化学仿制原料药DMF样本

此内容仅作为医药研发工作者撰写DMF文件时研究参考使

用，仅作为学术交流用途。

***(NameofDrugSubstance)

DRUGMASTERFILE

MODULE:3

***PharmaceuticalCo.,Ltd.

7，7，*1*7，*1*x""、1'7，7，7，

不不不不不不不不不i^nina不不不不不不

Telephone:86-***-********

Fax:86-***

March27,2018

Tabtle3-2-lTABLEOFCONTENTS

SectionTitlePageNo.

3.2.SDRUGSUBSTANCE

3.2.S.1GeneralInformation

3.2.S.1.1Nomenclature

3.2.S.1.2Structure

3.2.S.1.3GeneralProperties

3.2.S.2Manufacture

3.2.S.2.1Manufactures

3.2.S.2.1.1BriefIntroductionofManufacturer

3.2.S.2.1.2ContactInformationofManufacturer

3.2.S.2.1.3OrganizationChart

3.2.S.OrganizationChart

3.2.S.QualityManagementTeam

3.2.S.2.2DescriptionofManufacturingProcessandProcessControls

3.2.S.2.2.1RouteofChemicalReaction

3.2.S.2.2.2ProcessFlowDiagram

3.2.S.2.2.3ProceduresofManufacturingProcess

3.2.S.2.3ControlofMaterials

3.2.S.2.3.1GeneralInformation

3.2.S.2.3.2ControlofStartingMaterials

3・2・S.2.3.3ControlofReagents,Solvents,andAuxiliaryMaterials

3.2.S.2.4ControlofCriticalStepsandIntermediates

3.2.S.2.4.1ControlofCriticalSteps

3.2.S.2.4.2ControlofIntermediates

3.2.S.2.5ProcessValidationandEvaluation

3.2.S.2.5.1ProcessValidationPlan

3.2.S.2.5.2ResultsofProcessValidation

3.2.S.2.6ManufactureProcessDevelopment

3.2.S.2.6.1RouteSelectionandProcessOptimization

32s.262DeterminationofCriticalProcess

3.2.S.2.6.3ProcessScale-upResearch

3.2.S.3Characterization

3.2.S.3.1ElucidationofStructureandotherCharacteristics

3.2.S.3.1.1ElucidationofStructure

3.2.S.3.1.2OtherCharacteristics

3.2.S.SpecificOpticalRotation

3.2.S.MeltingPoint

3.2.S.Solubility

3.2.S.Hygroscopicity

3.2.S.ParticleSize

3.2.S.MicrobiologicalTest

3.2.S.Polymorphism

3.2.S.3.L2.8Solvateand/orHydrate

3.2.S.SpatialConfiguration

3.2.S.3.2Impurities

3.2.S.4ControlofDrugSubstance

3.2.S.4.1Specification

3.2.S.4.2AnalyticalProcedures

3.2.S.4.3ValidationofAnalyticalProcedures

3.2.S.4.3.1AnalyticalMethodValidationofAssay

3.2.S.4.3.2AnalyticalMethodValidationofRelatedSubstances

3.2.S.4.3.3AnalyticalMethodValidationofEnantiomers

3.2.S.4.3.4AnalyticalMethodValidationofResidualSolvents

3.2.S.4.3.5AnalyticalMethodValidationofMicrobiologicalTest

3.2.S.4.4BathAnalysis

3.2.S.4.5JustificationofSpecification

3.2.S.5ReferenceStandardsorMaterials

3.2.S.6ContainerClosureSystem

3.2.S.7Stability

3.2.S.7.1StabilitySummaryandConclusions

3.2.S.7.2Post-approvalstabilityProtocolandStabilityCommitment

3.2.S.7.3StabilityData

STATEMENTOFCOMMITMENT

***PharmaceuticalCo.,Ltd.herebycertifiesandsummitsthisStatementofCommitmentthat

the***ismanufacturedinaccordancewithmethodsandproceduresdescribedherewithinthisUS

DMF.Furtherthisalsotocertifythat***PharmaceuticalCo.,Ltd.confirmstoGMPguidelinefor

ActivePharmaceuticalIngredientsasrecommendedbyFDAandICH.Wearealready

implementingtheGMPofDrugActofChinaasapplicabletobulkactives.Wearealso

committingtoallowanyinspectionofproductionandqualityassurancefacilitiestoappropriate

authoritiesandprovidedthemallcooperationandassistance.

3.2.SDRUGSUBATANCE

3.2.S.1GeneralInformation

***isanoral***drugusedtotreat***bypreventing***from***.Itwasapprovedbythe

FDAinApril2018.

3.2.S.1.1Nomenclature

GeneralName:***

Chemicalname:***

Tradename:***

US.P./E.P./J.P./Ch.P.name:***

IUPACname:***

OtherNames:

CASname:***

CompanyorLaboratoryname:***Monohydrate

CAS#:******_**.*

3.2.S.1.2Structure

MolecularFormula:***

MolecularWeight:***

Stereochemistry:threechiralcenters,(1S,3R,4S)configuration

3.2.S.1.3GeneralProperties

Physicaldescription:Awhiteoralmostwhitecrystallinepowder.

Solubility:Freelysolubleindimethylsulfoxide;slightlysolubleinmethanolandethanol;very

slightlysolubleinwaterandisopropanol;practicallyinsolubleinacetone,diethyletherand

n-hexane.ThepHvalueofsaturatedaqueoussolutionis7.9(25±0.5°C).

Meltingpoint/Boilingpoint:185-188°C.

UVmax(入,methanol):350,340nm.

Opticalisomerism:(IS,3R,4S)configuration.

Chirality:threechiralcenters.

Specificopticalrotation：

pHinWater：

ParticleSize:D90=8-50um;D50=2-10um;D10<5um.

Polymorphism:FromX.

3.2.S.2Manufacture

3.2.S.2.1Manufacturers

3.2.S.2.1.1BriefIntroductionofManufacturer

***PharmaceuticalCo.,Ltd.isalargescaledmodernpharmaceuticalgroupthatintegrates

formulations,API(ActivePharmaceuticalIngredients)andintermediates.Itoccupiesanareaof

******squaremetersandhasastaffof****.

Thecompanyislocatedinawell-equippedfacilitywithsophisticatedanalyticalinstruments.

Thecompanyisspecializedintheresearch,development,manufacturingofAPI,intermediates.

***PharmaceuticalCo.,Ltd.isthelargestsupplierof***productsworldwide.

3.2.S.2.L2ContactInformationofManufacturer

***PharmaceuticalCo.,Ltd.ismanufacturingthedrugsubstance***atthebelowmentioned

address:

***PharmaceuticalCo.,Ltd.

*********,******

Telephone:86-***・********

Fax，86_***_********

NameofContactPersonandAddress:

Mr./Mrs,:***

DirectorofRegulatoryAffairandCompliance

***PharmaceuticalCo.,Ltd.

***************

Telephone:86・***・********

Fax，86_***_********

***********

E-mail：regulatory_affairs@***.com

3.2.S.2.1.3OrganizationChart

3.2.S.OrganizationChart

?

3.2.S.QualityManagementTeam

QualityManagementTeam

NO.NameDegreeGraduatedYearsofMajorPositionExperience

FromGraduation(Years)

1***Ph.DBeijing1998OrganicCEO20

UniversityChemistry

2***Ph.DNankai2008OrganicGeneral10

UniversityChemistryManager

ofR&D

3***M.ScTianjin2006MedicinalGeneral12

UniversityChemistryManager

of

Production

4***B.EngNanjing2004ChemicalGeneral14

UniversityEngineeringManager

ofQuality

3.2.S.2.2DescriptionofManufacturingProcessandProcessControl

3.2.S.2.2.1RouteofChemicalReaction

5：M-9

***waspreparedbythefollowingsteps:

1)***intermediate1(N-5)wassynthesizedbycondensingthestartingmaterial(N-4)and

4-methoxytriphenylchloromethane.Thecrudeproductwaspurifiedbycolumnchromatographyto

giveN-5withhighpurity;

2)***intermediate2(N-6)wassynthesizedbyoxidizingN-5withDess-Martinperiodinane;

3)***intermediate3(N-7)wassynthesizedbymethylenatingN-6withNystedreagent.The

crudeproductwaspurifiedbycolumnchromatographytogiveN-7withhighpurity;

4)***intermediate4(N-8)wassynthesizedbyhydrolyzingN-7withHC1;

5)***intermediate5(N-9)wassynthesizedbydeprotectingO-BninN-8withBCI3inDCM.The

***intermediate5(N-9)wasthecrude***;

6)Thecrude***(N-9)isfinallyrecrystallizedfromethanoltogivepure***.

3.2.S.2.2.2ProcessFlowDiagram

Stepl:CondensationProcess,thesynthesisof***N-5

Rawmaterlals/Reagents/SolventsTechnologicalOperationProcessControl

xx±5℃,x±0.5h

△HPLCmonitoring

Note1:theprocesscontrolpoint(markedwith△)wasonlyconfirmedintheprocessvalidation.

Thereactioncontrollinginroutineproductiondependedontime,temperature,etc.

Note2:Thesampling,purityandrelatedsubstancedetectionfollowedthesuggestionin

3.2.S.2.4-ControlofCriticalStepsandIntermediates.

Step2:OxidationProcess,thesynthesisof***N-6

Rawmaterials/Reagents/SoIventsTechnologicalOperationProcessControl

xx±5℃,x±Ih

△TLCmonitoring

Reducedpressure

distillation

***N-6

(intermediate2)

Note3:TheprocesswasmonitoredbyHPLCthatfollowedthesuggestionin3.2.S.2.4-Control

ofCriticalStepsandIntermediates.

Step3:MethylenationProcess,thesynthesisof***N-7

Rawmaterials/Reagents/SolventsTechnologicalOperationProcessControl

Nystedregent

—►Stirringxx±5℃

Cyclohexane

Dropwiseaddition,

Titaniumtetrachloride—►Temperaturexx±5℃

controlling

***N-6

(intermediate2)—►Stirring,Dissolution

Cyclohexane

r

Heating,

xx±5℃,xx±0.5h

Methylenation

△HPLCmonitoring

reaction

J

AqueoussolutionofsodiumCombination,

-►

bicarbonate,TetrahydrofuranStirring(quenching)

TetrahydrofuranFiltration

―►

(washingfiltercake)(diatomite)

Combinationof

filtrate,

Stillstratification

(

Extractingaqueous

Tetrahydrofuran—►

laver

▼

Combinationof

organicphase

Note4:Thesampling,purityandrelatedsubstancedetectionfollowedthesuggestionin

3.2.S.2.4-ControlofCriticalStepsandIntermediates.

Step4:HydrolyzationProcess,thesynthesisof***N-8

Rawmaterials/Reagents/SolventsTechnologicalOperationProcessControl

xx±5℃,xx±0.5h

△HPLCmonitoring

pHtoxx

Note5:Thesampling,purityandrelatedsubstancedetectionfollowedthesuggestionin

3.2.S.2.4-ControlofCriticalStepsandIntermediates.

Step5:DeprotectionProcess,thesynthesisof***N-9

Rawmaterials/Reagents/SolventsTechnologicalOperationProcessControl

xx±5℃,xx±0.5h

△HPLCmonitoring

xx±5℃,

aboutxxminutes

pHtoxx

Note6:Thesampling,purityandrelatedsubstancedetectionfollowedthesuggestionin

3.2.S.2.4-ControlofCriticalStepsandIntermediates.

Step6:RecrystallizationProcess,thesynthesisof***

Rawmaterials/Reagents/SolventsTechnologicalOperationProcessControl

Absoluteethylalcohol

Crude***/N-9——»Stirring,Heating,

(intermediates)Dissolution

3.2.S.2.2.3ProceduresofManufacturingProcess

Theproductioncapacityforregistrationbatchwas0,2Kg-0.3Kg,andforthecommercialbatch

was0.2Kg-3.0Kg.Thefollowprocessdescriptionwasbasedontheregistrationbatch(thecritical

processparameterswereinshadowmark).

Step1:Condensationprocess,thesynthesisof***N-5

ReactionMaterialMolar

Ratio(w/w)Mass

operationNameratio

Condensation

***N-411.001.075Kg

reaction

TriethylaminexxxxxxKg

4-MethoxytriphenylmethylchlorideXXXXxxKg

4-DimethylaminopyridineX-xxKg

Dichloromethane-雌xxKg

Quenching&

Sodiumbicarbonatea-XxxKg

extraction

Drinkingwater--XXKg

Dichloromethane-xxKg

Saturatedstablesaltsolution--XXKg

Anhydroussodiumsulfate-XXxxKg

Purificationby

SilicagelfbrcolumnXX

column--

chromatographyKg(x+xx)

chromatography

b

Ethylacetate-〜xxKg

Cyclohexane--〜xxKg

awasaddedintowatertoprepareaqueoussolution,andthesolutionwasusedtowashtheproduct

aftercondensationreaction(toquenchthereaction)

bwasusedastheelutionsolventforchromatographyseparation,xxKgwasestimationvalueand

theexactvaluewasdecidedbychromatographycondition.

XXKgtriethylamineand1.075Kg***N-4wereaddedtoareactor.Thereactorwasstirring

untilasolutionwasformed.XXg4-methoxytriphenylmethylchloride,XXg

4-dmethylaminopyridineandXXgdichloromethanewereaddedtothereactoratXX±5℃.The

reactionwasstoppedafterstirringforXX±0.5hatXX±5℃.

Asolutionofsodiumbicarbonate(XXKg)indrinkingwater(XXKg)waspumpedtothe

solutioninstirring.Afterastandingandlayeringprocess,theaboveaqueouslayerwasextracted

byXXgdichloromethane.ThecombinedorganiclayerswerewashedwithXXKgsaturatedtable

saltsolution,driedbyXXKganhydroussodiumsulfate,andthenfiltered.Thefiltrateandthe

washingstothefiltercakewereconcentratedinvacuumuntilnosolventwasobservedfromthe

rotaryevaporationbottle.

XXKgcyclohexanewaspumpedtotherotaryevaporationbottletodissolvethecrudeproduct.

XXKgsilicagel(100~200mesh)wasaddedtotherotaryevaporationbottle,anditwasstirring

for15mins.ThecyclohexanewasremovedinvacuumandleadedtoapowderofN-5andsilica

gel.Theproductwasseparatedbychromatographymethodwithsilicagel(XXKg100〜200

mesh)columnthatwashedbyXXKgethylacetate.

Afterethylacetatewasbeingremovedinvacuum,afurtherdistillationforXX±0.5hwas

neededtogivethe***N-5.Thepuritytestfollowedthemethodologyin3.2.S.2.4-Controlof

CriticalStepsandIntermediates.Theexpectedyieldswas90.0%^100.0%.

Step2:Oxidationprocess,thesynthesisof***N-6

ReactionMaterialMolar

Ratio(w/w)Mass

operationNameratio

Oxidation

***N-511.001.525Kga

reaction

Dess-MartinperiodinaneXXXXxxKg

DichloromethaneXXXXXXKg

4-Dimethylaminopyridine--xxKg

Dichloromethane-xxKg(x+x)

Quenching&xxKg

Drinkingwater--

extraction(xx+x)

Saturatedsaltsolution--XXKg

Sodiumsulfite-XXxxKg

Sodiumbicarbonate-XXxKg

Dichloromethane--xKg

Anhydroussodiumsulfate-XXxKg

a***N-51.525Kgwasestimationvalueandtheexactvaluewasdecidedbycondensationreaction

product.

XKgdichloromethaneandXXKgdess-martinperiodinanewereaddedtoareactor,andthen

N2protectionwasopened.Thereactorwasstirringuntilauniformdispersionwasformed.XXKg

dichloromethanewaspumpedtotherotaryevaporationbottlecontaining***N-5(1.525Kgfrom

thecondensationprocess)todissolvethe***N-5,andthenthesolutionwasaddedintothe

reactorcontainingdess-martinperiodinane.ThereactionwasstirringuntilrefluxingforXX±lh

atXX±5℃.

XXkgdrinkingwaterandXXKgsaturatedsaltsolutionwaspumpedtoanotherreactor,and

thenXXKgsodiumsulfiteandXXKgsodiumbicarbonatewereaddedintothereactor.Thereactor

wasstirringuntilasolutionwasformedatXX±5℃.ThereactionsolutionatXX±5℃inthefirst

reactorwaspumpedtothesecondreactor,andthefirstreactorwaswashedbymoderate

dichloromethane.Themixturewasstirredsequentially.Afterastandingandlayeringprocess,the

aboveaqueouslayerwasextractedoncebyXXgdichloromethane.Thecombinedorganiclayers

werewashedwithXXKgdrinkingwater,driedbyXXKganhydroussodiumsulfate,andthen

stin-edandfiltered.

Thefiltrateandthewashingstothefiltercakewereconcentratedundernormalpressureuntilno

solventwasobservedfromtherotaryevaporationbottle.Andtherotaryevaporationprocess

continuedforfurtherXX±0.5htogivethe***N-6.Thepuritytestfollowedthemethodologyin

3.2.S.2.4-ControlofCriticalStepsandIntermediates.Theexpectedyieldswas90.0%^100.0%.

Step3:Methylenationprocess,thesynthesisof***N-7

ReactionMaterialMolar

Ratio(w/w)Mass

operationNameratio

Methylenation

***N-611.001.445Kga

reaction

NystedregentXXXXxxKg

xxKg

Cyclohexane--

(xx+x)

TitaniumtetrachlorideXXXXXKg

Quenching&

Sodiumbicarbonateb-XxxKg

extraction

Drinkingwater--xxKg

TetrahydrofuranrxxKg(xx+x)

Diatomite-XxKg

Saturatedsaltsolution-hxxKg

Anhydroussodiumsulfate-XXxxKg

Purificationby

SilicagelforcolumnXX

column--

chromatographyKg(x+xx)

chromatography

Ethylacetate-〜xxKgc

Cyclohexane•*〜xxKg,

a***N-61.445Kgwasestimationvalueandtheexactvaluewasdecidedbyoxidationreaction

product.

bwasaddedintowatertoprepareaqueoussolution,andthesolutionwasusedtowashtheproduct

aftermethylenationreaction(toquenchthereaction)

cwasusedastheelutionsolventforchromatographyseparation,xxKgwasestimationvalueand

theexactvaluewasdecidedbychromatographycondition.

XXKgNystedregentwasaddedtothereactor,andthenXXKgcyclohexanewaspumpedinto

thesamereactoratXX±5℃.XXKgtitaniumtetrachloridewasdroppedtothereactoratXX±5℃.

XXKgcyclohexanewaspumpedtotherotaryevaporationbottlecontaining***N-6(1.445Kg

fromtheoxidizedprocess)todissolvethe***N-6,andthenthesolutionwasdroppedintothe

reactorcontainingnystedregent.ThereactionwasstirringforXX±0.5hafterdropping.

Thepreparedsodiumbicarbonateaqueoussolution(XKgsodiumbicarbonatedissolvedin

XXKgdrinkingwater),andthenXKgletrahydrofuranwereaddedtothesecondreactor.The

reactionsolutioninthefirstreactorwaspumpedtothesecondreactor,andthefirstreactorwas

washedbymoderatetetrahydrofuran.Themixturewasstirredsequentially.Afterstoppingstirring,

themixturewasfilteredbyfilterwithXXKgtileddiatomite.Thefilteredcakewaswashedby

moderatetetrahydrofuran.Thefilteredandwashingsolutionwerecombinedforastandingand

layeringprocess.ThebelowaqueouslayerwasextractedoncebyXXgtetrahydrofuran.The

combinedorganiclayerswerewashedwithXXKgsaturatedsaltsolution,driedbyXXKg

anhydroussodiumsulfate,andthenstirredandfiltered.Thefilteredcakewaswashedbymoderate

tetrahydrofuran.Thefiltrateandthewashingstothefiltercakewereconcentratedinvacuumuntil

nosolventwasobservedfromtherotaryevaporationbottle.

XXKgcyclohexanewaspumpedtotherotaryevaporationbottletodissolvethecrudeproduct.

XXKgsilicagel(100〜200mesh)wasaddedtotherotaryevaporationbottle,anditwasstirring

for30mins.ThecyclohexanewasremovedinvacuumandleadedtoapowerofN-7andsilicagel.

Theproductwasseparatedbychromatographymethodwithsilicagel(XXKg100〜200

mesh)columnthatwashedbyXXKgethylacetate.

Aftertheethylacetatewasbeingremovedinvacuum,afurtherdistillationforXX±0.5hwas

neededtogivethe***N-7.Thepuritytestfollowedthemethodologyin3.2.S.2.4-Controlof

CriticalStepsandIntermediates.Theexpectedyieldswas80.0%〜90.0%.

Step4:Hydrolyzationprocess,thesynthesisof***N-8

ReactionMaterialMolarRatio(w/w)Mass

operationNameratio

hydrolyzation

***N・711.001.225Kga

reaction

Methanol--xxKg

Tetrahydrofuran--xxKg

ConcentratedhydrochloricacidbXXXXXKg

Drinkingwater--xxKg

Dissociation&

Sodiumhydroxidec-XxxKg

purification

Ethylacetate统XXKg

Drinkingwater--xxKg

a***N-71.225Kgwasestimationvalueandtheexactvaluewasdecidedbymethylenation

reactionproduct.

bwasaddeddrinkingwatertomakeahydrochloricacidsolutioninordertoprovideconditionfor

hydrolyzationreaction.

,wasaddeddrinkingwatertomakeasodiumhydroxidesolutioninordertoadjustthepHtox.

XXKgmethanolandXXKgtetrahydrofuranwerepumpedtotherotaryevaporationbottle

containing***N-7(1.225Kgfromthemethylenationprocess)todissolvethe***N-7,andthen

thesolutionwastransferredtoreactorandhydrochloricacidsolution(XXKgconcentrated

hydrochloricacidinXXKgdrinkingwater)wasdroppedintothereactoratXX±5℃.Thereaction

wasstirringforXX±0.5hafterdropping.

ThepHofthereactionsolutionwasadjustedtoXbythepreparedsodiumhydroxidesolution

XX±5℃.Andthen,thereactionsolutionwaspumpedintorotaryevaporationbottleinbatches.

Thesolutionwasconcentratedundernormalpressureuntilnosolventwasobservedfromthe

rotaryevaporationbottle.7Kgethylacetatewaspumpedintotherotaryevaporationbottleafter

coolingthesolution.Theliquorwastransferredtothereactoranditwasstirringforxminutesat

XX±5℃.Theliquorofreactionandwashingtothereactorwerefiltered.Thefilteredcakewas

transferredintoreactorandXXKgdrinkingwaterwaspumpedintothereactorforbeatingand

purification.Afterstirring,theliquorofbeatingandwashingtothereactorwerefiltered.

Thewetproductofthisbatchwasdriedinvacuumandprovided***N-8.Thepuritytest

followedthemethodologyin3.2.S.2.4-ControlofCriticalStepsandIntermediates.Theexpected

yieldswasxx.O%〜xx.O%.

Step5:Deprotectionprocess,thesynthesisofcrude***

ReactionMaterialMolar

Ratio(w/w)Mass

operationNameratio

Deprotection

***N-811.000.5