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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



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)

................................................................................30

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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.

2016


212016


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


23

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.

2016


24

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)

2016


25

· 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.

2016


26

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.

2016


27

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.

2016


28

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.

2016


29

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.

2016


30

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.

2016


31

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.

2016


32

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

2016


33

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.

2016


34

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:



For Primary Structure analysis:

• Aminoacidsequence(fullaswellasNand/orCterminal)(CQA)

• IntactMassassessmentbyLC-ESI-MS/MALDI-TOFMS(CQA)

• Pep�demap(CQA)


• 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.


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)


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C. Physicochemical and biological characteriza�on of recombinant mAbs:




• Aminoacidsequence(fullaswellasNand/orCterminal)(CQA)

• IntactMassassessmentbyLC-ESI-MS/MALDI-TOFMS(CQA)



• 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)



• NearUVCircularDichroism(CQA)



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)


• C-Terminalsequenceconfirma�on(CQA)

• Ionexchangechromatographyforchargeheterogeneity(KQA)


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)


• 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.



• ResidualProteinA(ifapplicable)(KQA)


Drug Product characteris�cs


• 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.




• Amino acid sequence (full aswell as Nterminal)(CQA)

• IntactMass assessment by LC-ESI-MS /MALDI-TOFMS(CQA)



• Circular Dichroism Spectrum/ FTIRAnalysis(CQA)

• Tryp�cPep�deMap-1Dand2D(To check if secondary

• structure is conserved)(CQA)



• NearUV-CircularDichroism(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.


• 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)


• Apoptosisassay,(if applicable)(KQA)

In-vivo bioassay (if available) (KQA)

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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.



• ResidualProteinA(ifapplicable)(KQA)


Drug product characteris�cs


• 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)


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Acknowledgement:

2016


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




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