23236973E-mail:[email protected]
www.cdsco.nic.in
GovernmentofIndia
Effec�ve 15th August 2016