《塑料药包材可控添加剂及使用指南（征求意见稿）》英文版

ICS11.120

C10

SocialOrganizationStandard

T/CNPPAXXXX-20XX

ControllableAdditivesUsedinPlasticPharmaceuticalPackagingMaterials

andApplicationGuidance

（ExposureDraft）

Issuedon××××-××-××Effectiveon××××-××-×

IssuedbyChinaNationalPharmaceuticalPackagingAssociation

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TableofContents

FOREWORD......................................................................................................................................................................3

INTRODUCTION..............................................................................................................................................................4

1.SCOPE........................................................................................................................................................................6

2.NORMATIVEREFERENCES................................................................................................................................6

3.TERMINOLOGY.......................................................................................................................................................6

4.CLASSIFICATIONOFADDITIVESUSEDINPLASTICPHARMACEUTICALPACKAGING

MATERIALS.......................................................................................................................................................................7

5.LISTANDAPPLICATIONOFCONTROLLABLEADDITIVESFORPLASTICPHARMACEUTICAL

PACKAGINGMATERIALS.............................................................................................................................................8

5.1GENERALRULESFORCONTROLLABLEADDITIVESLISTOFPLASTICPHARMACEUTICALPACKAGING

MATERIALS..........................................................................................................................................................................................8

5.2BASICPRINCIPLESFORTHEUSEOFCONTROLLABLEADDITIVESFORPLASTICPHARMACEUTICAL

PACKAGINGMATERIALS...................................................................................................................................................................8

5.3REGULATIONSONTHEUSEOFCONTROLLABLEADDITIVESFORPLASTICPHARMACEUTICALPACKAGING

MATERIALS..........................................................................................................................................................................................9

6.FURTHERAPPLICATIONCONSIDERATIONOFADDITIVESFORPLASTICPHARMACEUTICAL

PACKAGINGMATERIALS.............................................................................................................................................9

REFERENCE...................................................................................................................................................................43

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Foreword

ThisstandardisdraftedinaccordancewiththeruleslistedinGB/T1.1-2020Directivesfor

standardization-Part1:Rulesforthestructureanddraftingofstandardizingdocuments.

Pleasebeawarethatsomecontentsinthisstandardmaybepatentable.ChinaNational

PharmaceuticalPackagingAssociationshallnotbeheldresponsibilityforidentifyingpatentrights.

ThisstandardwasproposedbyandisunderthejurisdictionofChinaNationalPharmaceutical

PackagingAssociation.

Unitsparticipatinginthedraftingofthestandards:

Maindraftersofthestandard:

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Introduction

Plasticadditivesarechemicalsubstancesthatareintentionallyaddedtoplasticmaterialstoachieve

aphysicalorchemicaleffectduringprocessingoftheplasticorinthefinalmaterialorcontainer.They

mayconsistofasinglechemicalsubstance,apolymericsubstanceoradefinedmixtureofdifferent.

Thetypesandamountsofplasticadditivesdirectlyaffectthemedicine’squalityandthepatient’ssafety.

Annex4oftheStateFoodandDrugAdministration[2012]No.267TechnicalGuidelineforResearch

onCompatibilityofChemicalInjectionandPlasticPackagingMaterials(Trial)liststhecommonlyused

additivesininjectionpackagingforpolyethyleneandpolypropyleneplasticsandtheadditives

permittedcontentinplastics.ChinaNationalStandardGB9685-2016NationalFoodSafetyStandard:

StandardfortheUseofAdditivesinFoodContactMaterialsandArticlesandtherelated

announcementslisttheallowableadditiveswiththeiruserequirementsthatcanbeusedinfood

contactplasticmaterialsandtheirproducts.Atpresent,thereisnocompletelistanduserequirements

ofadditivesforplasticpharmaceuticalpackagingmaterialsinChina.

EuropeanPharmacopoeia(EP)seriesgeneralchapter3.1materialsusedforthemanufactureof

containerslist48additivesandtheirmaximumpermittedcontentusedin7plasticmaterials,27of

whichareEuropeanPharmacopoeiaPlasticAdditivesasdescribedingeneralchapter3.1.13.EP

GeneralChaptersrequirethatunlessotherwisejustifiedandauthorized,additivesarechosenfrom

thelist,andmeetthelimitrequirementspecifiedforeachsubstance.UnitedStatesPharmacopoeia

(USP)GeneralChapter<661.1>PlasticAdditivesforPlasticComponentMaterialslists27additives

andlimitrequirementsfor9plasticmaterials.Theseadditivesinformationareimportantreferencesfor

appendixAofthisstandard.

Thisstandardintroducesthecommonlyusedadditivesforplasticpharmaceuticalpackagingmaterials,

summarizestheadditivesandusagelimitationforplasticpharmaceuticalpackagingmaterials

recordedindomesticandforeignpharmacopoeias,andpartiallyadoptsfoodcontactmaterialsand

productadditivesfororalpreparations.Theadditiveslistedinthisstandardareconsistentwiththe

CDE"TechnicalGuidelineforResearchonCompatibilityofChemicalInjectionandPlasticPackaging

Materials(Trial)",andamorecompleteadditivesanduserequirementsforplasticpharmaceutical

packagingmaterialsislistedwiththereferenceofdomesticfoodstandardsanddomesticandforeign

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pharmacopoeiastandards.Thisstandardprovidesguidancefortheapplicationofadditivesforplastic

pharmaceuticalpackagingmaterials.

Safetyistheprimaryconditionforselectingadditivesforplasticpharmaceuticalpackagingmaterials.

Theassessmentisdescribedinthefurtherapplicationconsiderationsofadditivesforplastic

pharmaceuticalpackagingmaterialsinChapter6ofthisstandard.Thisstandardisusedtoguide

packagingmaterialmanufacturerstoselectthetypesandusecontentsofadditivesforplastic

pharmaceuticalpackagingmaterials.Themaximumpermittedcontentisthemaximumallowableuse

content.Ifacompatibilitystudyisrequired,themaximumpermittedcontentcannotreplacethe

compatibilitystudy.

Thisstandardmaynotcoveralladditivesusedinplasticpharmaceuticalpackagingmaterials,andwith

thecontinuousdevelopmentofscienceandtechnology,additivesnotincludedinthelistmaywillbe

used,andtherelevantcontentofthisstandardwillalsobeadjustedappropriately.Thisstandard

doesn’tincludetheadministrativematterofregistrationandapproval,soitmustnotbereferredasa

regulationandshouldbeusedonthepremiseofrelevantregulations.

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ControllableAdditivesUsedinPlasticPharmaceuticalPackaging

MaterialsandApplicationGuidance

1.Scope

Thisstandardprovidesthebasicinformation,controllablelistanduserequirementsofadditivesused

inplasticpharmaceuticalpackagingmaterials.

Thecontrollablelistoftheadditivesincludedinthisstandardisasummaryoftheadditivesusedin

plastics,whicharespecifiedinthemainregulatorydocumentsathomeandabroad.

Thisstandardprovidesusemethodofadditivesusedinpharmaceuticalpackagingmaterialsfor

pharmaceuticalpackagingmaterialsmanufacturingenterprises.Theplasticmaterialsinclude

polyethylene(PE),polypropylene(PP),polyethyleneterephthalate(PET),polycarbonate(PC),cyclic

olefins(COC,COP,etc.),polyvinylchloride(PVC),polyvinylidenechloride(PVDC),poly(ethylene-

vinylacetate)(EVA),polyamide(nylonPA),etc.,andthecompositematerialsformedbycompounding

ofthematerials.Thisstandardisareferenceforpreparationenterprises.

2.Normativereferences

Thefollowingdocumentsareessentialfortheapplicationofthisstandard.Forreferencedocuments

withreferencedates,onlytheversionofthereferencedateappliestothisstandard.Thelatestversion

(includingallamendments)ofanyreferencedocumentwithnodatesalsoappliestothisstandard.

GB9685-2016NationalStandardsforFoodSafety:StandardfortheUseofAdditivesinFoodContact

MaterialsandArticles

NMPA-I-[2012]No.267TechnicalGuidelineforResearchonCompatibilityofChemicalInjectionand

PlasticPackagingMaterials(Trial)

3.Terminology

Thefollowingtermsanddefinitionsareapplicabletothisdocument.

3.1Plasticadditives

Chemicalsubstancesthatareintentionallyaddedtoplasticmaterialstoachieveaphysicalorchemical

effectduringprocessingoftheplasticorinthefinalmaterialorcontainer.Theymayconsistofasingle

chemicalsubstance,apolymericsubstanceoradefinedmixtureofdifferent.(EP11generalchapter

3.1.13)

3.2Maximumpermittedcontent

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Themaximumpermittedquantityofacertainadditiveoracertainclassofadditivesaddedduringthe

productionofaplasticpharmaceuticalpackagingmaterials,expressedasamassfraction(%).

4.Classificationofadditivesusedinplasticpharmaceuticalpackagingmaterials

Dependingontheintendeduseofamaterial,theymaycontainadditivestooptimizetheirprocessing

ortheirchemical,physicalandmechanicalproperties.Substancespresentthathavenotbeenadded

intentionallyareconsideredtobeimpuritiesandincludereactionanddegradationproducts,which

maybelimitedbyasuitablespecification.

Typesofadditivescommonlyusedinplasticpharmaceuticalpackagingmaterialsmainlyinclude

antioxidants,lightstabilizers,heatstabilizers,plasticizers,antistaticagents,colorants,processaids

andothers(suchasnucleatingagents,impactmodifiers)etc.

Antioxidantsandlightstabilizers:plasticaidsthatareaddedtoplasticmaterialstoeffectivelyinhibit

orreducethethermaloxidationandlightoxidationreactionrateofplasticmacromolecules,

significantlyimprovetheheatresistanceandlightresistanceofplasticmaterials,delaythedegradation

andagingprocessofplasticmaterials,andprolongtheservicelifeofplasticproducts.

Heatstabilizers:aidsaddedtopreventplasticsfromdegradingduetoheatduringhigh-temperature

processing,whichismainlyusedinPVC.

Plasticizers:aclassoffinechemicalproductsthatcanincreasetheplasticityofapolymersystem.

It’sthemostimportantadditiveusedduringprocessingofpolymermaterials,especiallyofPVCplastics,

toenhancetheflexibilityandfacilitateprocessing.

Antistaticagents:chemicalsthatreducethesurfaceresistanceofplasticobjectsandevacuatethe

surfacechargeofobjects.Withhighsurfaceresistivityandlowpermittivity,theplasticsurfaceis

inclinedtohavechargeaccumulatedandthereforeantistaticagentsareneededtosolvetheproblem

causedbystaticelectricity.

Colorants:additivesthatcanchangethecolorofplasticsintovariouscolorssuchaswhite,yellow,

green,blue,red,black,etc.Colorantscanbeclassifiedintotwocategoriesaccordingtothedifferent

physicalproperties:pigmentsthatareinsolubleinthemediumusedanddyesthataresolubleinthe

mediumused.

Processingaids:usuallyrefertoadditivesusedtoimprovetheprocessingperformanceofplastics.

Theymainlytakeeffectwhenthepolymersubstrateismolten,includingcompoundsthatreducethe

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viscosityofthemoltenobjectwithoutincreasingthequantityoftheplasticizer(viscosityinhibitors),

compoundsthatofferadditionalstabilitybyincreasingtheinternaladhesionoftheheterogeneous

systemoremulsion(emulsifiers/surfactants),oranaidthatofferslubricationduringprocessing(slip

agents),etc.

5.Listandapplicationofcontrollableadditivesforplasticpharmaceuticalpackagingmaterials

5.1Generalrulesforcontrollableadditiveslistofplasticpharmaceuticalpackagingmaterials

1)ThelistofadditivesinthisstandardreferstotheTechnicalGuidelineforResearchonCompatibility

ofChemicalInjectionandPlasticPackagingMaterials(Trial),relevantgeneralrulesofpharmacopoeias

athomeandabroadandrelevantstandardsindomesticfoodfield.Fordetailedinformation,please

refertoAppendixA,ControllableAdditivesUsedinPlasticPharmaceuticalPackagingMaterials

andApplicationRequirements,includingcontrollableadditivesforplasticpharmaceuticalpackaging

materials,maximumpermittedcontentandappliedplasticmaterials,examplesofgeneralapplication

scenarios,etc.Thegeneralapplicationscenariosofadditivesarenotalldescribedinthereferenced

additivedocuments,seeAppendixA.6ofthisstandardfordetails.

2)AppendixAisasummaryofprioriknowledge,whichprovidesreferenceforpharmaceutical

packagingmaterialsmanufacturingenterprisestochoosethetypesandusecontentsofadditives.

Choosingsuitableadditivesforplasticpharmaceuticalpackagingmaterialsandmeetingthe

requirementsofdosagesprovideareasonablebasisforselectingmaterialswhendesigningpackaging

systemsandminimizestheriskofsystematicinapplicabilitycausedbymaterialadditives.

3)TheadditiveslistedinAppendixAarewidelyusedintheindustry.Withthedevelopmentofscience

andtheapplicationofnewadditives,thecontentofAppendixAcanbeadjustedappropriately.

5.2Basicprinciplesfortheuseofcontrollableadditivesforplasticpharmaceuticalpackaging

materials

Plasticpharmaceuticalpackagingmaterialscontainadditivestoachievecertainprocessing,physical,

chemicalandmechanicaleffects.However,duetotheparticularityofdrugsandthediversityofdosage

formsandformulations,theuseofadditivesofplasticpharmaceuticalpackagingmaterialsshouldat

leastfollowthefollowingbasicprinciples:

1)Whenplasticpharmaceuticalpackagingmaterialscontactwithdrugsundertherecommended

conditionsofuse,thelevelsofadditivesandimpuritiesmigratedtodrugsshouldnotendangerhuman

health.

2)Thecontentofadditivesinplasticpharmaceuticalpackagingmaterialsshouldbereducedasmuch

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aspossibleundertheexpectedeffect,whilethestabilityandqualityofthefinalmaterialsand

containersshouldbeensured.

3)Additivestobeusedshouldconformtothecorrespondingqualityspecifications,theacceptable

criteriaforidentification,physicalandchemicalproperties,impuritiesandassayshouldbespecified.

4)WhenthesubstanceslistedinAppendixAareallowedtobeusedasadditivesforplastic

pharmaceuticalpackagingmaterials,theyshouldnotproducetechnicalfunctionsforthedrugs

themselves.

5.3Regulationsontheuseofcontrollableadditivesforplasticpharmaceuticalpackaging

materials

1)Theuseofadditivesforplasticpharmaceuticalpackagingmaterialsshouldcomplywiththe

provisionsofAppendixA

2)Unlessthereisareasonableexplanationorregulatoryapproval,theadditiveslistedinAppendixA

shouldbepreferredforplasticmaterials,andthecorrespondinguserequirementsshouldbemet.

3)ThelimitinAppendixAreferstothemaximumpermittedcontentofoneoraclassofadditives

containedinplasticpharmaceuticalpackagingmaterials,whichprovidesreferencefortheselectionof

additives.InAppendixA,nomorethan3kindsofantioxidantsshouldbeaddedtoeachplasticresin,

andthetotalamountshouldnotexceed0.3%.

4)UsingtheadditivesinAppendixAandmeetingthemaximumpermittedcontentrequirementsdoes

notnecessarilymeansafety.Itshouldbebasedontherisklevelofthepackageddrugs,andfurther

evaluationofadditivesmayberequiredaccordingtotheprinciplesinChapter6.Ifacompatibilitystudy

isrequired,themaximumpermittedcontentcannotreplacethecompatibilitystudy.

6.Furtherapplicationconsiderationofadditivesforplasticpharmaceuticalpackaging

materials

Inadditiontomeetingtherequirementsof5.2and5.3ofthisstandard,theselectionofadditivesfor

plasticpackagingmaterialsshouldalsoevaluatethesafetyrisks,suchasthetypeofadditives,the

maximumusecontent,monomerresidues,etc.

Safetyistheprimaryconditionforselectingadditivesforplasticpharmaceuticalpackagingmaterials.

Thesafetyevaluationofadditivesforplasticpharmaceuticalpackagingmaterialsreferstothefollowing

riskassessmentmodel.

1)Thecollectionofrelevantinformationisessentialfortheuseofadditives,whichprovidedby

suppliersorobtainedfromexperimentswhichmaterialitselfcontainsand/orbeaddedduring

processing.

2)Andthen,itshouldbeconsideredwhethertheadditiveisinthelistandwhethertheamountmeets

themaximumpermittedcontent.

3)Conductingthesafetyassessmentbasedontherisklevelofthepackageddrugs.

a)Forplasticpharmaceuticalpackagingadditivesusedinnon-high-riskpreparations,suchasoral

preparations,it‘ssuggestedtorefertotherequirementsofrelevantfoodpackagingmaterialsinvarious

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countries,suchasGB9685《StandardfortheUseofAdditivesinFoodContactMaterialsandArticles》

andrelatedannouncements,andthefeasibilityofreferringstandardsforadditivesusedinfoodin

othercountries.

b)Forplasticpharmaceuticalpackagingadditivesforhigh-riskpreparations,suchaspharmaceutical

packagingmaterialsforinhalationpreparations,injections,andophthalmicpreparations.Itisnot

necessarilysafethatadditivesinpackagingmaterialsarelistedinAppendixAandmeetthedosage

requirements.Thepackagingmaterialsmayhavebeensuffereddifferentprocessingandsterilization

treatment,sothatanadditivemayundergodifferentchemicalchangeswhenappliedtodifferent

products,suchasoxidationanddegradation.Extractable/leachablestudiesandcorresponding

toxicologicalriskassessmentsmayberequired.

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AppendixA

(Normative)

ControllableAdditivesUsedinPlasticPharmaceuticalPackagingMaterials

andApplicationRequirements

A.1:ThisappendixprovidesatabularsummaryoftheallowableadditivesforplasticslistedintheCDE

guidelines,theUnitedStatesPharmacopoeiaandtheEuropeanPharmacopoeia.Additivesshouldcomplywith

allrequirementsinthecolumnsofthetable.

A.2:TheadditivesinTableA.1aresortedbyCASnumber.TheadditiveswhichhavenoCASnumberare

listedattheendofTableA.1andsortedbythecharacters,digits,Englishletters,andthefirstletterofthe

Chinesephoneticalphabet.

A.3:TheadditivesinTableA.2aresortedaccordingtothecharacters,digits,Englishletters,andthefirstletter

oftheChinesephoneticalphabet.

A.4:ForthemaximumpermittedcontentofadditiveslistedinthecolumnCDE/USP/EPMaximumpermitted

contentofTableA.1andTableA.2,summarizethemaximumamountofaparticularorclassofadditivesthat

specifiedinTechnicalGuidelineforResearchonCompatibilityofChemicalInjectionandPlasticPackaging

Materials(Trial)(NMPA-I-[2012]No.267),USP<661.1>①andEPGeneralChapters3.1.3②、3.1.5③、3.1.6

④、3.1.7⑤、3.1.10⑥、3.1.11⑦、3.1.13⑧or3.1.14⑨.

A.5:ThetypesofplasticresinstowhichadditivescanbeappliedwerelistedinthecolumnTypesofPlastics

(①CDEGuidelines,②USP,③EP)ofTableA.1andTableA.2anddenotedbyresinabbreviations.Theresin

abbreviationmarks①②③respectivelyrepresenttheresinslistedby①TechnicalGuidelineforResearchon

CompatibilityofChemicalInjectionandPlasticPackagingMaterials(Trial)(NMPA-I-[2012]No.267),②USP

generalchapter<661.1>and③EPmaterialrelatedgeneralchapters.

A.6：ThechapternumberandspecifiedapplicationscenariosofadditivesinUSPandEPwerelistedinthe

columnExamplesofGeneralApplicationScenarios.USP:661.1(Unrestricted)referstotheapplication

scenariosofplasticadditivesnotrestrictedbyUSP661.1,EP:3.1.13(UnrestrictedPlasticadditives)refersto

theplasticmaterialsandapplicationscenariosnotrestrictedbyEP3.1.13,EP3.1.3(unrestrictedpolyolefin)

referstotheapplicationscenariosinpolyolefinnotrestrictedbyEP3.1.3,andotherapplicationscenariosare

describedinTableA.1andTableA.2.TheplasticadditivesincludedinCDETechnicalGuidelinefor

ResearchonCompatibilityofChemicalInjectionandPlasticPackagingMaterials(Trial)(NMPA-I-[2012]

No.267)areapplicabletopolyethyleneandpolypropyleneplastics,soit’snotlistedinthetableduplicately.

A.7:ThenamesofadditivesinTablesA.1andA.2complywiththeUnitedStatesPharmacopoeiaand/orthe

EuropeanPharmacopoeia.Someadditivesthatmaycontaindifferentdesignations,theCASnumbershall

prevail.

A.8:SomeadditivesmayhavemorethanoneCASnumberduetoisomersordifferentproportionsof

ingredients.AdditiveswithmultipleChinesenamesaredistinguishedaccordingtoCASnumber,which

withoutCASnumberaredistinguishedaccordingtoChinesename.

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A.9：Eachresinmaycontainatmost3antioxidants,andthetotalofantioxidantadditivesdoesnotexceed0.3

percent.

Note:

①USP661.1PlasticMaterialsofConstruction

②EP3.1.3Polyolefin

③EP3.1.5PolyethylenewithAdditivesforContainersforParenteralPreparationsandforOphthalmic

Preparations

④EP3.1.6PolypropyleneforContainersandClosuresforParenteralPreparationsandOphthalmicPreparations

⑤EP3.1.7Poly(ethylene-vinylacetate)forcontainersandtubingfortotalparenteralnutritionpreparations

⑥EP3.1.10MaterialsBasedonNon-plasticisedPoly(vinylchloride)forContainersforNon-injectable

AqueousSolutions

⑦EP3.1.11.MaterialsBasedonNon-plasticisedPoly(vinylchloride)forContainersforSolidDosageForms

forOralAdministration

⑧EP3.1.13PlasticAdditives

⑨EP3.1.14MaterialsBasedonPlasticisedPoly(vinylchloride)forContainersforAqueousSolutionsfor

IntravenousInfusion

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TableA.1ControllableAdditivesUsedinPlasticPharmaceuticalPackagingMaterials

andApplicationRequirementsSortedbyCASNumber

TypesofPlastics

AdditivesCDE/USP/EPMaximumExamplesofGeneralApplication

CASNo.Name(CDEguidelines,

NO.PermittedContentScenarios

USP,EP)

Non-plasticisedUSP:661.1(Unrestricted),

PVC②③EP:3.1.10(Materialsbasedonnon-

plasticisedpoly(vinylchloride)for

USP/EP:Notmorethancontainersfornon-injectable,aqueous

1[50-70-4]Sorbitol