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HealthSantéCanadaCanadaOurMandate:Topromotegoodnutritionandinformeduseofdrugs,food,medicaldevicesandnaturalhealthproducts,andtomaximizethesafetyandefficacyofdrugs,food,naturalhealthproducts,medicaldevices,biologicsandrelatedbiotechnologyproductsintheCanadianmarketplaceandhealthsystem.
HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)GuidelinesforActivePharmaceuticalIngredients(APIs)GUI-0104Supersedes:NewDocumentDateissued:December6th,2013DateofImplementation:November8th,2013DisclaimerThisdocumentdoesnotconstitutepartoftheFoodandDrugsAct(Act)oritsassociatedRegulationsandintheeventofanyinconsistencyorconflictbetweenthatActorRegulationsandthisdocument,theActortheRegulationstakeprecedence.
ThisdocumentisanadministrativedocumentthatisintendedtofacilitatecompliancebytheregulatedpartywiththeAct,theRegulationsandtheapplicableadministrativepolicies.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final2TableofContents1.
Introduction42.
Purpose.
43.
Scope.
44.
QualityManagement74.
1GuidingPrinciple74.
2RelationshipamongQualityElements84.
2.
1QualityAssurance.
84.
2.
2GoodManufacturingPracticesforAPIs.
94.
2.
3QualityControl.
105.
InterpretationofRegulations.
10Division2–GoodManufacturingPractices.
10C.
02.
00210C.
02.
002.
111Sale11C.
02.
00311C.
02.
003.
111C.
02.
003.
211UseinFabrication.
11C.
02.
003.
311Premises.
12C.
02.
00412Equipment.
14C.
02.
00514Personnel16C.
02.
00616Sanitation.
19C.
02.
00719C.
02.
00821RawMaterialTesting.
22C.
02.
00922C.
02.
01024ManufacturingControl26C.
02.
01126C.
02.
01235QualityControlDepartment39C.
02.
01339C.
02.
01439C.
02.
01542PackagingMaterialTesting48C.
02.
01648C.
02.
01748FinishedProductTesting51C.
02.
01851C.
02.
01953Records54C.
02.
02054C.
02.
02155C.
02.
02255C.
02.
02356C.
02.
02456C.
02.
024.
157Samples.
63HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3C.
02.
02563C.
02.
02663Stability.
64C.
02.
02764C.
02.
02865SterileProducts.
66C.
02.
02967MedicalGases.
67C.
02.
03067AppendixA68Acronyms.
68AppendixB.
68GlossaryofTerms.
68AppendixC.
77ICHQ7Guideline:Section18-SpecificGuidanceforAPIsManufacturedbyCellCulture/Fermentation.
77AppendixD80ICHQ7Guideline:Section19–APIsforUseinClinicalTrials80AppendixE.
82AnnexestotheCurrentEditionoftheseAPIGMPGuidelines.
82References.
83AppendixF.
85Cross-walkbetweenICHQ7andGUI-0001documents.
851.
IntroductionActivePharmaceuticalIngredients(API)andintermediatesforpharmaceuticaluse(i.
e.
pharmaceutical,radiopharmaceutical,andbiological)andthoseusedtomanufacturedrugsforclinicaltrialsareregulatedundertheDivisions1Aand2,PartCoftheFoodandDrugRegulations.
Division1A,PartCoftheFoodandDrugRegulationsdefinesactivitiesforwhichGoodManufacturingPractices(GMP)complianceisrequiredandmustbedemonstratedpriortotheissuanceofanAPIestablishmentlicence(EL).
Division2,PartCoftheFoodandDrugRegulationsdefinestherequirementsfortheGMPofAPIsandAPIintermediates,whichareinterpretedinthepresentguidancedocument.
TheseGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)guidelines,GUI-0104,aredesignedtofacilitatecompliancebytheregulatedindustryandtoenhanceconsistencyintheapplicationoftheregulatoryrequirements.
Itshouldbenotedthattheseguidelinesdonotcoversafetyaspectsforthepersonnelengagedinthefabrication,packaging/labelling,andtestingofAPIsandintermediates,oraspectsofprotectionoftheenvironment.
ThesecontrolsareinherentresponsibilitiesoftheAPIfabricator,packager/labellerandtester.
Inadditiontothepresentguidelines,alistoffurtherguidanceinspecificareasrelatedtoAPIsandAPIintermediatesisprovidedinAppendixCofthisdocument.
AlthoughthedefinitionofactiveingredientsinDivision2,PartCoftheFoodandDrugRegulationsincludesAPIsandbulkprocessintermediates(BPI),thepresentGUI-0104onlyappliestoAPIs.
Guidanceonthefabrication,packaging/labelling,testing,distribution,wholesaling,andimportationofdrugsindosageform,andBPIsforradiopharmaceuticalandbiologicaldrugsisprovidedintheGoodManufacturingPracticesGuidelines,2009Edition,Version2(GUI-0001).
Guidanceregardingthefabrication,packaging/labelling,testing,distribution,andimportationofmedicalgasesisprovidedintheGoodManufacturingPracticesforMedicalGases(GUI-0031).
ThecontentofthisdocumentshouldnotberegardedastheonlyinterpretationoftheGMPRegulations,nordoesitintendtocovereveryconceivablecase.
AlternativemeansofcomplyingwiththeseRegulationscanbeconsideredwiththeappropriatescientificjustification.
Differentapproachesmaybecalledforasnewtechnologiesemerge.
ThisdocumenthasbeenwrittenwithaviewtoharmonizewithGMPstandardsfromothercountriesandwiththoseofthePharmaceuticalInspectionCooperation/Scheme(PIC/S),andtheInternationalConferenceonHarmonisation(ICH).
2.
PurposeThepurposeofthisguide,GUI-0104,istoprovideinterpretiveguidanceforPartC,Division2,oftheFoodandDrugRegulationsforthemanufactureofAPIs(includingtheirintermediates).
Theseguidelinesaredesignedtofacilitatecompliancebytheregulatedindustryandtoenhanceconsistencyintheapplicationoftheregulatoryrequirements.
ItisalsointendedtohelpensurethatAPIsmeettherequirementsforqualityandpuritythattheypurportorarerepresentedtopossess.
3.
ScopeThefocusoftheseguidelinesisonthemanufactureofAPIssoldintheirfinallabelledcontainerand/orusedinthemanufactureoffinisheddosageformsforhumanuse.
AnyotherfurtherprocessingstepsaftertheAPIsareHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final5intheirfinallabelledcontaineraresubjecttoGUI-0001.
Morespecifically,theyapplytothefabrication,packaging/labelling,testing,importation,distribution,wholesale,andre-packaging/re-labellingofAPIs(includingtheirintermediates).
AgentsandbrokersofAPIswillbeconsideredtobewholesalersiftheysellAPIsasperthedefinitionof"sell"intheFoodandDrugsAct.
Whetheranagentorabrokerisactingasawholesalerwithinthemeaningoftheregulatoryschememayrequirefurtherreview/examination.
ThosewhoareinfactsellingAPIsshallcomplywiththerequirementsdefinedinDivision2,PartCoftheFoodandDrugRegulations,asapplicabletothem.
AnyregulatoryrequirementsotherthanDivision2requirementsthatappliesorappliedtoagivenactivityorproductstillapplies.
Thisguidedoesnotapplytothefollowing:vaccines,wholecells,wholebloodandplasma,bloodandplasmaderivatives(plasmafractionation),andgenetherapyAPIs.
However,itdoesincludeAPIsthatareproducedusingbloodorplasmaasrawmaterials.
cellsubstrates(mammalian,plant,insectormicrobialcells,tissueoranimalsourcesincludingtransgenicanimals)andearlyprocesssteps(althoughtheymaybesubjecttoGMP)medicalgases,bulk-packageddrug(medicinal)products,andmanufacturing/controlaspectsspecifictoradiopharmaceuticals.
medicaldevices,includingmedicaldevicesclassifiedascombinationproductswheretheprimarymodeofactionisamedicaldevice.
veterinarydrugsnaturalhealthproductsAlthoughBPIaredefinedasactiveingredientsinsubsectionC.
01A.
001(1)ofDivision1AintheFoodandDrugRegulations,thepresentguidedoesnotapplytoBPIs.
ForfurtherguidanceonthemanufactureofBPIs,pleaserefertotheAnnex3totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-ScheduleCDrugs(GUI-0026)andAnnex2totheCurrentEditionoftheGoodManufacturingPracticesGuidelinesScheduleDDrugs(BiologicalDrugs)(GUI-0027).
HealthCanadaconsidersfabrication,packaging/labeling,andtestingofsterileAPIsnotterminallysterilizedasbeingfinisheddosageformmanufactureandtherefore,theseguidelinesonlyapplytothemanufactureofsterileAPIsuptothepointimmediatelypriortotheAPIsbeingrenderedsterile.
ThesterilizationandasepticprocessingofsterileAPIsarenotcoveredbythisguidance,butshouldbeperformedinaccordancewiththeGoodManufacturingPracticesGuidelines,Edition2009,Version2(GUI-0001).
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final6Table1:GMPRegulations(Division2)ApplicabletoAPIActivities11.
ThefollowingarelicensableactivitiesasperDivision1A,PartCoftheFoodandDrugRegulations:fabrication,packaging/labelling,testingandimportationofAPIs.
2.
F:Fabricator,P/L:Packager/Labeller,T:Tester,I:Importer,D:Distributor,W:Wholesaler3.
ItshouldbenotedthatasperthenewdefinitionofwholesaleasstatedinDivision1A,PartCoftheFoodandDrugRegulations,agentsandbrokersareconsideredwholesalersandthusshouldcomplywithHealthCanada'sGMPregulatoryrequirements.
√RegulatorySectionappliestotheAPIactivity*Whereapplicabledependingonthenatureoftheactivities.
ThepointatwhichproductionoftheAPIbeginsandfromwhichcompliancetoGMPsshouldbeimplementedshouldbebasedontheapplicationfiledwithHealthCanada,whereapplicable,and/orothercriteriaincludingthebelowTable2.
WhetherornotallstepsofatypeofmanufacturingasshowninTable1arecompleted,thepresentguidelinesapplytothestepsshowninblue.
ThestringencyofGMPsinAPImanufacturingshouldincreaseastheprocessproceedsfromearlyAPIstepstofinalsteps,purification,andpackaging.
SectionRegulationF2P/LTIDW3PremisesC.
02.
004EquipmentC.
02.
005√√√PersonnelC.
02.
006SanitationC.
02.
007√√C.
02.
008√√RawMaterialTestingC.
02.
009√*C.
02.
010√*ManufacturingControlC.
02.
011√√√C.
02.
012QualityControlC.
02.
013C.
02.
014C.
02.
015PackagingMaterialTestingC.
02.
016√√C.
02.
017√√FinishedProductTestingC.
02.
018C.
02.
019√RecordsC.
02.
020√√√√C.
02.
021C.
02.
022√√√C.
02.
023C.
02.
024C.
02.
024.
1SamplesC.
02.
025√C.
02.
026√StabilityC.
02.
027√*√C.
02.
028√*√HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final7Table24:ApplicationofGUI-0104toAPIManufacturingTypeofmanufacturingManufacturingStepsa12345ChemicalManufacturingProductionoftheAPIStartingMaterialIntroductionoftheAPIStartingMaterialintoprocessbProductionofIntermediate(s)bIsolationandpurificationbPhysicalprocessing,andpackagingbAPIderivedfromanimalsourcesCollectionoforgan,fluid,ortissueCutting,mixing,and/orinitialprocessingIntroductionoftheAPIStartingMaterialintoprocessbIsolationandpurificationbPhysicalprocessing,andpackagingbAPIextractedfromplantsourcesCollectionofplantsCuttingandinitialextraction(s)IntroductionoftheAPIStartingMaterialintoprocessbIsolationandpurificationbPhysicalprocessing,andpackagingbHerbalextractsusedasAPICollectionofplantsCuttingandinitialextractionFurtherextractionbPhysicalprocessing,andpackagingbAPIconsistingofcomminutedorpowderedherbsCollectionofplantsand/orcultivationandharvestingCutting/comminutingPhysicalprocessing,andpackagingbBiotechnology:fermentation/cellcultureEstablishmentofmastercellbankandworkingcellbankMaintenanceofworkingcellbankbCellcultureand/orfermentationbIsolationandpurificationbPhysicalprocessing,andpackagingb"Classical"FermentationtoproduceanAPIEstablishmentofcellbankMaintenanceofthecellbankIntroductionofthecellsintofermentationbIsolationandpurificationbPhysicalprocessing,andpackagingb4.
ThistableisfromtheInternationalConferenceonHarmonizationGoodManufacturingPracticeGuideforActivePharmaceuticalIngredientsQ7,November2000.
ThistablediffersfromtheoriginaltablebutonlyinformatandnotincontentinordertomeettherequirementsoftheStandardonWebAccessibility(http://www.
tbs-sct.
gc.
ca/ws-nw/wa-aw/index-eng.
asp).
aTheGMPrequirementsincreaseincolumnsfromlefttoright.
bGUI-0104appliestothisstepusedinthistypeofmanufacturing.
4.
QualityManagement4.
1GuidingPrincipleTheholderofanestablishmentlicence,oranyactivitytowhichtherequirementsofDivision2PartCoftheFoodandDrugRegulationsareapplicable,mustensurethatthefabrication,packaging,labelling,testing,importation,distribution,andwholesalingofAPIscomplywiththeserequirementsandasperapprovedspecificationsinthemarketingauthorizationofthedrugindosageform,anddonotplaceconsumersatriskduetoinadequatesafetyandquality.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final8Theattainmentofthisqualityobjectiveistheresponsibilityofseniormanagementandrequirestheparticipationandcommitmentofpersonnelinmanydifferentdepartmentsandatalllevelswithintheestablishmentanditssuppliers.
Toensurecompliance,theremustbeacomprehensivelydesignedandcorrectlyimplementedqualitymanagementsystemthatincorporatesGMP,qualityassuranceandcontrol,lifecycleandriskmanagementasappropriatesuchastheorganisationalstructure,procedures,processesandresources,aswellasactivitiesnecessarytoensureconfidencethattheAPIwillmeetitsintendedspecificationsforqualityandpurity.
Thequalitymanagementsystemincludingallqualityrelatedactivitiesshouldbedefinedandfullydocumented,anditseffectivenessmonitored.
4.
2RelationshipamongQualityElementsThebasicconceptsofqualityassurance,GMP,andqualitycontrolareinter-related.
TheyaredescribedhereinordertoemphasizetheirrelationshipsandtheirfundamentalimportancetotheproductionandcontrolofAPIs.
4.
2.
1QualityAssuranceQualityassuranceisawide-rangingconceptthatcoversallmattersthatindividuallyorcollectivelyinfluencethequalityofanAPI.
ItisthetotaloftheorganizedarrangementsmadewiththeobjectiveofensuringthatAPIsareofthequalityrequiredfortheirintendeduse.
QualityassurancethereforeincorporatesGMP,alongwithotherfactorsthatareoutsidethescopeoftheseguidelines.
Asystemofqualityassuranceappropriateforthefabrication,packaging,labelling,testing,distribution,importation,andwholesaleofAPIsshouldensurethat:1.
APIsaredesignedanddevelopedinawaythattakesintoaccounttheGMPrequirements;2.
Eachfabricatorshouldestablish,document,andimplementaneffectivesystemformanagingqualitythatinvolvestheactiveparticipationofmanagementandappropriatemanufacturingpersonnel.
Managerialresponsibilitiesshouldbeclearlyspecified;3.
Systems,facilitiesandproceduresareadequateandqualified,whethertheyarenewormodified;4.
Productionandcontroloperationsareclearlyspecified;5.
Analyticalmethodsandcriticalprocessesarevalidated;6.
Arrangementsaremadeforthesupplyanduseofthecorrectrawandpackagingmaterials;7.
AllnecessarycontrolonAPIsandanyotherin-processmonitoringiscarriedout;8.
OutsourcedactivitiesaresubjecttoappropriatecontrolsandmeetGMPrequirements;9.
Fabrication,packaging/labelling,testing,distribution,importation,andwholesalingareperformedinaccordancewithestablishedprocedures;10.
APIsarenotreleasedforsaleorforfurtherfabricationbeforetheauthorizedpersonfromthequalitycontroldepartmenthasapprovedthateachlothasbeenproducedandcontrolledinaccordancewiththeapprovedspecifications;11.
SatisfactoryarrangementsexistforensuringthattheAPIsarestored,distributed,andsubsequentlyhandledinsuchawaythatqualityismaintainedthroughouttheirexpiryorretestdate;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final912.
Thequalityriskmanagementsystemshouldensurethat:-theevaluationoftherisktoqualityisbasedonscientificknowledge,experiencewiththeprocessandultimatelylinkstotheprotectionofthepatientand-thelevelofeffort,formalityanddocumentationofthequalityriskmanagementprocessiscommensuratewiththelevelofrisk.
13.
Theeffectiveness,applicability,andcontinuousimprovementofthequalitymanagementsystemisensuredthroughregularmanagementreviewandself-inspection;14.
AnannualproductqualityreviewofallAPIsandintermediatesshouldbeconductedwiththeobjectiveofverifyingtheconsistencyoftheexistingprocess,andtoidentifyproductandprocessimprovements.
15.
Allqualityrelatedactivitiesshouldberecordedatthetimetheyareperformed.
4.
2.
2GoodManufacturingPracticesforAPIsGMParethepartofqualityassurancethatensuresthatAPIsareconsistentlyproducedandcontrolledinsuchawaytomeetthequalitystandardsappropriatetotheirintendeduse,asrequiredbytheapprovedspecificationsinthemarketauthorizationofthedrugindosageform.
GMPbasicrequirementsareasfollows:1.
Manufacturingprocessesareclearlydefinedandcontrolledtoensureconsistencyandcompliancewithapprovedspecifications;2.
Criticalstepsofmanufacturingprocessesandsignificantchangestotheprocessarevalidated;3.
AllnecessarykeyelementsforGMPareprovided,includingthefollowing:-qualifiedandtrainedpersonnel,-adequatepremisesandfacilities,-suitableequipmentandutilities,-correctmaterials,containersandlabels,-approvedproceduresandinstructions,and-suitablestorageandtransport.
4.
Instructionsandproceduresarewritteninclearandunambiguouslanguage;5.
Operatorsaretrainedtocarryoutanddocumentprocedures;6.
Allqualityrelatedactivitiesshouldberecordedatthetimetheyareperformed.
Anydeviationfromestablishedproceduresshouldbedocumentedandexplained.
Criticaldeviationsareinvestigatedanddocumented;7.
Recordsoffabrication,packaging,labelling,testing,distribution,importation,andwholesalingthatenablethecompletehistoryofalottobetracedareretainedinacomprehensibleandaccessibleform;8.
Controlofstorage,handling,andtransportationoftheAPIsminimizesanyrisktotheirquality;9.
AsystemisavailableforrecallingofAPIsfromsale;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final1010.
ComplaintsaboutAPIsareexamined,thecausesofqualitydefectsareinvestigated,andappropriatemeasuresaretakenwithrespecttothedefectiveAPIsandtopreventrecurrence.
4.
2.
3QualityControlQualitycontrolisthepartofGMPthatisconcernedwithsampling,specifications,testing,documentation,andreleaseprocedures.
Qualitycontrolensuresthatthenecessaryandrelevanttestsarecarriedoutandthatrawmaterials,packagingmaterials,andAPIsarereleasedforuseorsale,onlyiftheirqualityissatisfactory.
QualitycontrolisnotconfinedtolaboratoryoperationsbutmustbeincorporatedintoallactivitiesanddecisionsconcerningthequalityoftheAPI.
Thebasicrequirementsofqualitycontrolareasfollows:1.
Adequatefacilities,trainedpersonnel,andapprovedproceduresareavailableforsampling,inspectingandtestingofrawmaterials,packagingmaterials,APIs,and,whereappropriatemonitoringenvironmentalconditionsforGMPpurposes;1.
1Samplesofrawmaterials,packagingmaterials,andAPIsaretakenaccordingtoproceduresapprovedbythequalitycontroldepartment;1.
2Testmethodsarevalidated;1.
3Recordsdemonstratethatalltherequiredsampling,inspecting,andtestingprocedureswerecarriedout,andanydeviationsarerecordedandcriticaldeviationsinvestigated;1.
4Recordsaremadeoftheresultsoftheself-inspectionprogram;1.
5Theproceduresforproductreleaseincludeareviewandevaluationofrelevantproductiondocumentationandanassessmentofdeviationsfromspecifiedprocedures;1.
6NoAPIisreleasedforsaleorforfurtherusepriortoapprovalbythequalitycontroldepartment;1.
7SufficientsamplesofrawmaterialandfinalAPIformsareretainedtopermitfutureexaminationifnecessary.
5.
InterpretationofRegulationsDivision2–GoodManufacturingPracticesSectionC.
02.
002InthisDivision,"medicalgas"meansanygasormixtureofgasesmanufactured,sold,orrepresentedforuseasadrug;(gazmédical)"packagingmaterial"includesalabel;(matérield'emballage)"specifications"meansadetaileddescriptionofadrug,therawmaterialusedinadrug,orthepackagingmaterialforadrugandincludes:(a)astatementofallpropertiesandqualitiesofthedrug,rawmaterialorpackagingmaterialthatarerelevanttothemanufacture,packaging,anduseofthedrug,includingtheidentity,potency,andpurityofthedrug,rawmaterial,orpackagingmaterial,HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final11(b)adetaileddescriptionofthemethodsusedfortestingandexaminingthedrug,rawmaterial,orpackagingmaterial,and(c)astatementoftolerancesforthepropertiesandqualitiesofthedrug,rawmaterial,orpackagingmaterial.
(spécifications)SectionC.
02.
002.
1ThisDivisiondoesnotapplytofabricating,packaging/labelling,testing,storingandimportingofantimicrobialagents.
SaleSectionC.
02.
003NodistributorreferredtoinparagraphC.
01A.
003(b)andnoimportershallselladrugunlessithasbeenfabricated,packaged/labelled,testedandstoredinaccordancewiththerequirementsofthisDivision.
SectionC.
02.
003.
1Nopersonshallselladrugthattheyhavefabricated,packaged/labelled,testedorstoredunlesstheyhavefabricated,packaged/labelled,testedorstoreditinaccordancewiththerequirementsofthisDivision.
SectionC.
02.
003.
2(1)NopersonshallimportanactiveingredientintoCanadaforthepurposeofsaleunlesstheyhaveinCanadaapersonwhoisresponsibleforitssale.
(2)NopersonwhoimportsanactiveingredientintoCanadashallsellanylotorbatchofitunlessthefollowingappearonitslabel:(a)thenameandcivicaddressofthepersonwhoimportsit;and(b)thenameandaddressoftheprincipalplaceofbusinessinCanadaofthepersonresponsibleforitssale.
UseinFabricationSectionC.
02.
003.
3Nopersonshalluseanactiveingredientinthefabricationofadrugunlessitisfabricated,packaged/labelled,testedandstoredinaccordancewiththerequirementsofthisDivision.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final12RationaleTherequirementsdescribedinthesesectionsareintendedtoassurethatAPIsofferedforsaleatalllevelsofthesupplychainorusedinthefabricationofdrugsindosageformarecomplianttothisDivision.
Interpretation1.
APIsusedinthefabricationofadrugindosageformshouldbefabricated,packaged/labelled,testedandstoredinaccordancewiththerequirementsofthisDivision.
2.
ThedistributorofadrugforwhichthatdistributorholdsthedrugidentificationnumberandimporterofadrugindosageformshouldensurethattheAPIcontainedinthedrugindosageformmeetstherequirementsofthisDivisionpriortosellingthedrugindosageform.
PremisesSectionC.
02.
004Thepremisesinwhichalotorbatchofadrugisfabricated,packaged/labelledorstoredshallbedesigned,constructedandmaintainedinamannerthat(a)permitstheoperationsthereintobeperformedunderclean,sanitaryandorderlyconditions;(b)permitstheeffectivecleaningofallsurfacestherein;and(c)preventsthecontaminationofthedrugandtheadditionofextraneousmaterialtothedrug.
RationaleThedesignandconstructionofAPIestablishmentsisinfluencedbyvariousfactorssuchasthenatureoftheAPIandthelocation(climaticregions).
APIestablishmentsshouldbedesignedandconstructedinamannerthatpermitscleanlinessandorderlinesswhilepreventingcontamination.
Thebuildingsandfacilitiesshouldberegularlymaintainedtopreventdeteriorationofthepremises.
Ultimately,theobjectiveofallendeavoursinthedesignandconstructionofanAPIestablishmentisproductquality.
Interpretation1.
BuildingsandfacilitiesusedintheproductionofAPIsshouldbelocated,designed,andconstructedtofacilitatecleaning,maintenance,andoperationsasappropriatetothetypeandstageofproduction.
Facilitiesshouldalsobedesignedtominimizepotentialcontamination.
WheremicrobiologicalspecificationshavebeenestablishedfortheAPI,facilitiesshouldalsobedesignedtolimitexposuretoobjectionablemicrobiologicalcontaminantsasappropriate.
2.
BuildingsusedintheproductionofAPIsshouldbeproperlymaintainedandrepairedandkeptinacleancondition.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final133.
Buildingsandfacilitiesshouldhaveadequatespacefortheorderlyplacementofequipmentandmaterialstopreventmix-upsandcontamination.
4.
Thereshouldbedefinedareasorothercontrolsystemsforthefollowingactivities:Receipt,identification,sampling,andquarantineofincomingmaterials,pendingreleaseorrejection;QuarantinebeforereleaseorrejectionofAPIs;SamplingofAPIs;Holdingrejectedmaterialsbeforefurtherdisposition(e.
g.
,return,reprocessingordestruction);Storageofreleasedmaterials;Productionoperations;Packagingandlabellingoperations;andLaboratoryoperations.
5.
Laboratoryareas/operationsshouldnormallybeseparatedfromproductionareas.
Somelaboratoryareas,inparticularthoseusedforin-processcontrols,canbelocatedinproductionareas,providedtheoperationsoftheproductionprocessdonotadverselyaffecttheaccuracyofthelaboratorymeasurements,andthelaboratoryanditsoperationsdonotadverselyaffecttheproductionprocessortheAPIs.
6.
Drainsshouldbeofadequatesizeandshouldbeprovidedwithanairbreakorasuitabledevicetopreventback-siphonage,whenappropriate.
7.
Allutilitiesthatcouldimpactonproductquality(e.
g.
,water,steam,gases,compressedair,andheating,ventilationandairconditioning)shouldbequalifiedandappropriatelymonitoredandactionshouldbetakenwhenlimitsareexceeded.
Drawingsfortheseutilitysystemsshouldbeavailable.
8.
Adequateventilation,airfiltrationandexhaustsystemsshouldbeprovided,whereappropriate.
Thesesystemsshouldbedesignedandconstructedtominimiserisksofcontaminationandcross-contaminationandshouldincludeequipmentforcontrolofairpressure,microorganisms(ifappropriate),dust,humidity,andtemperature,asappropriatetothestageofmanufacture.
ParticularattentionshouldbegiventoareaswhereAPIsareexposedtotheenvironment.
8.
1Ifairisrecirculatedtoproductionareas,appropriatemeasuresshouldbetakentocontrolrisksofcontaminationandcross-contamination.
9.
Adequate,cleanwashingandtoiletfacilitiesshouldbeprovidedforpersonnel.
Thesewashingfacilitiesshouldbeequippedwithhotandcoldwaterasappropriate,soapordetergent,airdriersorsingleservicetowels.
Thewashingandtoiletfacilitiesshouldbeseparatefrom,buteasilyaccessibleto,productionareas.
Adequatefacilitiesforshoweringand/orchangingclothesshouldbeprovided,whenappropriate.
10.
Theflowofmaterialsandpersonnelthroughthebuildingorfacilitiesshouldbedesignedtopreventmix-upsorcontamination.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final1411.
Adequatelightingshouldbeprovidedinallareastofacilitatecleaning,maintenance,andproperoperations.
12.
Permanentlyinstalledpipeworkshouldbeappropriatelyidentified.
Thiscanbeaccomplishedbyidentifyingindividuallines,documentation,computercontrolsystems,oralternativemeans.
PipeworkshouldbelocatedtoavoidrisksofcontaminationoftheAPI.
13.
Dedicatedproductionareas,whichcanincludefacilities,airhandlingequipmentand/orprocessequipment,shouldbeemployedintheproductionofcertainclassesofhighlysensitizingmaterials,suchaspenicillinsorcephalosporins.
14.
Dedicatedproductionareasshouldalsobeconsideredwhenmaterialofaninfectiousnatureorhighpharmacologicalactivityortoxicityisinvolved(e.
g.
,certainsteroidsorcytotoxicanti-canceragents)unlessvalidatedinactivationand/orcleaningproceduresareestablishedandmaintained.
15.
Anyproductionactivities(includingweighing,milling,orpackaging)ofhighlytoxicnon-pharmaceuticalmaterialssuchasherbicidesandpesticidesshouldnotbeconductedusingthebuildingsand/orequipmentbeingusedfortheproductionofAPIs.
Handlingandstorageofthesehighlytoxicnon-pharmaceuticalmaterialsshouldbeseparatefromAPIs.
16.
Wherewaterusedintheprocessistreatedbythefabricatortoachieveadefinedquality,thetreatmentprocessshouldbevalidatedandmonitoredwithappropriateactionlimits.
EquipmentSectionC.
02.
005Theequipmentwithwhichalotorbatchofadrugisfabricated,packaged/labelledortestedshallbedesigned,constructed,maintained,operatedandarrangedinamannerthat(a)permitstheeffectivecleaningofitssurfaces;(b)preventsthecontaminationofthedrugandtheadditionofextraneousmaterialtothedrug;and(c)permitsittofunctioninaccordancewithitsintendeduse.
RationaleThepurposeoftheserequirementsistopreventthecontaminationofAPIsbyotherAPIs,bydust,andbyforeignmaterialssuchasrust,lubricantandparticlescomingfromtheequipment.
Contaminationproblemsmayarisefrompoormaintenance,themisuseofequipment,exceedingthecapacityoftheequipmentandtheuseofworn-outequipment.
Equipmentarrangedinanorderlymannerpermitscleaningofadjacentareasanddoesnotinterferewithotherprocessingoperations.
Italsominimizesthecirculationofpersonnelandoptimizestheflowofmaterials.
ThefabricationofAPIsofconsistentqualityrequiresthatequipmentperforminaccordancewithitsintendeduse.
InterpretationHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final151.
EquipmentusedintheproductionofAPIsshouldbeofappropriatedesignandadequatesize,andsuitablylocatedforitsintendeduse,cleaning,sanitization,whereappropriate,andmaintenance.
2.
Equipmentshouldbeconstructedsothatsurfacesthatcontactrawmaterials,intermediatesorAPIsdonotalterthequalityoftheAPIsbeyondtheofficialorotherestablishedspecifications.
3.
Equipmentandutensilsshouldbecleaned,stored,and,whereappropriate,sanitizedorsterilizedtopreventcontaminationorcarry-overofamaterialthatwouldalterthequalityoftheAPIsbeyondtheofficialorotherestablishedspecifications.
4.
Anysubstancesassociatedwiththeoperationofequipment,suchaslubricants,heatingfluidsorcoolants,shouldnotcontactAPIssoastoaltertheirqualitybeyondtheofficialorotherestablishedspecifications.
Anydeviationsfromthisshouldbeevaluatedtoensurethattherearenodetrimentaleffectsuponthefitnessforpurposeofthematerial.
Whereverpossible,foodgradelubricantsandoilsshouldbeused.
5.
Closedorcontainedequipmentshouldbeusedwheneverappropriate.
Whereopenequipmentisused,orequipmentisopened,appropriateprecautionsshouldbetakentominimizetheriskofcontamination.
5.
1Ovens,autoclavesandsimilarequipmentcontainonlyoneAPIatatimeunlessprecautionsaretakentopreventcontaminationandmix-ups.
6.
Majorequipment(e.
g.
,reactors,storagecontainers)andpermanentlyinstalledprocessinglinesusedduringtheproductionofanAPIshouldbeappropriatelyidentified.
7.
Schedules,procedures,andlogs,includingassignmentofresponsibility,shouldbeestablishedforthepreventativemaintenanceofequipment.
8.
Equipmentthatisunsuitableforitsintendeduseshouldberemovedfromproductionareas.
Whenremovalisnotfeasibleunsuitableequipmentshouldbeclearlylabelledassuch.
9.
Control,weighing,measuring,monitoringandtestequipmentthatiscriticalforassuringthequalityofAPIsshouldbecalibratedaccordingtowrittenproceduresandanestablishedschedule.
Instrumentsthatdonotmeetcalibrationcriteriashouldbeclearlyidentifiedandnotused.
9.
1Equipmentcalibrationsshouldbeperformedusingstandardstraceabletocertifiedstandards,ifexistingandcurrentcalibrationstatusofcriticalequipmentshouldbeknownandverifiable.
9.
2DeviationsfromapprovedstandardsofcalibrationoncriticalinstrumentsshouldbeinvestigatedtodetermineifthesecouldhavehadanimpactonthequalityoftheAPIsmanufactureusingthisequipmentsincethelastsuccessfulcalibration.
10.
Weighingandmeasuringdevicesshouldbeofsuitableaccuracyfortheintendeduse.
11.
Productionequipmentshouldonlybeusedwithinitsqualifiedoperatingrange.
12.
GMPrelatedcomputerizedsystemsshouldbevalidated.
Thedepthandscopeofvalidationdependsonthediversity,complexityandcriticalityofthecomputerizedapplication.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final1613.
Appropriateinstallationqualification(IQ)andoperationalqualification(OQ)shoulddemonstratethesuitabilityofcomputerhardwareandsoftwaretoperformassignedtasks.
14.
Commerciallyavailablesoftwarethathasbeenqualifieddoesnotrequirethesameleveloftesting.
Ifanexistingsystemwasnotvalidatedattimeofinstallation,aretrospectivevalidationcouldbeconductedifappropriatedocumentationisavailable.
15.
Computerizedsystemsshouldhavesufficientcontrolstopreventunauthorizedaccessorchangestodata.
Thereshouldbecontrolstopreventomissionsindata(e.
g.
systemturnedoffanddatanotcaptured).
Thereshouldbearecordofanydatachangemadethatincludesthepreviousentry,whomadethechange,andwhenthechangewasmade.
16.
Ifcomputerizedsystembreakdownsorfailureswouldresultinthepermanentlossofrecords,aback-upsystemshouldbeprovided.
Ameansofensuringdataprotectionshouldbeestablishedforallcomputerizedsystems.
17.
Writtenproceduresshouldbeavailablefortheoperationandmaintenanceofcomputerizedsystems.
18.
Qualificationisusuallycarriedoutbyconductingthefollowingactivities,individuallyorcombined:DesignQualification(DQ)InstallationQualification(IQ)OperationalQualification(OQ)PerformanceQualification(PQ)PersonnelSectionC.
02.
006Everylotorbatchofadrugshallbefabricated,packaged/labelled,testedandstoredunderthesupervisionofpersonnelwho,havingregardtothedutiesandresponsibilitiesinvolved,havehadsuchtechnical,academic,andothertrainingastheDirectorconsiderssatisfactoryintheinterestsofthehealthoftheconsumerorpurchaser.
RationaleItisessentialthatqualifiedandcompetentpersonnelbeemployedtosupervisetheproductionandcontrolofAPIs.
Personnelrequireeducationappropriatetothetaskperformed.
Educationshouldbesupplementedbytrainingand/orexperienceintheparticulartaskperformed.
Theeducation,training,competencyandattitudeofallpersonneldirectlyimpact'sthequalityoftheproducts.
Interpretation1.
Thereshouldbeanadequatenumberofpersonnelqualifiedbyappropriateeducation,trainingandrelevantexperiencetoperformandsupervisethefabrication,packaging/labeling,testing,importation,distributionandstorageofAPIs.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final172.
Theindividualinchargeofthequalitycontroldepartmentofafabricator,packager/labeller,tester,importer,distributor,andwholesaler;andtheindividualinchargeofthemanufacturingdepartmentofafabricatorandpackager/labeller2.
1shoulddirectlycontrolandpersonallysuperviseonsite,eachworkingshiftduringwhichactivitiesundertheircontrolarebeingconducted.
2.
2maydelegatedutiesandresponsibility(e.
g.
,tocoverallshifts)toapersonqualifiedbyappropriateeducation,trainingandrelevantexperiencerelatedtotheworkbeingcarriedout,whileremainingaccountableforthosedutiesandresponsibility.
3.
Theresponsibilitiesofallpersonnelengagedinthefabrication,packaging/labeling,testing,importation,distributionandstorageofAPIsshouldbespecifiedinwritingandpersonnelshouldhaveauthoritytocarryouttheirresponsibilities.
4.
Trainingshouldberegularlyconductedbyqualifiedindividualsinaccordancewithawrittenprogram.
4.
1Thetrainingshouldcover,ataminimum,theparticularoperationsthattheemployeeperformsandGMPasitrelatestotheemployee'sfunctions.
4.
2Recordsoftrainingshouldbemaintained.
4.
3Trainingshouldbeperiodicallyassessedandperformanceofpersonnelperiodicallyreviewed.
4.
4TrainingshouldbeprovidedpriortoimplementationofneworrevisedSOPs.
4.
5Personnelworkinginareaswherehighlyactive,toxic,infectious,orsensitizingmaterialsarehandledshouldbegivenspecifictraining.
5.
ConsultantsandcontractorsadvisingonthemanufactureandcontrolofAPIsshouldhaveappropriateeducation,training,andrelevantexperience,oranycombinationthereof,toadviseonthesubjectforwhichtheyareretained.
6.
Theresponsibilityforproductionactivitiesshouldbedescribedinwriting,andshouldincludebutnotnecessarilybelimitedto:6.
1Preparing,reviewing,approvinganddistributingtheinstructionsfortheproductionofAPIsaccordingtowrittenprocedures;6.
2ProducingAPIsand,whenappropriate,intermediatesaccordingtopre-approvedinstructions;6.
3Reviewingallproductionbatchrecordsandensuringthatthesearecompletedandsigned;6.
4Ensuringthatallproductiondeviationsarereportedandevaluatedandthatcriticaldeviationsareinvestigatedandtheconclusionsarerecorded;6.
5Ensuringthatproductionfacilitiesarecleanandwhenappropriatedisinfected;6.
6Ensuringthatthenecessarycalibrationsareperformedandrecordskept;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final186.
7Ensuringthatthepremisesandequipmentaremaintainedandrecordskept;6.
8Ensuringthatvalidationprotocolsandreportsarereviewedandapproved;6.
9Evaluatingproposedchangesinproduct,processorequipment;and6.
10Ensuringthatnewand,whenappropriate,modifiedfacilitiesandequipmentarequalified.
7.
Themainresponsibilitiesofthequalityunit(s)inamanufacturingandpackaging/labellingestablishmentshouldnotbedelegated.
Theseresponsibilitiesshouldbedescribedinwritingandshouldincludeataminimumwhereapplicable,7.
1ReleasingorrejectingallAPIs;insomeinstances,thequalityunit(s)candelegatetotheproductionunittheresponsibilityandauthorityforreleaseofintermediates,exceptforthoseshippedoutsidethecontrolofthemanufacturingcompany.
7.
2Establishingasystemtoreleaseorrejectrawmaterials,intermediates,packagingandlabellingmaterials;7.
3ReviewingcompletedbatchproductionandlaboratorycontrolrecordsofcriticalprocessstepsbeforereleaseoftheAPIfordistribution;7.
4Ensuringthatcriticaldeviationsareinvestigatedandresolved;7.
5Approvingallspecificationsandmasterproductiondocuments;7.
6ApprovingallproceduresimpactingthequalityofAPIs;7.
7Ensuringthatinternalaudits(self-inspections)areperformed;7.
8ApprovingAPIandintermediatecontractfabricators;7.
9ApprovingchangesthatpotentiallyimpactAPIsquality;7.
10Reviewingandapprovingvalidationprotocolsandreports;7.
11Ensuringthatquality-relatedcomplaintsareinvestigatedandresolved;7.
12Ensuringthateffectivesystemsareusedformaintainingandcalibratingcriticalequipment;7.
13Ensuringthatmaterialsareappropriatelytestedandtheresultsarereported;7.
14EnsuringthatthereisstabilitydatatosupportretestorexpirydatesandstorageconditionsonAPIs,whereappropriate;7.
15Performingannualproductqualityreviews;and7.
16Ensuringthatqualitycontrolequipmentisappropriatetotestingactivitiesundertaken.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final19SanitationSectionC.
02.
007(1)Everypersonwhofabricatesorpackages/labelsadrugshallhaveawrittensanitationprogramthatshallbeimplementedunderthesupervisionofqualifiedpersonnel.
(2)Thesanitationprogramreferredtoinsubsection(1)shallinclude:(a)cleaningproceduresforthepremiseswherethedrugisfabricatedorpackaged/labelledandfortheequipmentusedinthefabricationorpackaging/labellingofthedrug;and(b)instructionsonthesanitaryfabricationandpackaging/labellingofdrugsandthehandlingofmaterialsusedinthefabricationandpackaging/labellingofdrugs.
RationaleSanitationinanAPIplant,aswellasemployeeattitude,influencesthequalityofdrugproducts.
Thequalityrequirementfordrugproductsdemandthatsuchproductsbefabricatedandpackagedinareasthatarefreefromenvironmentalcontaminationandfreefromcontaminationbyanotherdrug.
Thereisasignificantdifferencebetweenafinishedproductproductionenvironment(physicalprocess)andanAPIproductionenvironment(chemicalprocess),whereaggressiveandcorrosivereagentsmaybeused.
ThelevelofcleanlinessrequiredforanAPIproductionenvironmentmayvarydependingonwhetheritisanopenorclosedproductionsystemandthestageofproduction.
Openproductionsystems(e.
g.
,vesselwithnolid)orprocessesclosertotheendofproduction(e.
g.
,purification)wouldrequireahigherlevelofenvironmentalcontrolstopreventand/orminimisecontamination.
Overall,thesanitationprogramimplementedatasiteshouldbeeffectiveinpreventingunsanitaryconditions.
Interpretation1.
Writtenproceduresshouldbeestablishedassigningresponsibilityforsanitationanddescribingthecleaningschedules,methods,equipment,andmaterialstobeusedincleaningbuildingsandfacilities.
1.
1Thereshouldbeanenvironmentalmonitoringprogramwithalertandactionlimitsinareaswheresusceptibleproductsarefabricatedorpackaged,whenapplicable.
1.
2Thedescriptionoftheresponsibilitiesofanyoutsidecontractorsshouldbeavailableinwriting.
2.
Non-dedicatedequipmentshouldbecleanedbetweenproductionsofdifferentmaterialstopreventcross-contamination.
3.
Acceptancecriteriaforresiduesandthechoiceofcleaningproceduresandcleaningagentsshouldbedefinedandjustified.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final204.
Sewage,refuse,andotherwaste(e.
g.
,solids,liquids,orgaseousby-productsfrommanufacturing)inandfrombuildingsandtheimmediatesurroundingareashouldbedisposedofinasafe,timely,andsanitarymanner.
Containersand/orpipesforwastematerialshouldbeclearlyidentified.
5.
Cleaningproceduresshouldnormallybevalidated.
Ingeneral,cleaningvalidationshouldbedirectedtosituationsorprocessstepswherecontaminationorcarryoverofmaterialsposesthegreatestrisktotheAPIquality.
Forexample,inearlyproductionitmaybeunnecessarytovalidateequipmentcleaningprocedureswhereresiduesareremovedbysubsequentpurificationsteps.
6.
Validatedanalyticalmethodshavingsensitivitytodetectresiduesorcontaminantsshouldbeused.
Thedetectionlimitforeachanalyticalmethodshouldbesufficientlysensitivetodetecttheestablishedacceptableleveloftheresidueorcontaminant.
Themethod'sattainablerecoverylevelshouldbeestablished.
Residuelimitsshouldbepractical,achievable,andverifiableandbasedonthemostdeleteriousresidue.
Limitscanbeestablishedbasedontheminimumknownpharmacological,toxicological,orphysiologicalactivityoftheAPIoritsmostdeleteriouscomponent.
FurtherguidanceisdetailedinHealthCanada'sdocumententitledCleaningValidationGuidelines(GUI-0028).
7.
Equipmentcleaning/sanitizationstudiesshouldaddressmicrobiologicalandendotoxincontaminationforthoseprocesseswherethereisaneedtoreducetotalmicrobiologicalcountorendotoxinsintheAPI,orotherprocesseswheresuchcontaminationcouldbeofconcern(e.
g.
,non-sterileAPIsusedtomanufacturesterileproducts).
8.
Whennecessary,writtenproceduresshouldalsobeestablishedfortheuseofsuitablerodenticides,insecticides,fungicides,fumigatingagents,andcleaningandsanitizingagentstopreventthecontaminationofequipment,rawmaterials,packaging/labellingmaterials,intermediates,andAPIs.
9.
WrittenproceduresshouldbeestablishedforcleaningofequipmentanditssubsequentreleaseforuseinthemanufactureofAPIs.
Cleaningproceduresshouldcontainsufficientdetailstoenableoperatorstocleaneachtypeofequipmentinareproducibleandeffectivemanner.
Theseproceduresshouldinclude:Assignmentofresponsibilityforcleaningofequipment;Cleaningschedules,including,whereappropriate,sanitizingschedules;Acompletedescriptionofthemethodsandmaterials,includingdilutionofcleaningagentsusedtocleanequipment;Whenappropriate,instructionsfordisassemblingandreassemblingeacharticleofequipmenttoensurepropercleaning;Instructionsfortheremovalorobliterationofpreviousbatchidentification;Instructionsfortheprotectionofcleanequipmentfromcontaminationpriortouse;Inspectionofequipmentforcleanlinessimmediatelybeforeuse,ifpractical;andEstablishingthemaximumtimethatmayelapsebetweenthecompletionofprocessingandequipmentcleaning,whenappropriate.
10.
WhereequipmentisassignedtocontinuousproductionorcampaignproductionofsuccessivebatchesofthesameAPI,equipmentshouldbecleanedatappropriateintervalstopreventbuild-upandcarry-overofcontaminants(e.
g.
degradantsorobjectionablelevelsofmicro-organisms).
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final2111.
Recordsofmajorequipmentuse,cleaning,sanitizationand/orsterilizationandmaintenanceshouldshowthedate,time,ifappropriate,product,andbatchnumberofeachbatchprocessedintheequipment,andthepersonwhoperformedthecleaningandmaintenance.
12.
Cleaningproceduresshouldbemonitoredatappropriateintervalsaftervalidationtoensurethattheseproceedingsareeffectivewhenusedduringroutineproduction.
Equipmentcleanlinesscanbemonitoredbyanalyticaltestingandvisualexamination,wherefeasible.
Visualinspectioncanallowdetectionofgrosscontaminationconcentratedinsmallareasthatcouldotherwisegoundetectedbysamplingand/oranalysis.
13.
Dustyoperationsshouldbecontained.
Theuseofunitorportabledustcollectorsshouldbeavoidedinfabricationareasespeciallyindispensing,unlesstheeffectivenessoftheirexhaustfiltrationisdemonstratedandtheunitsareregularlymaintainedinaccordancewithwrittenapprovedprocedures.
SectionC.
02.
008(1)Everypersonwhofabricatesorpackages/labelsadrugshallhave,inwriting,minimumrequirementsforthehealthandthehygienicbehaviourandclothingofpersonneltoensurethecleanandsanitaryfabricationandpackaging/labellingofthedrug.
(2)Nopersonshallhaveaccesstoanyareawhereadrugisexposedduringitsfabricationorpackaging/labellingiftheperson(a)isaffectedwithorisacarrierofadiseaseinacommunicableform;or(b)hasanopenlesiononanyexposedsurfaceofthebody.
RationaleEmployee'shealth,behaviour,andclothingmaycontributetothecontaminationoftheproduct.
Poorpersonalhygienewillnullifythebestsanitationprogramandgreatlyincreasetheriskofproductcontamination.
Interpretation1.
Personnelandvisitorsshouldpracticegoodsanitationandhealthhabits.
1.
1Requirementsconcerningcosmeticsandjewellerywornbyemployeesshouldbeoutlinedandobservedbyemployees.
2.
PersonnelsufferingfromaninfectiousdiseaseorhavingopenlesionsontheexposedsurfaceofthebodyshouldnotengageinactivitiesthatcouldresultincompromisingthequalityofAPIs.
Anypersonshownatanytime(eitherbymedicalexaminationorsupervisoryobservation)tohaveanapparentillnessoropenlesionsshouldbeexcludedfromactivitieswherethehealthconditioncouldadverselyaffectthequalityoftheAPIsuntiltheconditioniscorrectedorqualifiedmedicalpersonneldeterminethattheperson'sinclusionwouldnotjeopardizethesafetyorqualityoftheAPIs.
2.
1EmployeesshouldbeinstructedtoreporttotheirsupervisoranyhealthconditionstheyhavethatcouldadverselyaffectAPIs.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final222.
2Aprocedureshouldbeinplacetodescribetheactionstobetakenintheeventthatapersonwithacommunicablediseasehasbeenidentifiedashavinghandledexposedmaterials.
3.
Personnelshouldwearcleanclothingsuitableforthemanufacturingactivitywithwhichtheyareinvolvedandthisclothingshouldbechangedwhenappropriate.
Additionalprotectiveapparel,suchashead,face,hand,andarmcoverings,shouldbewornwhennecessary,toprotectAPIsfromcontamination.
3.
1Soiledprotectivegarments,ifreusable,shouldbestoredinseparatecontainersuntilproperlylaunderedand,ifnecessary,disinfectedorsterilized,accordingtoawrittenprocedure.
Washinggarmentsinadomesticsettingisunacceptable.
4.
PersonnelshouldavoiddirectcontactwithAPIs.
5.
Smoking,eating,drinking,chewingandthestorageoffoodshouldberestrictedtocertaindesignatedareasseparatefromthemanufacturingareas.
RawMaterialTestingSectionC.
02.
009(1)Eachlotorbatchofrawmaterialshallbetestedagainstthespecificationsforthatrawmaterialpriortoitsuseinthefabricationofadrug.
(2)Nolotorbatchofrawmaterialshallbeusedinthefabricationofadrugunlessthatlotorbatchofrawmaterialcomplieswiththespecificationsforthatrawmaterial.
(3)Notwithstandingsubsection(1),watermay,priortothecompletionofitstestsunderthatsubsection,beusedinthefabricationofadrug.
(4)Whereanypropertyofarawmaterialissubjecttochangeonstorage,nolotorbatchofthatrawmaterialshallbeusedinthefabricationofadrugafteritsstorageunlesstherawmaterialisretestedafteranappropriateintervalandcomplieswithitsspecificationsforthatproperty.
(5)Wherethespecificationsreferredtoinsubsections(1),(2)and(4)arenotprescribed,theyshall(a)beinwriting;(b)beacceptabletotheDirectorwhoshalltakeintoaccountthespecificationscontainedinanypublicationmentionedinScheduleBtotheAct;and(c)beapprovedbythepersoninchargeofthequalitycontroldepartment.
RationaleHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final23Thetestingofrawmaterialsbeforetheirusehasthreeobjectives:toconfirmtheidentityoftherawmaterials,toprovideassurancethatthequalityofAPIswillnotbealteredbyrawmaterialdefects,andtoobtainassurancethattherawmaterialshavethecharacteristicsthatwillprovidethedesiredquantityoryieldinagivenmanufacturingprocess.
Interpretation1.
Specificationsshouldbeestablishedanddocumentedforrawmaterials,intermediatesandwherenecessary,APIs.
Inaddition,specificationsmaybeappropriateforcertainothermaterials,suchasprocessaidsorothermaterialsusedduringtheproductionofAPIsthatcouldcriticallyimpactonquality.
Acceptancecriteriashouldbeestablishedanddocumentedforin-processcontrols.
SpecificationsareapprovedanddatedbythepersoninchargeofthequalitycontroldepartmentorbyadesignatedalternatewhomeetstherequirementsdescribedunderRegulationC.
02.
006,Interpretation1.
2.
Specificationsforrawmaterialsshouldbeestablishedbasedonprocessdesignandoverallcontrolstrategytoensurefinalproductquality.
3.
Rawmaterialsshouldbepurchasedagainstanagreedspecification,fromsuppliersapprovedbythequalityunit(s).
4.
WaterusedinthemanufactureofAPIsshouldbedemonstratedtobesuitableforitsintendeduse.
5.
Unlessotherwisejustified,processwatershould,ataminimum,meetWorldHealthOrganization(WHO)guidelinesfordrinking(potable)waterquality.
6.
Ifdrinking(potable)waterisinsufficienttoassureAPIquality,andtighterchemicaland/ormicrobiologicalwaterqualityspecificationsarecalledfor,appropriatespecificationsforphysical/chemicalattributes,totalmicrobialcounts,objectionableorganismsand/orendotoxinsshouldbeestablished.
7.
Wherethefabricatorofanon-sterileAPIeitherintendsorclaimsthatitissuitableforuseinfurtherprocessingtoproduceasteriledrug,waterusedinthefinalisolationandpurificationstepsshouldbemonitoredandcontrolledfortotalmicrobialcounts,objectionableorganisms,andendotoxins.
8.
Analyticalmethodsshouldbevalidatedunlessthemethodemployedisincludedintherelevantpharmacopoeiaorotherrecognisedstandardreference.
Thesuitabilityofallanalyticalmethodsusedshouldnonethelessbeverifiedunderactualconditionsofuseanddocumented.
9.
MethodsshouldbevalidatedtoincludeconsiderationofcharacteristicsincludedwithintheICHguidelinesonvalidationofanalyticalmethods.
ThedegreeofanalyticalvalidationperformedshouldreflectthepurposeoftheanalysisandthestageoftheAPIproductionprocess.
Note:GuidanceforthevalidationofparticulartypesofmethodscanbeobtainedinpublicationssuchastheICHdocumententitledICHQ2(R1):ValidationofAnalyticalProcedures:TextandMethodologyorinanystandardlistedinScheduleBtotheFoodandDrugsAct.
10.
Rawmaterialsshouldbere-evaluatedasappropriatetodeterminetheirsuitabilityforuse(e.
g.
,afterprolongedstorageorexposuretoheatorhumidity).
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final24SectionC.
02.
010(1)ThetestingreferredtoinsectionC.
02.
009shallbeperformedonasampletaken(a)afterreceiptofeachlotorbatchofrawmaterialonthepremisesofthefabricator;or(b)subjecttosubsection(2),beforereceiptofeachlotorbatchofrawmaterialonthepremisesofthefabricator,if(i)thefabricator(A)hasevidencesatisfactorytotheDirectortodemonstratethatrawmaterialssoldtohimbythevendorofthatlotorbatchofrawmaterialareconsistentlymanufacturedinaccordancewithandconsistentlycomplywiththespecificationsforthoserawmaterials,and(B)undertakesperiodiccompleteconfirmatorytestingwithafrequencysatisfactorytotheDirector,and(ii)therawmaterialhasnotbeentransportedorstoredunderconditionsthatmayaffectitscompliancewiththespecificationsforthatrawmaterial.
(2)Afteralotorbatchofrawmaterialisreceivedonthepremisesofthefabricator,thelotorbatchofrawmaterialshallbetestedforidentity.
RationaleSectionC.
02.
010outlinesoptionsastowhenthetestingprescribedbySectionC.
02.
009iscarriedout.
Thepurchaseofrawmaterialsisanimportantoperationthatrequiresaparticularandthoroughknowledgeoftherawmaterialsandtheirsuppliers.
TomaintainconsistencyinthefabricationofAPIs,rawmaterialsshouldoriginatefromreliablesuppliers.
Interpretation1.
FabricatorsofAPIsshouldhaveawrittensystemforevaluatingthesuppliersofcriticalmaterials.
2.
SpecificidentitytestingofeachbatchofmaterialreceivedonthepremisesoftheAPIfabricatorshouldbeconducted,withtheexceptionofthematerialsdescribedbelowin4.
Asupplier'sCertificateofAnalysis(CoA)canbeusedinplaceofperformingothertests,providedthatthefabricatorhasasysteminplacetoevaluatesuppliers.
2.
1Providedthattheidentitytestreferredtoininterpretation2isperformed,thelotofrawmaterialselectedforconfirmatorytestingmaybeusedinfabricationpriortocompletionofalltestswiththeapprovalofthequalitycontroldepartment.
3.
Vendorapprovalshouldincludeawrittenevaluationthatprovidesadequateevidence(e.
g.
,pastqualityhistory)thatthefabricatorcanconsistentlyprovidematerialmeetingspecifications.
CompleteHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final25confirmatorytestingshouldbeconductedonatleastthreebatchesbeforereducingin-housetestingandaftersignificantchangetothemanufacturingprocess.
However,asaminimum,completeconfirmatorytestingshouldbeperformedatappropriateintervalsandcomparedwiththeCoA.
ReliabilityofCoAsshouldbecheckedatregularintervals.
3.
1Adocumentisissuedverifyingthatthesuppliermeetsthecriteriaforcertification.
Thedocumentisapprovedbythequalitycontroldepartmentandisreviewedperiodically.
3.
2Awrittensystemshouldbeinplacetoaddresstestingfailuresandanysubsequentre-qualificationofthesupplierifrequired.
4.
Processingaids,hazardousorhighlytoxicrawmaterials,otherspecialmaterials,ormaterialstransferredtoanotherunitwithinthecompany'scontroldonotneedtobetestedifthefabricator'sCoAisobtained,showingthattheserawmaterialsconformtoestablishedspecifications.
Visualexaminationofcontainers,labels,andrecordingofbatchnumbersshouldhelpinestablishingtheidentityofthesematerials.
Thelackofon-sitetestingforthesematerialsshouldbejustifiedanddocumented.
5.
Samplesshouldberepresentativeofthebatchofmaterialfromwhichtheyaretaken.
Samplingmethodsshouldspecifythenumberofcontainerstobesampled,whichpartofthecontainertosample,andtheamountofmaterialtobetakenfromeachcontainer.
Thenumberofcontainerstosampleandthesamplesizeshouldbebaseduponasamplingplanthattakesintoconsiderationthecriticalityofthematerial,materialvariability,pastqualityhistoryofthesupplier,andthequantityneededforanalysis.
6.
Thereshouldbewrittenproceduresdescribingtheidentification,andtestingofmaterials.
7.
Ifthesupplierofacriticalmaterialisnotthefabricatorofthatmaterial,thenameandaddressofthatfabricatorshouldbeknownbytheAPIfabricator.
8.
ChangingthesourceofsupplyofcriticalrawmaterialsshouldbetreatedaccordingtoSectionC.
02.
015,ChangeControl.
9.
Whereappropriate,acopyoftheresidualsolventprofileshouldbeobtained.
Additionally,forAPIs,acopyoftheimpurityprofileshouldbeobtained.
10.
Whenabrokerorwholesalersuppliesmaterialsreceivedfromtheoriginalvendorwithoutchangingtheexistinglabels,packaging,certificateofanalysis,andgeneralinformation,thencertificationoftheoriginalsourceisstillacceptable.
11.
Conditionsoftransportationandstorageshouldbesuchthattheypreventalterationstothepotency,purity,orphysicalcharacteristicsofthecriticalrawmaterials.
12.
Ifadeliveryorshipmentofrawmaterialismadeupofdifferentbatches,eachbatchshouldbeconsideredasseparateforthepurposesofsampling,testing,andrelease.
13.
Ifthesamebatchofrawmaterialissubsequentlyreceived,thisbatchshouldalsobeconsideredasseparateforthepurposeofsampling,testing,andrelease.
However,fulltestingtospecificationsmaynotbenecessaryonsuchabatchprovidedthatallthefollowingconditionsaremet:13.
1aspecificallydiscriminatingidentitytestisconducted;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final2613.
2therawmaterialhasnotbeenrepackagedorre-labelled;13.
3therawmaterialiswithinthere-testdateassignedbyitsvendor;and13.
4evidenceisavailabletodemonstratethatallpre-establishedtransportationandstorageconditionshavebeenmaintainedwhenapplicable.
ManufacturingControlSectionC.
02.
011(1)Everyfabricator,packager/labeller,distributorreferredtoinparagraphC.
01A.
003(b)andimporterofadrugshallhavewrittenprocedurespreparedbyqualifiedpersonnelinrespectofthedrugtoensurethatthedrugmeetsthespecificationsforthatdrug.
(2)Everypersonrequiredtohavewrittenproceduresreferredtoinsubsection(1)shallensurethateachlotorbatchofthedrugisfabricated,packaged/labelledandtestedincompliancewiththoseprocedures.
RationaleThisRegulationrequiresthatmeasuresbetakentomaintaintheintegrityofanAPIfromthemomentthevariousrawmaterialsentertheplanttothetimetheAPIisreleasedforsaleorforfurtherfabrication.
Thesemeasuresensurethatallmanufacturingprocessesareclearlydefined,systematicallyreviewedinlightofexperience,anddemonstratedtobecapableofconsistentlymanufacturingAPIsoftherequiredqualitythatcomplywiththeirestablishedspecifications.
RefertoTable2forthepointatwhichproductionoftheAPIbeginsandfromwhichcompliancetoGMPsshouldbeimplemented.
Interpretation1.
Accesstoproductionareasisrestrictedtodesignatedpersonnel.
2.
Allhandlingofrawmaterials,products,andpackagingmaterialssuchasreceipt,identification,quarantine,storage,sampling,testing,approvalorrejectionofmaterials,tracking,labeling,packaging,dispensing,processing,anddistributionshouldbedoneinaccordancewithwrittenproceduresorinstructionsandrecorded.
3.
ValidationshouldextendtothoseoperationsdeterminedtobecriticaltothequalityandpurityoftheAPI.
3.
1ThepotentialimpactoftheproposedchangeonthequalityoftheAPIshouldbeevaluated.
Aclassificationproceduremayhelpindeterminingtheleveloftesting,validation,anddocumentationneededtojustifychangestoavalidatedprocess.
Changescanbeclassified(e.
g.
,asminorormajor)dependingonthenatureandextentofthechanges,andtheeffectsthesechangesmayimpartontheprocess.
Scientificjudgementshoulddeterminewhatadditionaltestingandvalidationstudiesareappropriatetojustifyachangeinavalidatedprocess.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final27Wherenosignificantchangeshavebeenmadetothesystemorprocess,andaqualityreviewconfirmsthatthesystemorprocessisconsistentlyproducingmaterialmeetingitsspecifications,thereisnormallynoneedforrevalidation.
4.
Awrittenvalidationprotocolshouldbeestablishedthatspecifieshowvalidationofaparticularprocesswillbeconducted.
Theprotocolshouldbereviewedandapprovedbythequalityunit(s)andotherdesignatedunits.
Formoreinformationonthismatter,refertoSection12ValidationoftheICHQ7Guidelines.
4.
1Thevalidationprotocolshouldspecifycriticalprocessstepsandacceptancecriteriaaswellasthetypeofvalidationtobeconducted(e.
g.
retrospective,prospective,concurrent)andthenumberofprocessruns.
4.
2Avalidationreportthatcross-referencesthevalidationprotocolshouldbeprepared,summarisingtheresultsobtained,commentingonanydeviationsobserved,anddrawingtheappropriateconclusions,includingrecommendingchangestocorrectdeficiencies.
4.
3Anyvariationsfromthevalidationprotocolshouldbedocumentedwithappropriatejustification.
5.
Beforestartingprocessvalidationactivities,appropriatequalificationofcriticalequipmentandancillarysystemsshouldbecompleted.
6.
Anydeviationshouldbedocumentedandexplained.
Anycriticaldeviation(i.
e.
onewhichcouldaffectthequalityand/orpurityoftheAPI)shouldbeinvestigated.
7.
Actualyieldsshouldbecomparedwithexpectedyieldsatdesignatedstepsintheproductionprocess.
Expectedyieldswithappropriaterangesshouldbeestablishedbasedonpreviouslaboratory,pilotscale,ormanufacturingdata.
Deviationsinyieldassociatedwithcriticalprocessstepsshouldbeinvestigatedtodeterminetheirimpactorpotentialimpactontheresultingqualityofaffectedbatches.
8.
ResidualmaterialscanbecarriedoverintosuccessivebatchesofthesameAPIaslongasthereisadequatecontrol.
Examplesincluderesidueadheringtothewallofamicronizer,residuallayerofdampcrystalsremaininginacentrifugebowlafterdischarge,andincompletedischargeoffluidsorcrystalsfromaprocessingvesselupontransferofthematerialtothenextstepintheprocess.
SuchcarryovershouldnotresultinthecarryoverofdegradantsormicrobialcontaminationthatmayadverselyaltertheestablishedAPIimpurityprofile.
9.
Providedthatvalidatedchangeoverproceduresareimplemented,non-medicinalproductsmaybefabricatedorpackaged/labelledinareasorwithequipmentthatisalsousedfortheproductionofAPIs.
10.
FacilitieswhereAPIsarefabricated,packagedandlabelledshouldbeinspectedimmediatelybeforeusetoensurethatallmaterialsnotneededforthenextoperationhavebeenremoved.
Thisexaminationshouldbedocumentedinthebatchproductionrecords,thefacilitylog,orotherdocumentationsystem.
11.
ProductionoperationsshouldbeconductedinamannerthatwillpreventcontaminationofAPIsbyothermaterials.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final2812.
In-processsamplingshouldbeconductedusingproceduresdesignedtopreventcontaminationofthesampledmaterialandotherAPIs.
Proceduresshouldbeestablishedtoensuretheintegrityofsamplesaftercollection.
13.
WrittenproceduresshouldbeestablishedtomonitortheprogressandcontroltheperformanceofprocessingstepsthatcausevariabilityinthequalitycharacteristicsofAPIs.
In-processcontrolsandtheiracceptancecriteriashouldbedefinedbasedontheinformationgainedduringthedevelopmentstageorhistoricaldata.
14.
TheacceptancecriteriaandtypeandextentoftestingcandependonthenatureoftheAPIbeingmanufactured,thereactionorprocessstepbeingconducted,andthedegreetowhichtheprocessintroducesvariabilityintheproduct'squality.
Lessstringentin-processcontrolsmaybeappropriateinearlyprocessingsteps,whereastightercontrolsmaybeappropriateforlaterprocessingsteps(e.
g.
,isolationandpurificationsteps).
15.
Criticalin-processcontrols(andcriticalprocessmonitoring),includingthecontrolpointsandmethods,shouldbestatedinwritingandapprovedbythequalityunit(s).
16.
In-processcontrolscanbeperformedbyqualifiedproductiondepartmentpersonnelandtheprocessadjustedwithoutpriorqualityunit(s)approvaliftheadjustmentsaremadewithinpre-establishedlimitsapprovedbythequalityunit(s).
Alltestsandresultsshouldbefullydocumentedaspartofthebatchrecord.
17.
Writtenproceduresshoulddescribethesamplingmethodsforin-processmaterials,intermediates,andAPIs.
Samplingplansandproceduresshouldbebasedonscientificallysoundsamplingpractices.
18.
PrecautionstoavoidcontaminationshouldbetakenwhenAPIsarehandledafterpurification.
19.
Productionoperationsondifferentproductsmaybecarriedoutinthesameareaprovidedthatappropriatemeasuresandcontrolsareinplacetopreventmix-uporcross-contamination.
19.
1Appropriatemeasuresshouldbeestablishedandimplementedtopreventcross-contaminationfrompersonnel,materials,etc.
movingfromonededicatedareatoanother.
19.
2Whereapplicable,checksshouldbecarriedouttoensurethatremovableandinterchangeabletransferlinesandotherpiecesofequipmentusedforthetransferofmaterialsfromoneareatoanotherarecorrectlyconnected.
20.
Equipmentorsegregatedprocessareasshouldbeidentifiedastoitscontents,includingnameofproductandbatchnumber,anditscleanlinessstatusbyappropriatemeans.
21.
Theprocessingstatusofmajorunitsofequipmentshouldbeindicatedeitherontheindividualunitsofequipmentorbyappropriatedocumentation,computercontrolsystems,oralternativemeans.
22.
Rejectedmaterialsshouldbeidentifiedandcontrolledunderaquarantinesystemdesignedtopreventtheirunauthorizeduseinmanufacturing.
23.
Materialstobereprocessedorreworkedshouldbeappropriatelycontrolledtopreventunauthorizeduse.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final2924.
Uponreceiptandbeforeacceptance,eachcontainerorgroupingofcontainersofmaterialsshouldbeexaminedvisuallyforcorrectlabelling(includingcorrelationbetweenthenameusedbythesupplierandthein-housename,ifthesearedifferent),containerdamage,brokensealsandevidenceoftamperingorcontamination.
Allcontainersareverifiedtoensurethattheinformationontheorder,thedeliverynoteandthevendor'slabelsisinagreement.
24.
1Materialsshouldbeheldunderquarantineuntiltheyhavebeensampled,examinedortestedasappropriate,andreleasedforuse.
25.
Beforeincomingmaterialsaremixedwithexistingstocks(e.
g.
,solventsorstocksinsilos),theyshouldbeidentifiedascorrect,tested,ifappropriate,andreleased.
Proceduresshouldbeavailabletopreventdischargingincomingmaterialswronglyintotheexistingstock.
26.
Ifbulkdeliveriesaremadeinnon-dedicatedtankers,thereshouldbeassuranceofnocross-contaminationfromthetanker.
Meansofprovidingthisassurancecouldincludeoneormoreofthefollowing:certificateofcleaning,testingfortraceimpurities,andauditofthesupplier.
27.
Intermediatesheldforfurtherprocessingshouldbestoredunderappropriateconditionstoensuretheirsuitabilityforuse.
28.
Criticalmaterialsshouldbetransportedinamannerthatdoesnotadverselyaffecttheirquality.
29.
SpecialtransportorstorageconditionsforanAPIshouldbestatedonthelabel.
30.
Samplingshouldbeconductedatdefinedlocationsandbyproceduresdesignedtopreventcontaminationofthematerialsampledandcontaminationofothermaterials.
31.
Containersfromwhichsamplesarewithdrawnshouldbeopenedcarefullyandsubsequentlyreclosed.
Theyshouldbemarkedtoindicatethatasamplehasbeentaken.
32.
Largestoragecontainers,andtheirattendantmanifolds,fillinganddischargelinesshouldbeappropriatelyidentified.
33.
Eachcontainerorgroupingofcontainers(batches)ofmaterialsshouldbeassignedandidentifiedwithadistinctivecode,batch,orreceiptnumber.
Theidentificationnumbershouldbeusedinrecordingthedispositionofeachbatch.
Asystemshouldbeinplacetoidentifythestatusofeachbatch.
34.
Materialsshouldbehandledandstoredinamannertopreventdegradation,contamination,andcross-contamination.
35.
Materialsstoredinfiberdrums,bags,orboxesshouldbestoredoffthefloorand,whenappropriate,suitablyspacedtopermitcleaningandinspection.
36.
Materialsshouldbestoredunderconditionsandforaperiodthathavenoadverseeffectontheirquality,andshouldnormallybecontrolledsothattheoldeststockisusedfirst.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3037.
Certainmaterialsinsuitablecontainerscanbestoredoutdoors,providedidentifyinglabelsremainlegibleandcontainersareappropriatelycleanedbeforeopeninganduse.
38.
RawmaterialsforAPImanufacturingshouldbeweighedormeasuredunderappropriateconditionsthatdonotaffecttheirsuitabilityforuse.
39.
Criticalweighing,measuring,orsubdividingoperationsshouldbewitnessedorsubjectedtoanequivalentcontrol.
Priortouse,productionpersonnelshouldverifythatthematerialsarethosespecifiedinthebatchrecordfortheintendedAPI.
40.
Othercriticalactivitiesshouldbewitnessedorsubjectedtoanequivalentcontrol.
41.
Allqualityrelatedactivitiesshouldberecordedatthetimetheyareperformed.
42.
Whenentriesaremadeinrecords,theseshouldbemadeindeliblyinspacesprovidedforsuchentries,directlyafterperformingtheactivities,andshouldidentifythepersonmakingtheentry.
Correctionstoentriesshouldbedatedandsignedandleavetheoriginalentrystillreadable.
43.
AlldocumentsrelatedtothemanufactureofAPIsshouldbeprepared,reviewed,approvedanddistributedaccordingtowrittenprocedures.
43.
1Toensureuniformityfrombatchtobatch,masterproductioninstructionsforeachAPIshouldbeprepared,dated,andsignedbyonepersonandindependentlychecked,dated,andsignedbyapersoninthequalityunit(s).
ManufacturingOperations44.
Masterproductiondocumentsshouldinclude:ThenameoftheAPIbeingmanufactured,batchsize,andanidentifyingdocumentreferencecode,ifapplicable;Acompletelistofrawmaterialsandintermediatesdesignatedbynamesorcodessufficientlyspecifictoidentifyanyspecialqualitycharacteristics;Anaccuratestatementofthequantityorratioofeachrawmaterialorintermediatetobeused,includingtheunitofmeasure.
Wherethequantityisnotfixed,thecalculationforeachbatchsizeorrateofproductionshouldbeincluded.
Variationstoquantitiesshouldbeincludedwheretheyarejustified;Theproductionlocationandmajorproductionequipmenttobeused;Theprocedures,orreferencetotheprocedures,tobeusedinproduction;Detailedproductioninstructions,includingthe:sequencestobefollowed,rangesofprocessparameterstobeused,samplinginstructionsandin-processcontrolswiththeiracceptancecriteria,whereappropriate,HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final31timelimitsforcompletionofindividualprocessingstepsand/orthetotalprocess,whereappropriate;andexpectedyieldrangesatappropriatephasesofprocessingortime;Whereappropriate,specialnotationsandprecautionstobefollowed,orcross-referencestothese;andTheinstructionsforstorageoftheintermediateorAPItoassureitssuitabilityforuse,includingthelabellingandpackagingmaterialsandspecialstorageconditionswithtimelimits,whereappropriate.
45.
BatchproductionrecordsshouldbepreparedforeachAPIandshouldincludecompleteinformationrelatingtotheproductionandcontrolofeachbatch.
Thebatchproductionrecordshouldbecheckedbeforeissuancetoassurethatitisthecorrectversionandalegibleaccuratereproductionoftheappropriatemasterproductioninstruction.
Ifthebatchproductionrecordisproducedfromaseparatepartofthemasterdocument,thatdocumentshouldincludeareferencetothecurrentmasterproductioninstructionbeingused.
46.
Thebatchproductionrecordsshouldbenumberedwithauniquebatchoridentificationnumber,datedandsignedwhenissued.
Incontinuousproduction,theproductcodetogetherwiththedateandtimecanserveastheuniqueidentifieruntilthefinalnumberisallocated.
47.
Documentationofcompletionofeachsignificantstepinthebatchproductionrecords(batchproductionandcontrolrecords)shouldinclude:Datesand,whenappropriate,timesofcommencementandcompletionofsignificantintermediatestages(blending,heating,etc.
)andofproduction;Identityofmajorequipment(e.
g.
,reactors,driers,mills,etc.
)used;Specificidentificationofeachbatch,includingweights,measures,andbatchnumbersofrawmaterials,intermediates,oranyreprocessedmaterialsusedduringmanufacturing;Actualresultsrecordedforcriticalprocessparameters;Anysamplingperformed;Signaturesofthepersonsperforminganddirectlysupervisingorcheckingeachcriticalstepintheoperation;In-processandlaboratorytestresultsActualyieldatappropriatephasesortimes;Anydeviationnoted,itsevaluation,investigationconducted(ifappropriate)orreferencetothatinvestigationifstoredseparately;andResultsofreleasetesting.
Uponcompletion,thesignatureofthepersonresponsiblefortheprocessingoperations.
48.
Ifamaterialissubdividedforlateruseinproductionoperations,thecontainerreceivingthematerialshouldbesuitableandshouldbesoidentifiedthatthefollowinginformationisavailable:HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final32Materialnameand/oritemcode;Receivingorcontrolnumberordistinctivecode;Weightormeasureofmaterialinthenewcontainer;andRe-evaluationorretestdateifappropriate.
Blending49.
Forthepurposeofthisdocument,blendingisdefinedastheprocessofcombiningmaterialswithinthesamespecificationtoproduceahomogeneousAPI.
In-processmixingoffractionsfromsinglebatches(e.
g.
,collectingseveralcentrifugeloadsfromasinglecrystallizationbatch)orcombiningfractionsfromseveralbatchesforfurtherprocessingisconsideredtobepartoftheproductionprocessandisnotconsideredtobeblending.
50.
Out-of-Specificationbatchesshouldnotbeblendedwithotherbatchesforthepurposeofmeetingspecifications.
Eachbatchincorporatedintotheblendshouldhavebeenmanufacturedusinganestablishedprocessandshouldhavebeenindividuallytestedandfoundtomeetappropriatespecificationspriortoblending.
51.
Acceptableblendingoperationsincludebutarenotlimitedto:BlendingofsmallbatchestoincreasebatchsizeBlendingoftailings(i.
e.
,relativelysmallquantitiesofisolatedmaterial)frombatchesofthesameAPItoformasinglebatch.
52.
Blendingprocessesshouldbeadequatelycontrolledanddocumentedandtheblendedbatchshouldbetestedforconformancetoestablishedspecificationswhereappropriate.
53.
Thebatchrecordoftheblendingprocessshouldallowtraceabilitybacktotheindividualbatchesthatmakeuptheblend.
54.
WherephysicalattributesoftheAPIarecritical(e.
g.
,APIsintendedforuseinsolidoraldosageformsorsuspensions),blendingoperationsshouldbevalidatedtoshowhomogeneityofthecombinedbatch.
Validationshouldincludetestingofcriticalattributes(e.
g.
,particlesizedistribution,bulkdensity,andtapdensity)thatmaybeaffectedbytheblendingprocess.
55.
Iftheblendingcouldadverselyaffectstability,stabilitytestingofthefinalblendedbatchesshouldbeperformed.
56.
Theexpiryorretestdateoftheblendedbatchshouldbebasedonthemanufacturingdateoftheoldesttailingsorbatchintheblend.
RecoveryHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3357.
Recovery(e.
g.
,frommotherliquororfiltrates)ofreactants,intermediates,ortheAPIisconsideredacceptable,providedthatapprovedproceduresexistfortherecoveryandtherecoveredmaterialsmeetspecificationssuitablefortheirintendeduse.
58.
Solventscanberecoveredandreusedinthesameprocessesorindifferentprocesses,providedthattherecoveryproceduresarecontrolledandmonitoredtoensurethatsolventsmeetappropriatestandardsbeforereuseorco-minglingwithotherapprovedmaterials.
59.
Freshandrecoveredsolventsandreagentscanbecombinedifadequatetestinghasshowntheirsuitabilityforallmanufacturingprocessesinwhichtheymaybeused.
60.
Theuseofrecoveredsolvents,motherliquors,andotherrecoveredmaterialsshouldbeadequatelydocumented.
PackagingOperations61.
Packagingoperationsshouldbeperformedaccordingtocomprehensiveanddetailedwrittenoperatingproceduresorspecifications,whichincludeidentificationofequipmentandpackaginglinesusedtopackagetheAPIorintermediate,thededicationofpackaginglines,ifnecessary,anddisposalproceduresfortheunusedprintedpackagingmaterials.
Packagingordersshouldbeindividuallynumbered.
62.
Labellingoperationsshouldbedesignedtopreventmix-ups.
ThereshouldbephysicalorspatialseparationfromoperationsinvolvingotherAPIs.
63.
Accesstothelabelstorageareasshouldbelimitedtoauthorisedpersonnel.
64.
Packagingandlabellingfacilitiesshouldbeinspectedimmediatelybeforeusetoensurethatallmaterialsnotneededforthenextpackagingoperationhavebeenremoved.
Thisexaminationshouldbedocumentedinthebatchproductionrecords,thefacilitylog,orotherdocumentationsystem.
65.
Thereshouldbedocumentedproceduresdesignedtoensurethatcorrectpackagingmaterialsandlabelsareused.
66.
Printingdevicesusedtoprintlabelsforpackagingoperationsshouldbecontrolledtoensurethatallimprintingconformstotheprintspecifiedinthebatchproductionrecord.
67.
Printedlabelsissuedforabatchshouldbecarefullyexaminedforproperidentityandconformitytospecificationsinthemasterproductionrecord.
Theresultsofthisexaminationshouldbedocumented.
68.
Containersshouldbecleanand,whereindicatedbythenatureoftheAPI,sanitizedtoensurethattheyaresuitablefortheirintendeduse.
Thesecontainersshouldnotbereactive,additive,orabsorptivesoastoalterthequalityoftheAPIbeyondthespecifiedlimits.
69.
Ifcontainersarere-used,theyshouldbecleanedinaccordancewithdocumentedproceduresandallpreviouslabelsshouldberemovedordefaced.
70.
LabelsusedoncontainersofAPIsshouldindicatethenameoridentifyingcode,thebatchnumberoftheproduct,andstorageconditions,whensuchinformationiscriticaltoassurethequalityofAPIs.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3471.
IftheAPIisintendedtobetransferredoutsidethecontrolofthefabricator'smaterialmanagementsystemthenameandaddressofthefabricator,quantityofcontents,andspecialtransportconditionsandanyspeciallegalrequirementsshouldalsobeincludedonthelabel.
ForAPIswithanexpirydate,theexpirydateshouldbeindicatedonthelabelandCoA.
ForAPIswitharetestdate,theretestdateshouldbeindicatedonthelabeland/ortheCoA.
72.
APIcontainersthataretransportedoutsideofthefabricator'scontrolshouldbesealedinamannersuchthat,ifthesealisbreachedormissing,therecipientwillbealertedtothepossibilitythatthecontentsmayhavebeenaltered.
73.
PackagedandlabelledAPIsshouldbeexaminedtoensurethatcontainersandpackagesinthebatchhavethecorrectlabel.
Thisexaminationshouldbepartofthepackagingoperation.
Resultsoftheseexaminationsshouldberecordedinthebatchproductionorcontrolrecords.
74.
Proceduresshouldbeusedtoreconcilethequantitiesoflabelsissued,used,destroyedandreturned.
Alldiscrepanciesfoundbetweenthenumberofcontainerslabelledandthenumberoflabelsissuedshouldbeinvestigated,andtheinvestigationshouldbeapprovedbythequalityunit(s).
75.
Uponcompletionofthelabellingoperation,allexcesslabelsbearingbatchnumbersorotherbatch-relatedprintingshouldbedestroyedandtheirdestructionrecorded.
Returnedlabelsshouldbestoredinamannerthatpreventsmix-upsandprovidesproperidentification.
76.
Obsoleteandout-datedlabelsshouldbedestroyed.
77.
AllAPIsthathavebeenpackagedandlabelledshouldbeheldinquarantineandbesoidentifieduntilreleasedbythequalitycontrolleddepartment.
78.
Packagingordersshouldincludethefollowinginformation(recordedatthetimeeachactionistaken):78.
1Thedate(s)andtime(s)ofthepackagingoperations;78.
2Theidentificationofthepersonnelwhoaresupervisingorverifyingpackagingoperationsandthewithdrawalofbulks;78.
3Theidentificationoftheoperatorsofthedifferentsignificantsteps;78.
4Whetherthecorrectproductsandpackagingmaterialsareused;78.
5Whetheranyon-lineprintingiscorrect;78.
6Wheneverpossible,samplesoftheprintedpackagingmaterialsused,includingspecimensbearingthebatchnumber,expirydate,andanyadditionaloverprinting,areattachedtopackagingorders.
78.
7Thecorrectfunctioningoflinemonitors;78.
8Handlingprecautionsappliedtoapartlypackagedproduct;andHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3578.
9Notesonanyspecialproblems,includingdetailsofanydeviationfromthepackaginginstructionswithwrittenapprovalbyqualifiedpersonnel.
ProductQualityReview79.
RegularqualityreviewsofAPIsshouldbeconductedbythefabricatorwiththeobjectiveofverifyingtheconsistencyoftheprocess.
Suchreviewsshouldnormallybeconductedanddocumentedannuallyandshouldincludeatleast:79.
1Areviewofcriticalin-processcontrolandcriticalAPItestresults;79.
2Areviewofallbatchesthatfailedtomeetestablishedspecification(s);79.
3Areviewofallcriticaldeviationsornon-conformancesorrelatedinvestigations;79.
4Areviewofanychangescarriedouttotheprocessesoranalyticalmethods;79.
5Areviewofresultsofthestabilitymonitoringprogram;79.
6Areviewofallquality-relatedreturns,complaintsandrecalls;and79.
7Areviewofadequacyofcorrectiveactions.
80.
Theresultsofthisreviewshouldbeevaluatedandanassessmentmadeofwhethercorrectiveactionoranyrevalidationshouldbeundertaken.
Reasonsforsuchcorrectiveactionshouldbedocumented.
Agreedcorrectiveactionsshouldbecompletedinatimelymanner.
SectionC.
02.
012(1)Everyfabricator,packager/labeller,distributorreferredtoinsectionC.
01A.
003,importerandwholesalerofadrugshallmaintain(a)asystemofcontrolthatpermitscompleteandrapidrecallofanylotorbatchofthedrugthatisonthemarket;and(b)aprogramofself-inspection.
(2)Everyfabricatorandpackager/labellerand,subjecttosubsections(3)and(4),everydistributorreferredtoinparagraphC.
01A.
003(b)andimporterofadrugshallmaintainasystemtoensurethatanylotorbatchofthedrugfabricatedandpackaged/labelledonpremisesotherthantheirownisfabricatedandpackaged/labelledinaccordancewiththerequirementsofthisDivision.
(3)Subsection(2)doesnotapplytoadistributorifthedrugisfabricated,packaged/labelledandtestedinCanadabyapersonwhoholdsanestablishmentlicencethatauthorizesthoseactivitiesinrespectofthatdrug.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final36(4)Subsection(2)doesnotapplytoadistributororimporterifthedrugisfabricatedorpackaged/labelledinanMRAcountryatarecognizedbuildingandbothofthefollowingrequirementsaremet:(a)theaddressofthebuildingissetoutintheirestablishmentlicence;and(b)theyretainacopyofthebatchcertificateforeachlotorbatchofthedrugthattheyreceive.
RationaleThepurposeofarecallistoremovefromthemarket,anAPIthatrepresentsanunduehealthrisk.
APIsthathaveleftthepremisesofafabricator,packager/labeller,distributor,andimporterofAPIscanbefoundinavarietyoflocations.
Dependingontheseverityofthehealthrisk,itmaybenecessarytorecallaproducttooneleveloranother.
Fabricators,packagers/labellers,distributors,importersandwholesalersofAPIsareexpectedtobeabletorecallfromalltheirdirectcustomersthroughoutthesupplychain.
AdditionalguidanceregardingrecallscanbefoundinHealthCanada'sdocumentsentitledRecallPolicy(POL-0016)andGUI-0001.
ThisRegulationalsorequiresfabricators,packagers/labellers,distributors,andimportertomaintainaprogramofself-inspection.
Thepurposeofself-inspectionistoevaluatethecompliancewithGMPinallaspectsofproductionandqualitycontrol.
Theself-inspectionprogramisdesignedtodetectanyshortcomingsintheimplementationofGMPandtorecommendthenecessarycorrective/preventativeactions.
APIsofferedforsaleinCanada,regardlessofwhethertheyaredomesticallyproducedorimported,mustmeettherequirementsofPartC,Division2oftheFoodandDrugRegulations.
Contractproductionandanalysismustbecorrectlydefined,agreedon,andcontrolledinordertoavoidmisunderstandingsthatcouldresultinaproduct,workoranalysisofunsatisfactoryquality.
Normally,awrittenagreementexistsbetweenthepartiesinvolved,andthatdocumentclearlyestablishesthedutiesofeachparty.
Interpretation1.
Proceduresshouldexistfornotifyingresponsiblemanagementinatimelymannerofregulatoryinspections,seriousGMPdeficiencies,productdefectsandrelatedactions(e.
g.
,qualityrelatedcomplaints,recalls,regulatoryactions,etc.
).
2.
ThereshouldbeawrittenprocedurethatdefinesthecircumstancesunderwhicharecallofanAPIshouldbeconsidered.
3.
Therecallprocedureshoulddesignatewhoshouldbeinvolvedinevaluatingtheinformation,howarecallshouldbeinitiated,whoshouldbeinformedabouttherecallandhowtherecalledmaterialshouldbetreated),specifically:3.
1HealthCanadashouldbenotifiedoftherecall.
3.
2Therecallprocedureshouldbecapableofbeingputintooperationatanytime,duringandoutsidenormalworkinghours.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final373.
3Theprogressandefficacyoftherecallshouldbeassessedandrecordedatintervals,andafinalreportshouldbeissued(includingafinalreconciliation).
4.
AsystemshouldbeinplacebywhichthedistributionofeachbatchofAPIcanbereadilydeterminedtopermititsrecall.
Thisshouldincludeanyproductsintransit,anysamplesremovedbythequalitycontroldepartmentandanyprofessionalsamplesthathavebeendistributed.
4.
1Awrittenagreementshouldclearlydescriberespectiveresponsibilitiesofallpartiesinvolvedwithrespecttorecalls.
5.
Unlessthereisanalternativesystemtopreventtheunintentionalorunauthorizeduseofquarantined,rejected,returned,orrecalledmaterials,separatestorageareasshouldbeassignedfortheirtemporarystorageuntilthedecisionastotheirfutureusehasbeentaken.
6.
AllCanadianandforeignestablishmentsinvolvedintheproduction,distributionandimportation,includingagents,brokers,re-packagersandre-labellersoftherecalledAPIshouldbenotifiedandmaintainrecordsofallcomplaintsandrecallsthatcometotheirattention.
7.
InordertoverifycompliancewithDivision2,PartCoftheFoodandDrugRegulations,regularself-inspectionsappropriatetothetypeofoperationsofthecompanyshouldbeperformedinaccordancewithanapprovedschedule.
7.
1Theself-inspectionteamshouldincludepersonnelwhoaresuitablytrainedandqualifiedinGMP.
8.
Acomprehensivewrittenprocedurethatdescribesthefunctionoftheself-inspectionprogramshouldbeavailable.
Self-inspectionfindingsandcorrective/preventiveactionsshouldbedocumentedandbroughttotheattentionofresponsiblemanagementofthefirm.
Agreedcorrective/preventiveactionsshouldbecompletedinatimelyandeffectivemanner.
9.
AllCanadianandforeignestablishmentsinvolvedintheproduction,distributionandimportation,includingagents,brokers,re-packagersandre-labellersshouldcomplywithGMPasdefinedinthisGuide.
10.
Contractfabricators(includinglaboratories)shouldbeevaluatedbythecontractgivertoensureGMPcomplianceofthespecificoperationsoccurringatthecontractsites.
11.
Toensurecomplianceofcontractorsperformingfabricationorpackaging/labelling:11.
1Allarrangementsforcontractfabricationorpackaging/labellingshouldbeinaccordancewiththecurrentregulatoryfilingfortheAPIconcerned.
11.
2Thereshouldbeawrittenagreementcoveringthefabricationorpackaging/labellingarrangedamongthepartiesinvolved.
TheagreementshouldspecifytheirrespectiveGMPresponsibilitiesrelatingtothefabricationorpackaging/labellingandqualitycontroloftheAPI.
11.
2.
1Technicalaspectsoftheagreementshouldbedrawnupbyqualifiedpersonnelsuitablyknowledgeableinpharmaceuticaltechnology,andGMP.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final3811.
2.
2TheagreementshouldpermitthecontractgivertoauditthefacilitiesofthecontractorforcompliancewithGMP.
11.
2.
3Theagreementshouldclearlydescribeasaminimumwhoisresponsiblefor:11.
2.
3.
1purchasing,sampling,testingandreleasingmaterials;11.
2.
3.
2undertakingproduction,quality,andin-processcontrols;and11.
2.
3.
3processvalidation.
11.
2.
4Nosubcontractingofanyworkshouldoccurwithoutwrittenauthorizationbythecontractgiverandapprovalofthearrangements.
11.
2.
5Theagreementshouldspecifythewayinwhichthequalitycontroldepartmentofthedistributororimporterreleasingthelotorbatchforsale,ensuresthateachlotorbatchhasbeenfabricatedandpackaged/labelledincompliancewiththecurrentregulatoryfilingfortheAPIconcerned,ifapplicable.
11.
2.
6Theagreementshoulddescribethehandlingofrawmaterials,packagingmaterials,intermediates,andAPIsiftheyarerejected.
11.
3Thecontractor'scomplaint/recallproceduresshouldspecifythatanyrecordsrelevanttoassessingthequalityofadrugproductintheeventofcomplaintsorasuspecteddefectareaccessibletothedistributororimporter.
11.
4Thefabricator,packager/labeller,distributor,orimportershouldprovidethecontractorwithalltheinformationnecessarytocarryoutthecontractedoperationscorrectlyinaccordancewiththecurrentregulatoryfilingassociatedtotheAPIconcerned,ifapplicable,andanyotherlegalrequirements.
Thefabricator,packager/labeller,distributor,orimportershouldensurethatthecontractorisfullyawareofanyproblemsassociatedwiththeproduct,workorteststhatmightposeahazardtopremises,equipment,personnel,othermaterialsorotherproducts.
11.
4.
1Changesintheprocess,equipment,testmethods,specifications,orothercontractualrequirementsshouldnotbemadeunlessthecontractgiverisinformedandapprovesthechanges.
11.
5Thefabricator,packager/labeller,distributor,orimportershouldberesponsibleforassessingthecontractor'scontinuingcompetencetocarryouttheworkortestsrequiredinaccordancewiththeprinciplesofGMPdescribedintheseguidelines.
11.
5.
1DistributorsofAPIsfabricated,packaged/labelledandtestedatCanadiansitesshouldberequiredonlytohaveacopyoftherelevantvalidCanadianestablishmentlicenceheldbytheCanadianfabricatororpackager/labellerortester.
11.
5.
2ImportersofAPIsfabricated,packaged/labelled,ortestedataforeignsiteshouldmeettherequirementsdescribedinHealthCanada'sgeneralNoticetoStakeholders–AmendedFoodandDrugsRegulationsforActiveIngredients.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final39QualityControlDepartmentSectionC.
02.
013(1)Everyfabricator,packager/labeller,wholesaler,distributorreferredtoinsectionC.
01A.
003andimporterofadrugshallhaveontheirpremisesinCanadaaqualitycontroldepartmentthatissupervisedbypersonneldescribedinsectionC.
02.
006.
(2)ExceptinthecaseofawholesaleroradistributorreferredtoinparagraphC.
01A.
003(a),thequalitycontroldepartmentshallbeadistinctorganizationalunitthatfunctionsandreportstomanagementindependentlyofanyotherfunctionalunit,includingthemanufacturing,processing,packagingorsalesunit.
RationaleQualitycontrolisthepartofGMPconcernedwithsampling,specifications,andtestingandwiththeorganization,documentation,andreleaseprocedures.
ThisRegulationensuresthatthenecessaryandrelevanttestsareactuallycarriedoutandthatrawmaterialsandpackagingmaterialsarenotreleasedforuseandAPIsarenotreleasedforsaleorfurtherusedinfabrication,untiltheirqualityhasbeenjudgedtobesatisfactory.
QualitycontrolisnotconfinedtolaboratoryoperationsbutmustbeincorporatedintoallactivitiesanddecisionsconcerningthequalityoftheAPI.
TherationalefortherequirementthatthequalitycontroldepartmentbesupervisedbyqualifiedpersonnelisoutlinedunderRegulationC.
02.
006.
Interpretation1.
Thequalityunit(s)shouldbeinvolvedinallquality-relatedmatters.
2.
Thequalityunitshouldreviewandapproveallquality-relateddocuments.
Approvedwrittenproceduresshouldbeavailableforthereceipt,identification,quarantine,storage,handling,sampling,label,dispensing,processing,distribution,inspecting,testing,andapprovalorrejectionofrawmaterials,packagingmaterials,in-processAPIs,APIs,andfortherecordingandstorageoflaboratorydata.
3.
Thequalityunitofthefabricatorandpackager/labellershouldbeindependentofproductionandfulfillbothqualityassurance(QA)andqualitycontrol(QC)responsibilities.
ThiscanbeintheformofseparateQAandQCunitsorasingleindividualorgroup,dependinguponthesizeandstructureoftheorganization.
4.
Thequalityunitshouldhaveaccesstofacilities,includingalaboratory,trainedpersonnel,andequipmentinordertofulfillitsdutiesandresponsibilities.
SectionC.
02.
014HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final40(1)ExceptinthecaseofawholesaleroradistributorreferredtoinparagraphC.
01A.
003(a),nolotorbatchofadrugmaybemadeavailableforfurtheruseinfabricationorforsaleunlessthepersoninchargeofthequalitycontroldepartmentapprovesthefurtheruseorthesale.
(2)Adrugthatisreturnedtoitsfabricator,packager/labeller,wholesaler,distributorreferredtoinsectionC.
01A.
003orimportershallnotbemadeavailableforfurtheruseinfabricationorforfurthersaleunlessthepersoninchargeofthequalitycontroldepartmentapprovesthefurtheruseorfurthersale.
(3)Nolotorbatchofarawmaterialorpackaging/labellingmaterialshallbeusedinthefabricationorpackaging/labellingofadrugunlessthepersoninchargeofthequalitycontroldepartmentapprovestheuse.
(4)Nolotorbatchofadrugshallbereprocessedunlessthepersoninchargeofthequalitycontroldepartmentapprovesthereprocessing.
RationaleTheresponsibilityfortheapprovalofallrawmaterials,packagingmaterialsandAPIsisvestedinthequalitycontroldepartment.
Itisveryimportantthatadequatecontrolsbeexercisedbythisdepartmentinordertoguaranteethequalityoftheendproduct.
Tomaintainthislevelofquality,itisalsoimportanttoexamineallreturnedAPIsandtogivespecialattentiontoreprocessedAPIs.
Interpretation1.
AlldecisionsmadebythequalitycontroldepartmentpursuanttoRegulationC.
02.
014shouldbesignedanddatedbythepersoninchargeofthequalitycontroldepartmentorbyadesignatedalternatemeetingtherequirementsdescribedunderSectionC.
02.
006.
Thenamesofsuchpersonsshouldbespecified.
2.
Nomaterialsshouldbereleasedorusedbeforethesatisfactorycompletionofevaluationbythequalityunit(s)unlessthereareappropriatesystemsinplacetoallowforsuchuse(e.
g.
releaseunderquarantineortheuseofrawmaterialsorintermediatespendingcompletionofevaluation).
3.
TheassessmentforthereleaseofAPIsshouldembraceallrelevantfactors,includingtheproductionconditions,theresultsofin-processtesting,thefabricationandpackagingdocumentation,compliancewiththeAPIsspecifications,anexaminationofthefinishedpackage,andifapplicable,areviewofthestorageandtransportationconditions.
4.
APIsshouldonlybereleasedfordistributiontothirdpartiesaftertheyhavebeenreleasedbythequalityunit(s).
APIscanbetransferredunderquarantinetoanotherunitunderthecompany'scontrolwhenauthorizedbythequalityunit(s)andifappropriatecontrolsanddocumentationareinplace.
5.
Thequalitycontroldepartmentshouldensurethatrawmaterialsandpackagingmaterialsarequarantined,sampled,tested,andreleasedpriortotheiruseinthefabricationorpackaging/labellingofadrug.
6.
Anydeviations,non-conformances,andmalfunctionsorerrorsincludingthosepertainingtopremises,equipment,sanitation,andtesting,suchasdeviationsfromwrittenprocedures,thatmayhaveanimpactHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final41onthequalityandsafetyofbatchespendingreleaseorreleased,shouldbeassessed.
Criticaldeviationsshouldbeinvestigated,andtheinvestigationanditsconclusionshouldbedocumented.
7.
Rejectedmaterials,suchasAPIs,failingtomeetestablishedspecifications,shouldbeidentifiedassuchandquarantined.
Thesematerialsshouldbereturnedtothevendors,reprocessed,reworked,ordestroyed.
Actionstakenshouldberecorded.
8.
APIsreturnedfromthemarketshouldbedestroyedunlessithasbeenascertainedthattheirqualityissatisfactory.
Returnedgoodsmaybeconsideredforresaleonlyaftertheyhavebeenassessedinaccordancewithawrittenprocedure.
Thereasonforthereturn,thenatureoftheproduct,thestorageandtransportationconditions,theAPI'sconditionandhistory,andthetimeelapsedsinceitwasoriginallysoldshouldbetakenintoconsiderationinthisassessment.
IftheconditionsunderwhichreturnedAPIshavebeenstoredorshippedbeforeorduringtheirreturnortheconditionoftheircontainerscastsdoubtontheirquality,thereturnedAPIsshouldbereprocessed,reworked,ordestroyed,asappropriate.
Recordsofanyactiontakenshouldbemaintained.
8.
1Documentationshouldbeavailabletosupporttherationaletoplacereturnedgoodsintoinventoryforfurtherresale.
Reworking9.
Beforeadecisionistakentoreworkbatchesthatdonotconformtoestablishedstandardsorspecifications,aninvestigationintothereasonfornon-conformanceshouldbeperformed.
10.
Batchesthathavebeenreworkedshouldbesubjectedtoappropriateevaluation,testing,stabilitytestingifwarranted,anddocumentationtoshowthatthereworkedproductisofequivalentqualitytothatproducedbytheoriginalprocess.
Concurrentvalidationisoftentheappropriatevalidationapproachforreworkprocedures.
Thisallowsaprotocoltodefinethereworkprocedure,howitwillbecarriedout,andtheexpectedresults.
Ifthereisonlyonebatchtobereworked,thenareportcanbewrittenandthebatchreleasedonceitisfoundtobeacceptable.
11.
Proceduresshouldprovideforcomparingtheimpurityprofileofeachreworkedbatchagainstbatchesmanufacturedbytheestablishedprocess.
Whereroutineanalyticalmethodsareinadequatetocharacterizethereworkedbatch,additionalmethodsshouldbeused.
Reprocessing12.
IntroducinganintermediateorAPI,includingonethatdoesnotconformtostandardsorspecifications,backintotheprocessandreprocessingbyrepeatingacrystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps(e.
g.
,distillation,filtration,chromatography,milling)thatarepartoftheestablishedmanufacturingprocessisgenerallyconsideredacceptable.
However,ifsuchreprocessingisusedforamajorityofbatches,suchreprocessingshouldbeincludedaspartofthestandardmanufacturingprocess.
13.
Continuationofaprocessstepafteranin-processcontroltesthasshownthatthestepisincompleteisconsideredtobepartofthenormalprocess.
Thisisnotconsideredtobereprocessing.
14.
Introducingunreactedmaterialbackintoaprocessandrepeatingachemicalreactionisconsideredtobereprocessingunlessitispartoftheestablishedprocess.
SuchreprocessingshouldbeprecededbycarefulHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final42evaluationtoensurethatthequalityoftheintermediateorAPIisnotadverselyimpactedduetothepotentialformationofby-productsandover-reactedmaterials.
15.
DocumentsshouldbeavailableandapprovedbytheQCDepartment.
SectionC.
02.
015(1)Allfabrication,packaging/labelling,testing,storage,andtransportationmethodsandproceduresthatmayaffectthequalityofadrugshallbeexaminedandapprovedbythepersoninchargeofthequalitycontroldepartmentbeforetheirimplementation.
(2)Thepersoninchargeofthequalitycontroldepartmentshallcausetobeinvestigatedanycomplaintorinformationthatisreceivedrespectingthequalityofadrugoritsdeficienciesorhazardsandcauseanynecessarycorrectiveactiontobetaken,inthecasewherethecomplaintorinformationrelatestoanactivityoverwhichthedepartmentexercisesqualitycontrol.
(2.
1)Inthecasewherethecomplaintorinformationthatisreceiveddoesnotrelatetoanactivityoverwhichthequalitycontroldepartmentexercisesqualitycontrol,thepersoninchargeofthedepartmentshallforwardthecomplaintorinformationtothepersoninchargeofthequalitycontroldepartmentthatexercisesqualitycontroloverthatactivity.
(3)ThepersoninchargeofthequalitycontroldepartmentshallcausealltestsorexaminationsrequiredpursuanttothisDivisiontobeperformedbyacompetentlaboratory.
RationalePharmaceuticalprocessesandproductsmustbedesignedanddevelopedtakingGMPrequirementsintoaccount.
Productionproceduresandothercontroloperationsareindependentlyexaminedbythequalitycontroldepartment.
Properstorage,transportation,anddistributionofmaterialsandproductsminimizeanyrisktotheirquality.
Complaintsmayindicateproblemsrelatedtoquality.
Bytracingtheircauses,onecandeterminewhichcorrectivemeasuresshouldbetakentopreventrecurrence.
Havingtestscarriedoutbyacompetentlaboratoryprovidesassurancethattestresultsaregenuineandaccurate.
Writtenagreementsforconsultantsshoulddescribetheeducation,training,andexperienceoftheirpersonnelandthetypeofservicesprovided,andshouldbeavailableforexaminationandinspection.
WrittenagreementsforcontractlaboratoriesshoulddescribethetypeofservicesprovidedandtheircompliancewithGMPsandshouldbeavailableforexaminationandinspection.
Recordsoftheactivitiescontractedshouldbemaintained.
Interpretation1.
Proceduresshouldexistfornotifyingresponsiblemanagementinatimelymannerofregulatoryinspections,seriousGMPdeficiencies,productdefectsandrelatedactions(e.
g.
,qualityrelatedcomplaints,recalls,regulatoryactions,etc.
).
2.
AformalchangecontrolsystemshouldbeestablishedtoevaluateallchangesthatmayaffecttheproductionandcontroloftheAPI.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final433.
Writtenproceduresshouldprovidefortheidentification,documentation,appropriatereview,andapprovalofchangesinrawmaterials,specifications,analyticalmethods,facilities,supportsystems,equipment(includingcomputerhardware),processingsteps,labellingandpackagingmaterials,andcomputersoftware.
4.
AnyproposalsforGMPrelevantchangesshouldbedrafted,reviewed,andapprovedbytheappropriateorganisationalunits,andreviewedandapprovedbythequalityunit(s).
5.
ThepotentialimpactoftheproposedchangeonthequalityoftheAPIshouldbeevaluated.
Ariskassessmentmayhelpindeterminingtheleveloftesting,validation,anddocumentationneededtojustifychangestoavalidatedprocess.
Changescanbeclassified(e.
g.
,asminorormajor)dependingonthenatureandextentofthechanges,andtheeffectsthesechangesmayimpartontheprocess.
Scientificjudgementshoulddeterminewhatadditionaltestingandvalidationstudiesareappropriatetojustifyachangeinavalidatedprocess.
5.
1Thepotentialforcriticalchangestoaffectestablishedretestorexpirydatesshouldbeevaluated.
Ifnecessary,samplesoftheAPIproducedbythemodifiedprocesscanbeplacedonanacceleratedstabilityprogramand/orcanbeaddedtothestabilitymonitoringprogram.
5.
2Afterthechangehasbeenimplemented,thereshouldbeanevaluationofthefirstbatchesproducedortestedunderthechange.
5.
3Whenimplementingapprovedchanges,measuresshouldbetakentoensurethatalldocumentsaffectedbythechangesarerevised.
6.
CurrentdosageformfabricatorsshouldbenotifiedofchangesfromestablishedproductionandprocesscontrolproceduresthatcanimpactthequalityoftheAPI.
7.
Allestablishmentsinvolvedintheproduction,distributionandimportation,includingagents,brokers,re-packagersandre-labellersshouldhaveasysteminplacetorecordandinvestigateallqualityrelatedcomplaint,whetherreceivedorallyorinwriting,inaccordancewithwrittenprocedures.
7.
1Ifthesituationwarrants,theagents,brokers,traders,distributors,re-packagers,orre-labellersshouldreviewthecomplaintwiththeoriginalAPIfabricatorinordertodeterminewhetheranyfurtheraction,eitherwithothercustomerswhomayhavereceivedthisAPIorwiththeregulatoryauthority,orboth,shouldbeinitiated.
Theinvestigationintothecauseforthecomplaintorrecallshouldbeconductedanddocumentedbytheappropriateparty.
7.
2WhereacomplaintisreferredtotheoriginalAPIfabricator,therecordmaintainedbytheagents,brokers,traders,distributors,re-packagers,orre-labellersshouldincludeanyresponsereceivedfromtheoriginalAPIfabricator(includingdateandinformationprovided).
8.
Recordsofcomplaintsshouldberetainedinordertoevaluatetrends,product-relatedfrequencies,andseveritywithaviewtotakingadditional,andifappropriate,immediatecorrectiveactions.
Alldecisionsandmeasurestakenasaresultofacomplaintarerecorded.
9.
Allspecifications,samplingplans,andtestproceduresshouldbescientificallysoundandappropriatetoensurethatrawmaterials,APIs,andlabelsandpackagingmaterialsconformtoestablishedstandardsofqualityand/orpurity.
SpecificationsandtestproceduresshouldbeconsistentwiththoseincludedintheHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final44registration/filing.
Therecanbespecificationsinadditiontothoseintheregistration/filing.
Specifications,samplingplans,andtestprocedures,includingchangestothem,shouldbedraftedbytheappropriateorganizationalunitandreviewedandapprovedbythequalityunit(s).
10.
Laboratorycontrolsshouldbefollowedanddocumentedatthetimeofperformance.
Anydeparturesfromtheabovedescribedproceduresshouldbedocumentedandexplained.
11.
Laboratorycontrolrecordsshouldincludecompletedataderivedfromalltestsconductedtoensurecompliancewithestablishedspecificationsandstandards,includingexaminationsandassays,asfollows:11.
1Adescriptionofsamplesreceivedfortesting,includingthematerialnameorsource,batchnumberorotherdistinctivecode,datesamplewastaken,and,whereappropriate,thequantityanddatethesamplewasreceivedfortesting;11.
2Astatementoforreferencetoeachtestmethodused;11.
3Astatementoftheweightormeasureofsampleusedforeachtestasdescribedbythemethod;dataonorcross-referencetothepreparationandtestingofreferencestandards,reagentsandstandardsolutions;11.
4Acompleterecordofallrawdatageneratedduringeachtest,inadditiontographs,charts,andspectrafromlaboratoryinstrumentation,properlyidentifiedtoshowthespecificmaterialandbatchtested;11.
5Arecordofallcalculationsperformedinconnectionwiththetest,including,forexample,unitsofmeasure,conversionfactors,andequivalencyfactors;11.
6Astatementofthetestresultsandhowtheycomparewithestablishedacceptancecriteria;11.
7Thesignatureofthepersonwhoperformedeachtestandthedate(s)thetestswereperformed;and11.
8Thedateandsignatureofasecondpersonshowingthattheoriginalrecordshavebeenreviewedforaccuracy,completeness,andcompliancewithestablishedstandards.
12.
Reagentsandstandardsolutionsshouldbepreparedandlabelledfollowingwrittenprocedures.
"Useby"datesshouldbeappliedasappropriateforanalyticalreagentsorstandardsolutionsanddatashouldbeavailabletosupporttheseexpiryorretestdates.
13.
ThetestsshouldbeperformedbyalaboratorythatmeetsallrelevantGMPrequirements.
13.
1Laboratoryfacilitiesaredesigned,equipped,andmaintainedtoconducttherequiredtesting.
13.
1.
1Inthemicrobiologylaboratory,environmentalmonitoringshouldbeperformedperiodically.
Microbiologicalculturesandsampletestingarehandledinanenvironmentthatminimizescontamination.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final4513.
1.
2ThefacilityusedtoperformthesterilitytestingshouldcomplywiththemicrobiallimitsofanasepticproductionfacilitywhichshouldconformtoGradeAwithinaGradeBbackgroundorinanisolatorofaGradeAwithinandappropriatebackgroundandlimitedaccesstonon-essentialpersonnel.
13.
2TheindividualinchargeofthelaboratoryshouldmeetpersonnelrequirementsassetforthinC.
02.
006andreporttoapersonwhohasthesequalifications.
13.
3Laboratorypersonnelshouldbesufficientinnumberandbequalifiedtocarryouttheworktheyundertake.
13.
4Laboratorycontrolequipmentandinstrumentsshouldbesuitedtothetestingproceduresundertaken.
EquipmentandrecordsshouldbemaintainedaspertheinterpretationsunderC.
02.
005.
13.
5Computerizedsystemsarevalidated,andspreadsheetsarequalified.
13.
6Waterusedformicrobialandanalyticaltestsmeetstherequirementsofthetestorassayinwhichitisused.
13.
7Allreagentsandculturemediaarerecordeduponreceiptorpreparation.
Reagentsmadeupinthelaboratoryarepreparedaccordingtowrittenproceduresandareproperlylabelled.
13.
7.
1Preparedmediaaresterilizedusingvalidatedproceduresandstoredundercontrolledtemperatures.
13.
7.
2Preparedmediaareproperlylabelledwiththelotnumbers,expirationdateandmediaidentification.
Theexpirationdateofmediaissupportedbygrowth-promotiontestingresultsthatshowtheperformanceofthemediastillmeetsacceptancecriteriauptotheexpirationdate.
13.
7.
3Sterilityandgrowth-promotiontestingareperformedtoverifythesuitabilityofculturemedia.
13.
7.
4Allpurchasedreadytousemediareceivedareaccompaniedbyacertificateofanalysiswithexpirydateandrecommendedstorageconditionsaswellasthequalitycontrolorganismsusedingrowth-promotionandselectivitytestingofthatmedia.
13.
7.
4.
1Proceduresareinplacetoensurethatmediaaretransportedunderconditionsthatminimizethelossofmoistureandcontrolthetemperature.
13.
7.
4.
2Mediaarestoredaccordingtothevendor'sinstructions.
13.
7.
4.
3Sterilityandgrowth-promotiontestingareperformedonlotsreceived,unlessthevendoriscertified.
Periodicconfirmatorytestingisperformedforreadytousemediareceivedfromeachcertifiedvendor.
13.
7.
4.
4Recordsaremaintained.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final4613.
8ReferencestandardsareavailableintheformofthecurrentreferencestandardslistedinScheduleBtotheFoodandDrugsAct.
Whensuchstandardshavenotbeenestablishedorareunavailable,primarystandardscanbeused.
SecondarystandardsareverifiedagainstaScheduleBreferencestandardoragainsttheprimarystandardandaresubjecttocompleteconfirmatorytestingatpredeterminedintervals.
Allreferencestandardsarestoredandusedinamannerthatwillnotadverselyaffecttheirquality.
Recordsrelatingtotheirtesting,storage,andusearemaintained.
13.
9OutofSpecification(OOS)testresultsareinvestigatedtodeterminethecauseoftheOOS.
13.
9.
1Proceduresareinplacetodescribethestepstobetakenaspartoftheinvestigation.
13.
9.
2Inthecaseofaclearlyidentifiedlaboratoryorstatisticalerror,theoriginalresultsmaybeinvalidated,andthetestrepeated.
Theoriginalresultsshouldberetainedandanexplanationrecorded.
13.
9.
3Whenthereisnoclearlyidentifiedlaboratoryorstatisticalerrorandretestingisperformed,thenumberofreteststobeperformedontheoriginalsampleand/oranewsample,andthestatisticaltreatmentoftheresultantdata,arespecifiedinadvanceintheprocedure.
13.
9.
4Allvalidtestresults,bothpassingandsuspect,shouldbereportedandconsideredinbatchreleasedecisions.
13.
9.
5IftheoriginalOOSresultisfoundtobevalid,acompleteinvestigation,includingthebatchaffected,isconductedandrecorded.
Theinvestigationshouldbeperformedinaccordancetowrittenproceduresandshouldincludeanassessmentofrootcause,descriptionofcorrectiveactionsandpreventiveactionscarriedoutandconclusions.
13.
9.
6Out-of-specificationinvestigationsarenotnormallyneededforin-processteststhatareperformedforthepurposeofmonitoringand/oradjustingtheprocess.
14.
PrimaryreferencestandardsshouldbeobtainedasappropriateforthemanufactureofAPIs.
Thesourceofeachprimaryreferencestandardshouldbedocumented.
Recordsshouldbemaintainedofeachprimaryreferencestandard'sstorageanduseinaccordancewiththesupplier'srecommendations.
Primaryreferencestandardsobtainedfromanofficiallyrecognisedsourcearenormallyusedwithouttestingifstoredunderconditionsconsistentwiththesupplier'srecommendations.
15.
Whereaprimaryreferencestandardisnotavailablefromanofficiallyrecognizedsource,an"in-houseprimarystandard"shouldbeestablished.
Appropriatetestingshouldbeperformedtoestablishfullytheidentityandpurityoftheprimaryreferencestandard.
Appropriatedocumentationofthistestingshouldbemaintained.
16.
Secondaryreferencestandardsshouldbeappropriatelyprepared,identified,tested,approved,andstored.
Thesuitabilityofeachbatchofsecondaryreferencestandardshouldbedeterminedpriortofirstusebycomparingagainstaprimaryreferencestandard.
Eachbatchofsecondaryreferencestandardshouldbeperiodicallyre-qualifiedinaccordancewithawrittenprotocol.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final4717.
Completerecordsshouldalsobemaintainedfor:17.
1Anymodificationstoanestablishedanalyticalmethod;17.
2Periodiccalibrationoflaboratoryinstruments,apparatus,gauges,andrecordingdevices;17.
3AllstabilitytestingperformedonAPIs;and17.
4Out-of-specificationinvestigations.
18.
Wherecriticaldataareenteredintoacomputerizedsystemmanually,thereshouldbeanadditionalcheckontheaccuracyoftheentry.
Thiscanbedonebyasecondoperatororbythesystemitself.
19.
IncidentsrelatedtocomputerizedsystemsthatcouldaffectthequalityofAPIsorthereliabilityofrecordsortestresultsshouldberecordedandinvestigated.
20.
Changestothecomputerizedsystemshouldbemadeaccordingtoachangeprocedureandshouldbeformallyauthorized,documentedandtested.
Recordsshouldbekeptofallchanges,includingmodificationsandenhancementsmadetothehardware,softwareandanyothercriticalcomponentofthesystem.
Theserecordsshoulddemonstratethatthesystemismaintainedinavalidatedstate.
21.
Alldeviation,investigation,andOOSreportsshouldbereviewedaspartofthebatchrecordreviewbeforethebatchisreleased.
22.
ToensurecomplianceofcontractorsconductingtestingrequiredunderPartC,Division2oftheFoodandDrugRegulations:22.
1ACanadiancontractlaboratorymusthavearelevantvalidcurrentestablishmentlicence.
AforeigntestingsitemustbelistedonaCanadianestablishmentlicence,asdescribedinHealthCanada'spolicydocumententitledGuidanceonEvidencetoDemonstrateDrugGMPComplianceofForeignSites(GUI-0080),22.
2AllarrangementsforexternaltestingareinaccordancewiththecurrentregulatoryfilingfortheAPIconcernedifapplicable,includingthetestingofintermediates,rawmaterials,packagingmaterialsandallothernecessarytestingrequiredbyPartC,Division2oftheFoodandDrugRegulations,and22.
3Thereisawrittenagreementcoveringallactivitiesoftestingbetweenthecontractlaboratoryandthepartiesinvolved.
Theagreementspecifiestheirrespectiveresponsibilitiesrelatingtoallaspectsoftesting.
22.
3.
1TechnicalaspectsoftheagreementaredrawnupbyqualifiedpersonnelsuitablyknowledgeableinanalysisandGMP,22.
3.
2Theagreementpermitsauditofthefacilitiesandoperationsoftheexternallaboratory,22.
3.
3Theagreementclearlydescribes,asaminimum,whoisresponsiblefor:22.
3.
3.
1collection,transportationandstorageconditionsofsamplesbeforetesting,HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final4822.
3.
3.
2keepingstabilitysamplesatpredeterminedtemperaturesandhumidity,ifapplicable,22.
3.
3.
3testingmethodstobeused,limitsandtestmethodvalidation,and22.
3.
3.
4retentionofanalyticalresultsandsupportingdocumentation(additionalguidanceunderinterpretationsofC.
02.
021).
22.
3.
4Nosubcontractingofanyworkshouldoccurwithoutwrittenauthorization.
23.
Thefabricatorshouldensurethatthecontractacceptor(contractor)fortransportationoftheAPIknowsandfollowstheappropriatetransportandstorageconditions.
PackagingMaterialTestingSectionC.
02.
016(1)Eachlotorbatchofpackagingmaterialshall,priortoitsuseinthepackagingofadrug,beexaminedortestedagainstthespecificationsforthatpackagingmaterial.
(2)Nolotorbatchofpackagingmaterialshallbeusedinthepackagingofadrugunlessthelotorbatchofpackagingmaterialcomplieswiththespecificationsforthatpackagingmaterial.
(3)Thespecificationsreferredtoinsubsections(1)and(2)shall(a)beinwriting;(b)beacceptabletotheDirectorwhoshalltakeintoaccountthespecificationscontainedinanypublicationmentionedinScheduleBtotheAct;and(c)beapprovedbythepersoninchargeofthequalitycontroldepartment.
SectionC.
02.
017(1)TheexaminationortestingreferredtoinsectionC.
02.
016shallbeperformedonasampletaken(a)afterreceiptofeachlotorbatchofpackagingmaterialonthepremisesofthepersonwhopackagesadrug;or(b)subjecttosubsection(2),beforereceiptofeachlotorbatchofpackagingmaterialonthepremisesofthepersonwhopackagesadrug,if(i)thatpersonHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final49(A)hasevidencesatisfactorytotheDirectortodemonstratethatpackagingmaterialssoldtohimbythevendorofthatlotorbatchofpackagingmaterialareconsistentlymanufacturedinaccordancewithandconsistentlycomplywiththespecificationsforthosepackagingmaterials;and(B)undertakesperiodiccompleteconfirmatoryexaminationortestingwithafrequencysatisfactorytotheDirector,(ii)thepackagingmaterialhasnotbeentransportedorstoredunderconditionsthatmayaffectitscompliancewiththespecificationsforthatpackagingmaterial.
(2)Afteralotorbatchofpackagingmaterialisreceivedonthepremisesofthepersonwhopackagesadrug,(a)thelotorbatchofthepackagingmaterialshallbeexaminedortestedforidentity;and(b)thelabelsshallbeexaminedortestedinordertoensurethattheycomplywiththespecificationsforthoselabels.
RationaleThesuitabilityofAPIsfortheirsubsequentusedependsnotonlyontheproductionprocessbutalsoontheprotectionoftheAPIfromcontaminationordegradationbeforeuse.
Careshouldbetakeninthechoiceofcontainer,and,asthefillingofsolidAPIsisoftenadustyoperation,howthisisfilledandclosedwillaffectthequality.
PackagingmaterialsarerequiredtobetestedorexaminedpriortotheiruseinapackagingoperationtoensurethatmaterialsofacceptablequalityareusedinthepackagingofAPIs.
Theinnerpackagingshouldbecontrolledbytheestablishmentwithrespecttoidentityandtraceability.
Labelling,storage,anddistributioncontributemateriallytofinalsuitabilityforuseinthemanufactureofmedicinalproducts.
RegulationC.
02.
017outlinesoptionsastowhenthetestingorexaminationprescribedbyRegulationC.
02.
016iscarriedout.
Aswithrawmaterials,thepurchaseofpackagingmaterialsisanimportantoperationthatinvolvespersonnelwhohavethoroughknowledgeofthepackagingmaterialsandsupplier.
Packagingmaterialsoriginateonlyfromsuppliernamedintherelevantspecifications.
Itisofbenefitthatallaspectsoftheproductionandcontrolofpackagingmaterialsbediscussedbetweenthefabricatorandthesupplier.
Particularattentionispaidtoprintedpackagingmaterials;labelsareexaminedortestedafterreceiptonthepremisesofthepersonwhopackagesanAPI.
Interpretation1.
Thereshouldbewrittenproceduresdescribingthereceipt,identification,quarantine,sampling,examinationand/ortestingandrelease,andhandlingofpackagingandlabellingmaterials.
2.
Eachpackagingmaterialusedinthepackaging/labellingofanAPIshouldbecoveredbyspecifications(asdefinedunderC.
02.
002)thatareapprovedanddatedbythepersoninchargeofthequalitycontroldepartmentorbyadesignatedalternatewhomeetstherequirementsdescribedunderRegulationC.
02.
006,interpretation1.
4.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final502.
1Whereapplicable,specificationsshouldbeofpharmacopeialorequivalentstatus,andshouldbeincompliancewiththeapprovedspecificationsinthemarketingauthorizationforthedrugindosageform.
2.
2Theadequacyoftestorexaminationmethodsthatarenotofpharmacopeialorequivalentstatusshouldbeestablishedanddocumented.
2.
3Theuseofrecycledorreprocessedprimarypackagingcomponentsshouldbepermittedonlyafterafullevaluationoftherisksinvolved,includinganypossibledeleteriouseffectsonproductintegrity.
Specificprovisionshouldbemadeforsuchasituationinthespecifications.
2.
4Thesecontainersshouldnotbereactive,additive,orabsorptivesoastoalterthequalityoftheAPIbeyondthespecifiedlimits.
2.
5AnypackagingmaterialindirectcontactwiththeAPIshouldbeatminimumoffoodgradequality.
3.
Samplingshouldtakeplaceinanappropriateenvironmentandwithprecautionstopreventcontamination,wherenecessary.
4.
Positiveidentificationofallpackagingmaterials,alongwithexaminationofalllabelsandotherprintedpackagingmaterialsshouldbeconductedfollowingtheirreceiptonthepremisesofthepersonwhopackagestheAPI.
4.
1Masterlabelsshouldbemaintainedforcomparisontoissuedlabels.
5.
Packagingandlabellingmaterialsshouldconformtoestablishedspecifications.
Thosethatdonotcomplywithsuchspecificationsshouldberejectedtopreventtheiruseinoperationsforwhichtheyareunsuitable.
6.
Onlypackagingmaterialsreleasedbythequalitycontroldepartmentshouldbeusedinpackaging/labelling.
7.
ContainersshouldprovideadequateprotectionagainstdeteriorationorcontaminationoftheAPIthatmayoccurduringtransportationandrecommendedstorage.
8.
Containersshouldbecleanand,whereindicatedbythenatureoftheAPI,sanitizedtoensurethattheyaresuitablefortheirintendeduse.
9.
Outdatedorobsoletepackagingmaterialshouldbeadequatelyidentifiedandsegregateduntilitsdisposition.
10.
Thetestingorexaminationofthepackagingmaterialshouldbeperformedonasampletakenaftertheirreceiptonthepremisesofthepersonthatpackagesthedrugunlessthevendoriscertified.
Apackagingmaterialvendorcertificationprogram,ifemployed,shouldbedocumentedinastandardoperatingprocedure.
10.
1Vendorapprovalshouldincludeawrittenevaluationthatprovidesadequateevidence(e.
g.
,pastqualityhistoryorevidenceofaqualitysystem)thatthefabricatorcanconsistentlyprovideHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final51materialmeetingspecifications.
Confirmatorytestingshouldbeconductedonatleastthreebatchesbeforereducingin-housetesting.
However,asaminimum,confirmatorytestingshouldbeperformedatappropriateintervals,atleastonelotperyear,andcomparedwiththeCertificatesofAnalysis.
ReliabilityofCertificatesofAnalysisshouldbecheckedatregularintervals.
FinishedProductTestingSectionC.
02.
018(1)Eachlotorbatchofadrugshall,beforeitismadeavailableforfurtheruseinfabricationorforsale,betestedagainstthespecificationsforthatdrug.
(2)Nolotorbatchofadrugshallbemadeavailableforfurtheruseinfabricationorforsaleunlessitcomplieswiththespecificationsforthatdrug.
(3)Thespecificationsreferredtoinsubsections(1)and(2)shall(a)beinwriting;(b)beapprovedbythepersoninchargeofthequalitycontroldepartment;and(c)complywiththeActandtheseRegulations.
RationaleTestsontheAPIcomplementthecontrolsemployedduringthemanufacturingprocess.
Itistheresponsibilityofeachfabricator,packager/labeller,distributorandimportertohaveadequatespecifications,testmethodsand/orevidencethatwillhelpensurethateachdrugsoldissafeandmeetsthestandardunderwhichitisrepresented.
Interpretation1.
ForeachbatchofAPI,appropriatelaboratorytestsshouldbeconductedtodetermineconformancetospecifications.
2.
Allspecifications,samplingplans,andtestproceduresshouldbescientificallysoundandappropriatetoensurethatAPIsconformtoestablishedstandardsofqualityand/orpurity.
Specificationsandtestproceduresshouldbeconsistentwiththoseincludedintheregistration/filing.
Therecanbespecificationsinadditiontothoseintheregistration/filing.
Specifications,samplingplans,andtestprocedures,includingchangestothem,shouldbedocumentedandapprovedbytheappropriateorganizationalunitandreviewedandapprovedbythequalityunit(s).
2.
1SpecificationsshouldbeequaltoorexceedarecognizedstandardaslistedinScheduleBtotheFoodandDrugsActandshouldbeincompliancewiththespecifications.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final522.
2Wherearecognizedpharmacopoeia(ScheduleBtotheFoodandDrugsAct)containsaspecificationformicrobialcontent,thatrequirementisincluded.
3.
AppropriatespecificationsshouldbeestablishedforAPIsinaccordancewithacceptedstandardsandconsistentwiththemanufacturingprocess.
Thespecificationsshouldincludeacontroloftheimpurities(e.
g.
organicimpurities,inorganicimpurities,andresidualsolvents).
IftheAPIhasaspecificationformicrobiologicalpurity,appropriateactionlimitsfortotalmicrobialcountsandobjectionableorganismsshouldbeestablishedandmet.
IftheAPIhasaspecificationforendotoxins,appropriateactionlimitsshouldbeestablishedandmet.
4.
Analyticalmethodsshouldbevalidatedunlessthemethodemployedisincludedintherelevantpharmacopoeiaorotherrecognizedstandardreference.
Thesuitabilityofalltestingmethodsusedshouldnonethelessbeverifiedunderactualconditionsofuseanddocumented.
5.
MethodsshouldbevalidatedtoincludeconsiderationofcharacteristicsincludedwithinpublicationssuchastheICHdocumententitledICHQ3(R1):ValidationofAnalyticalProcedures:TextandMethodology.
ThedegreeofanalyticalvalidationperformedshouldreflectthepurposeoftheanalysisandthestageoftheAPIproductionprocess.
6.
Alltestsareperformedaccordingtotheapprovedspecifications.
Thesetestsmaybecarriedoutbythefabricatororbytheircontractedtestinglaboratorywhenawrittencontractspecifiestheresponsibilitiesofeachparty.
7.
AnimpurityprofiledescribingtheidentifiedandunidentifiedimpuritiespresentinatypicalbatchproducedbyaspecificcontrolledproductionprocessshouldnormallybeestablishedforeachAPI.
Theimpurityprofileshouldincludetheidentityorsomequalitativeanalyticaldesignation(e.
g.
retentiontime),therangeofeachimpurityobserved,andclassificationofeachidentifiedimpurity(e.
g.
inorganic,organic,solvent).
TheimpurityprofileisnormallydependentupontheproductionprocessandoriginoftheAPI.
ImpurityprofilesarenormallynotnecessaryforAPIsfromherbaloranimaltissueorigin.
BiotechnologyconsiderationsarecoveredinICHGuidelineQ6B.
8.
TheimpurityprofileshouldbecomparedatappropriateintervalsagainsttheimpurityprofileintheregulatorysubmissionorcomparedagainsthistoricaldatainordertodetectchangestotheAPIresultingfrommodificationsinrawmaterials,equipmentoperatingparameters,ortheproductionprocess.
9.
InformationonthenameoftheAPIincludingwhereappropriateitsgrade,thebatchnumber,andthedateofreleaseshouldbeprovidedontheCertificateofAnalysis(CoA).
ForAPIswithanexpirydate,theexpirydateshouldbeprovidedonthelabelandCoA.
ForAPIswitharetestdate,theretestdateshouldbeindicatedonthelabeland/orCoA.
10.
AuthenticCoAsshouldbeissuedforeachbatchofAPI.
11.
TheCoAshouldlisteachtestperformedinaccordancewithcompendialorcustomerrequirements,includingtheacceptancelimits,andthenumericalresultsobtained(iftestresultsarenumerical).
12.
CertificatesofAnalysisshouldbedatedandsignedbyauthorisedpersonnelofthequalityunit(s)andshouldshowthename,addressandtelephonenumberoftheoriginalfabricator.
Wheretheanalysishasbeencarriedoutbyarepackagerorreprocessor,theCoAshouldshowthename,addressandtelephonenumberoftherepackager/reprocessorandareferencetothenameoftheoriginalfabricator.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final5313.
IfnewCertificatesareissuedbyoronbehalfofrepackagers/reprocessors,agentsorbrokers,theseCertificatesshouldshowthename,addressandtelephonenumberofthelaboratorythatperformedtheanalysis.
TheyshouldalsocontainareferencetothenameandaddressoftheoriginalfabricatorandtotheoriginalbatchCertificate,acopyofwhichshouldbeattached.
14.
AnylotorbatchofanAPIthatdoesnotcomplywithspecificationsshouldbequarantinedpendingfinaldisposition,investigatedanddocumentedaccordingtoaprocedure,andisnotmadeavailableforsale.
SectionC.
02.
019(1)Apackager/labellerofadrug,adistributorreferredtoinparagraphC.
01A.
003(b)andanimporterofadrugotherthananactiveingredientshallperformthefinishedproducttestingonasampleofthedrugthatistakeneither(a)afterreceiptofeachlotorbatchofthedrugontheirpremisesinCanada;or(b)beforereceiptofeachlotorbatchofthedrugontheirpremisesinCanadaifthefollowingconditionsaremet:(i)thepackager/labeller,distributororimporter(A)hasevidencesatisfactorytotheDirectortodemonstratethatdrugssoldtothembythevendorofthatlotorbatchareconsistentlymanufacturedinaccordancewithandconsistentlycomplywiththespecificationsforthosedrugs,and(B)undertakesperiodiccompleteconfirmatorytesting,withafrequencysatisfactorytotheDirector,and(ii)thedrughasnotbeentransportedorstoredunderconditionsthatmayaffectitscompliancewiththespecificationsforthatdrug.
(2)Ifthepackager/labeller,distributororimporterreceivesalotorbatchofadrugontheirpremisesinCanadatheusefullifeofwhichismorethan30days,thelotorbatchshallbetestedforidentityandthepackager/labellershallconfirmtheidentityafterthelotorbatchispackaged/labelled.
(3)Subsections(1)and(2)donotapplytoadistributorifthedrugisfabricated,packaged/labelledandtestedinCanadabyapersonwhoholdsanestablishmentlicencethatauthorizesthatactivity.
(4)Subsections(1)and(2)donotapplytoadistributororimporterifthedrugisfabricated,packaged/labelledandtestedinanMRAcountryatarecognizedbuildingandbothofthefollowingrequirementsaremet:(a)theaddressofthebuildingissetoutintheirestablishmentlicence;and(b)theyretainacopyofthebatchcertificateforeachlotorbatchofthedrugthattheyreceive.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final54RationaleC.
02.
019outlinesconditionsandexemptionsastowhenthefinishedproduct(API)testingistobeperformed.
ParagraphC.
02.
019(1)(b)outlinesrequirementsthataretobemetifthefinishedproducttestingisdonebeforereceiptonthepremisesofthepackager/labellerofthedrug.
Interpretation1.
PositiveidentificationofeachlotorbatchinashipmentofthatAPIshouldbecarriedoutonasampletakenafterpackaging.
2.
EachlotshouldbeaccompaniedbyanauthenticCoAorbyacopythereof(anelectroniccopywithanelectronicsignatureisacceptable).
TheCoAshouldexhibitactualnumericalresultsandmakereferencetotheproductspecificationsandtestmethodsused;3EvidenceshouldbeavailabletodemonstratethateachlotorbatchreceivedhasbeentransportedandstoredinamannerthatmaintainsthequalityoftheAPI.
FurtherrequirementsaredescribedinGUI-0069.
RecordsSectionC.
02.
020(1)Everyfabricator,packager/labeller,distributorreferredtoinparagraphC.
01A.
003(b)andimportershallmaintainallofthefollowingrecordsontheirpremisesinCanadaforeachdrugthattheyfabricate,package/label,distributeorimport:(a)Exceptinthecaseofanimporterofanactivepharmaceuticalingredient,masterproductiondocumentsforthedrug;(b)evidencethateachlotorbatchofthedrughasbeenfabricated,packaged/labelled,testedandstoredinaccordancewiththeproceduresdescribedinthemasterproductiondocuments;(c)evidencethattheconditionsunderwhichthedrugwasfabricated,packaged/labelled,testedandstoredareincompliancewiththerequirementsofthisDivision;(d)evidencethatestablishestheperiodduringwhichthedruginthecontainerinwhichitissoldormadeavailableforfurtheruseinfabricationwillmeetthespecificationsforthatdrug;and(e)evidencethatthefinishedproducttestingreferredtoinsectionC.
02.
018wascarriedout,andtheresultsofthattesting.
(2)EverydistributorreferredtoinparagraphC.
01A.
003(b)andimportershallmakeavailabletotheDirector,onrequest,theresultsoftestingperformedonrawmaterialsandpackaging/labellingmaterialsforeachlotorbatchofdrugthatitdistributesorimports.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final55(3)EveryfabricatorshallmaintainontheirpremiseswrittenspecificationsforallrawmaterialsandadequateevidenceofthetestingofthoserawmaterialsreferredtoinsectionC.
02.
009andofthetestresults.
(4)EverypersonwhopackagesadrugshallmaintainontheirpremiseswrittenspecificationsforallpackagingmaterialsandadequateevidenceoftheexaminationortestingofthosematerialsreferredtoinsectionC.
02.
016andofanytestresults.
(5)Everyfabricator,packager/labellerandtestershallmaintainontheirpremisesinCanadadetailedplansandspecificationsofeachbuildinginCanadawheretheyfabricatepackage/labelortestdrugsandadescriptionofthedesignandconstructionofthosebuildings.
(6)Everyfabricator,packager/labellerandtestershallmaintainontheirpremisesinCanadapersonnelrecordsinrespectofeachpersonwhoisemployedtosupervisethefabrication,packaging/labellingandtestingofdrugs,includingtheperson'stitle,responsibilities,qualifications,experienceandtraining.
SectionC.
02.
021(1)Allrecordsandevidenceonthefabrication,packaging/labelling,finishedproducttestingreferredtoinsectionC.
02.
018andstorageofadrugindosageformthatarerequiredtobemaintainedunderthisDivisionshallberetainedforoneyearaftertheexpirationdateofthedrugunlesstheperson'sestablishmentlicencespecifiessomeotherperiod.
(2)Subjecttosubsection(4),allrecordsandevidenceofthefabrication,packaging/labelling,finishedproducttestingreferredtoinsectionC.
02.
018andstorageofanactiveingredientthatarerequiredtobemaintainedunderthisDivisionshallberetainedinrespectofeachlotorbatchoftheactiveingredientforthefollowingperiodunlessthepersonholdsanestablishmentlicencethatspecifiessomeotherperiod:(a)inthecaseofanactiveingredientthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed;and(b)inanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
(3)Subjecttosubsection(4),allrecordsandevidenceoftherawmaterialtestingreferredtoinsectionC.
02.
009andofthetestingofpackaging/labellingmaterialsthatarerequiredtobemaintainedunderthisDivisionshallberetainedforfiveyearsaftertherawmaterialsandpackaging/labellingmaterialswerelastusedinthefabricationorpackaging/labellingofadrugunlesstheperson'sestablishmentlicencespecifiessomeotherperiod.
(4)Ifafabricatorisrequiredtomaintainrecordsandevidenceinrespectofthesameactiveingredientundersubsections(2)and(3),theyshallmaintainthemforthelongestperiodthatisapplicable.
SectionC.
02.
022(1)Everywholesaler,distributorreferredtoinC.
01A.
003andimporterofadrugindosageformshallretainrecordsofsaleofeachlotorbatchofthedrug,whichenablethemtorecallthelotorbatchfromtheHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final56market,foroneyearaftertheexpirationdateofthatlotorbatch,unlesstheirestablishmentlicencespecifiessomeotherperiod.
(2)EverydistributorofanactiveingredientreferredtoinparagraphC.
01A.
003(a)andeverywholesalerandimporterofanactiveingredientshallretainrecordsofsaleofeachlotorbatchoftheactiveingredient,whichenablethemtorecallthelotorbatchfromthemarket,forthefollowingperiodunlessthepersonholdsandestablishmentlicencethatspecifiessomeotherperiod:(a)inthecaseanactiveingredientthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed;or(b)inanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
SectionC.
02.
023(1)Onreceiptofacomplaintoranyinformationrespectingthequalityofadrugoritsdeficienciesorhazards,everyfabricator,packager/labeller,wholesaler,distributorreferredtoinparagraphC.
01A.
003andimporterofthedrugshallmakearecordofthecomplaintorinformationthatcontainsthefollowing:(a)theresultsofanyinvestigationcarriedoutundersubsectionC.
02.
015(2)and,ifapplicable,thecorrectiveactiontaken;or(b)thenameandbusinessaddressofthepersoninchargeofthequalitycontroldepartmenttowhomthecomplaintorinformationwasforwardedundersubsectionC.
02.
015(2.
1)andthedateonwhichitwasforwarded.
(2)Recordsreferredtoinsubsection(1)shallberetainedforthefollowingperiodunlessthepersonholdsanestablishmentlicencethatspecifiessomeotherperiod:(a)inthecaseofadrugindosageform,oneyearaftertheexpirationdateofthelotorbatchofthedrug;and(b)inthecaseofanactiveingredient,(i)iftheactiveingredienthasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed,or(ii)inanyothercase,oneyearaftertheexpirationdateofthelotorbatchoftheactiveingredient.
SectionC.
02.
024(1)Everyfabricator,packager/labeller,distributorreferredtoinsectionC.
01A.
003,importerandwholesalershall(a)maintainrecordsoftheresultsoftheself-inspectionprogramrequiredbysectionC.
02.
012andofanyactiontakeninconnectionwiththatprogram;andHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final57(b)retainthoserecordsforaperiodofatleastthreeyears.
(2)Everypersonwhofabricatesorpackages/labelsadrugshall(a)maintainrecordsontheoperationofthesanitationprogramrequiredtobeimplementedundersectionC.
02.
007;and(b)retainthoserecordsforaperiodofatleastthreeyears.
SectionC.
02.
024.
1EverydistributorofanactiveingredientreferredtoinparagraphC.
01A.
003(a)andeveryfabricator,packager/labeller,wholesalerandimporterofanactiveingredientshalladdallofthefollowinginformationtothedocumentationthataccompaniestheactiveingredient,immediatelyafteranylikeinformationthathasbeenaddedbyanotherperson:(a)theirestablishmentlicencenumber,orifthereisnone,theirname,address,telephonenumber,faxnumberandemailaddress;(b)anindicationwhethertheyhavefabricated,packaged/labelled,wholesaled,distributedorimportedtheactiveingredientandthedateonwhichthatactivitywascarriedout;(c)theexpirationdate;and(d)thelotnumber.
RationaleGooddocumentationisanessentialpartofthequalityassurancesystemandshouldthereforebeappliedtoallaspectsofGMP.
Itsaimsaretodefinethespecificationsforallmaterialsandmethodsoffabrication,packaging/labelling,andcontrol;toensurethatthequalitycontroldepartmenthasalltheinformationnecessarytomakeadecisionastowhetherornotabatchofanAPIshouldbereleasedforsale;andtoprovideanaudittrailthatwillallowforthoroughinvestigationofthehistoryofanybatchthatissuspectedtobedefective.
EvidencethatAPIshavebeenfabricated,packaged/labelled,tested,andstoredunderprescribedconditionscanbemaintainedonlyafterdevelopingadequaterecordsystems.
ThisevidenceandrelatedinformationshouldprovideassurancethatimportedAPIsarefabricatedandpackaged/labelledinalikemannertothoseproducedinCanada.
Interpretation1.
AnydocumentationrequestedforevaluationbyHealthCanadashouldbeprovidedinoneoftheofficiallanguages.
2.
Fabricator,packagers/labellers,testers,importers,distributors,andwholesalersareresponsibleforobtainingallqualityorregulatoryinformation,asapplicable,relatedtotheproductionofAPIsfromanypartythatprovidesservicessuchas,butnotlimitedto,agents,brokers,distributors,repackagers,orrelabellers.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final583.
ForallsectionsoftheseGoodManufacturingPracticesguidelinesforAPIs,standardoperatingprocedures(SOPs)shouldbeestablishedandretainedforreferenceandinspection.
TheseSOPsshouldberegularlyreviewedandkeptuptodatebyqualifiedpersonnel.
ThereasonsforanyrevisionsshouldbedocumentedandasystemshouldbeinplacetoensurethatonlycurrentSOPsareinuse.
3.
1Theissuance,revision,supersedingandwithdrawalofalldocumentsshouldbecontrolledwithmaintenanceofrevisionhistories.
3.
2SOPsshouldbereviewed,approved,signed,anddatedbythequalitycontroldepartment.
3.
3SOPsshouldnotbealteredwithouttheapprovalofthequalitycontroldepartment.
3.
4TheretentionperiodofdocumentsshouldbespecifiedinapplicableSOPs.
Forexample,thetypeofdocumentsthatneedtoberetainedaredevelopmenthistoryreports,scale-upreports,technicaltransferreports,processvalidationreports,trainingrecords,productionrecords,controlrecords,anddistributionrecords.
4.
Specifications,instructions,procedures,andrecordscanberetainedeitherasoriginalsorastruecopiessuchasphotocopies,microfilm,microfiche,orotheraccuratereproductionsoftheoriginalrecords.
Theabovemayalsobemaintainedinelectronicformatprovidedthatbackupcopiesarealsomaintainedandthattheelectronicrecordsarereadilyretrievableinaprintedformat.
Duringtheretentionperiod,suchrecordsshouldbesecuredandreadilyavailablebythefabricator,packager/labeller,orimporterwithin48hoursoftheInspector'srequest.
Recordsthatcanbepromptlyretrievedfromanotherlocationbyelectronicorothermeansareacceptable.
4.
1Manufacturingandlaboratoryrecordsshouldbekeptatthesitewheretheactivityoccursandbereadilyavailable.
5.
Whereanelectronicsystemisusedtocreate,modifyorstorerecordsrequiredtobemaintainedundertheseRegulations,thesystemshouldbequalifiedandtestedforsecurity,validity,andreliability,andrecordsofthosequalificationsandtestsshouldbemaintained.
5.
1Anelectronicsignatureisanacceptablealternativetoahandwrittensignatureaslongasitisauthenticatedandsecure.
Thevalidationofelectronicsignatureidentificationsystemsshouldbedocumented.
6.
Analterationmadetoadocumentshouldbesignedanddated;thealterationshouldpermitthereadingoftheoriginalinformation.
Whereappropriate,thereasonforthechangeshouldberecorded.
7.
Fabricatorsandpackagers/labellersofAPIsshouldmaintainevidencethattheconditionsunderwhichtheAPIwasfabricated,packaged/labelled,tested,andstoredshouldbeincompliancewiththerequirementsofPartC,Division2oftheFoodandDrugRegulations.
Alloftheserecordsshouldberetainedfor(a)inthecaseofanAPIthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed;and(b)inanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
7.
1DetailedplansandspecificationsofeachbuildinginCanadawherefabrication,packaging/labellingortestingoccurred,includingadescriptionofthedesignandconstructionofthosebuildings,shouldbemaintainedinthepremisesoftheestablishmentwheretheAPIHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final59activityoccurred.
TheserecordsshouldberetainedforaperiodofatleastoneyearpasttheexpirationdateoftheAPItowhichtherecordsapply.
7.
2ThisevidenceincludesrecordsgeneratedundersubsectionC.
02.
012(2)andevidencethatmanufacturingandpackagingprocessesandanalyticalmethodsarevalidated.
.
7.
3Incaseswhereequipmentisemployed,therecordsofcleaning,calibration,maintenance,andusecanbepartofthebatchrecordormaintainedseparately.
7.
4Recordsofequipmentcalibrationsshouldbemaintainedonthepremises.
7.
5Recordsinrespectofeachpersonwhoisemployedtosupervisethefabrication,packaging/labelling,andtestingofAPIs,includingorganizationcharts;eachperson'stitle,jobdescription,responsibilities,qualifications,experience,andtraining;andthename(s)ofeachperson'sdesignatedalternate(s).
7.
6Recordsshouldbemaintaineddetailingthename,address,qualifications/experienceofanyconsultantemployedforGMPpurposes,alongwiththeservicesthateachconsultantprovides.
7.
7Recordsontheoperationofthesanitationprogram.
7.
8Batchproductionandlaboratorycontrolrecordsofcriticalprocessstepsshouldbereviewedandapprovedbythequalityunit(s)beforeanAPIbatchisreleasedordistributed.
Productionandlaboratorycontrolrecordsofnon-criticalprocessstepscanbereviewedbyqualifiedproductionpersonnelorotherunitsfollowingproceduresapprovedbythequalityunit(s).
7.
9Recordsoftheself-inspectionprogramincludingtheevaluation,conclusions,andcorrectivemeasuresimplemented.
7.
10EvidenceestablishingtheperiodoftimeduringwhichtheAPIinthecontainerinwhichitissoldormadeavailableforfurtheruseinfabricationshouldmeetthespecificationsforthatAPI.
7.
10.
1Thedocumentationtobemaintainedshouldincludethewrittenstabilityprogram,thedatageneratedinaccordancewiththatprogram,andtheconclusionsleadingtotheestablishmentoftheperiodoftimeduringwhicheachAPIinthepackageinwhichitissoldcomplieswiththespecificationsforthatAPI.
7.
11Recordsofstorageconditionsformaterials(e.
g.
controlledtemperatureandhumiditywhennecessary).
8.
EvidencethateachlotorbatchoftheAPIhasbeenfabricated,packaged/labelled,tested,andstoredinaccordancewiththeproceduresdescribedinthemasterproductiondocuments.
Thisevidenceshouldincludethefollowing:8.
1Writtenproceduresfollowedforthereviewandapprovalofbatchproductionandlaboratorycontrolrecords,includingpackagingandlabelling,todeterminecomplianceoftheAPIwithestablishedspecificationsbeforeabatchisreleasedordistributed.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final608.
2Manufacturingrecords,packagingrecords,testmethods,andtestresultsforrawmaterials,packagingmaterials,andAPIs.
8.
3WhentheAPIisfabricatedorpackagedoutsideCanada/premisesoftheimporter,recordsshouldbereadilyavailablebytheimporterwithin48hours,uponHealthCanada'srequest.
9.
Thefollowingdocumentsshouldbemaintainedbythefabricator,packager/labeller,wholesaler(agents,brokers,tradersandanyotherpartyprovidingservices),distributorreferredtoinparagraphC.
01A.
003(a)andimporterofanAPIastheyrelatetoalloperationsinCanada.
Theserecordsshouldberetainedforaperiod,inthecaseofanAPIthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributedorinanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
9.
1DistributionrecordsofallsalesofanAPI.
9.
1.
1RecordsofallsalesofeachlotorbatchoftheAPIshouldberetainedorkeptreadilyaccessibleinamannerthatwillpermitacompleteandrapidrecallofanylotorbatchoftheAPI.
9.
1.
2RecordstoindicatethatallcustomerswhohavereceivedarecalledAPIhavebeennotified.
9.
1.
3RecordsofreturnedAPIsshouldbemaintained.
Foreachreturn,documentationshouldinclude:thenameandaddressoftheconsignee;theAPI,lotorbatchnumber,andquantityreturned;thereasonforreturn;andtheuseordisposalofthereturnedAPI.
9.
2RecordsofcomplaintsoranyinformationreceivedorallyorinwritingrespectingthequalityofanAPIoritsdeficienciesorhazards,andofsubsequentinvestigationsofcomplaints,includingcorrectiveactionstaken.
9.
2.
1Complaintrecordsshouldincludethefollowinginformation:thenameandaddressofthecomplainant(ifavailable);thenameandphonenumberofthepersonsubmittingthecomplaint(ifavailable);thenatureofthecomplaint(includingthenameandbatchnumberoftheAPI);thedateonwhichthecomplaintwasreceived;theactioninitiallytaken(includingthedatesandidentityofthepersontakingtheaction);theactionstaken,ifany;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final61theresponseprovidedtothecomplainant,wherepossible(includingthedateonwhichtheresponsewassent);andthefinaldecisionontheAPIbatchorlot.
10.
Thefollowingdocumentsshouldbemaintainedbythefabricatorandthepackager/labellerontheirpremisesandretainedforaperiodofatleastfiveyearsafterthematerialswerelastusedinthefabricationorpackaging/labellingoftheAPI,unlesstheperson=sestablishmentlicencespecifiessomeotherperiod.
10.
1Thewrittenspecificationsforthematerials.
10.
2AdequateevidenceofthereceiptandsourcesofeachshipmentofmaterialsforthemanufactureofAPIs.
Thefollowinginformationshouldbeincluded:thenameofthefabricator,thedateofreceiptandthenumberallocatedonreceipt;theidentityandquantityofeachshipmentofeachbatch;thenameofthesupplier;andthesupplier'scontrolnumber(s),ifknown,orotheridentificationnumber.
10.
3Adequateevidenceofthetesting,orexaminationofthosematerialsaspersectionC.
02.
009andC.
02.
016andoftheresultsofthistesting.
Thefollowinginformationshouldbeincluded:documentationoftheexaminationand/ortestsofmaterialsforconformitywithestablishedspecificationsandconclusionsderivedfromthis;thefinaldecisionastowhetherthebatcheswereacceptedorrejected;andrecordstracingtheuseofthematerials.
10.
3.
1Laboratoryrecordsshouldbemaintained.
11.
Thefollowingdocumentsshouldbemaintainedbythefabricator,and/orpackager/labeller,ofanAPI.
Alloftheserecordsshouldberetainedfor(a)inthecaseofanAPIthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed;and(b)inanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
11.
1MasterproductiondocumentsforeachAPI.
Themasterproductiondocumentsshouldbesignedanddatedbyaqualifiedpersonandthenindependentlychecked,dated,andsignedbyapersoninthequalityunit.
Thesedocumentsshouldincludethefollowinginformation:HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final62ThenameoftheAPImanufacturedandanidentifyingdocumentreferencecode,ifapplicable;Thelistofrawmaterialsusedanddesignatedbynamesorcodessufficientlyspecifictoidentifyanyspecialqualitycharacteristics;Theaccuratequantitywithaunitofmeasureorratioofeachrawmaterialused.
Wherethequantityisnotfixed,thecalculationforeachbatchsizeorrateofproductionshouldbeincluded.
Variationstoquantitiesshouldbeincludedwheretheyarejustified;Thelocationofproductionandmajorproductionequipmentused;Thedetailedproductioninstructions,includingthesequencestofollow,rangesofprocessparameterstouse,samplinginstructionsandin-processcontrolswiththeiracceptancecriteria,whereappropriate,timelimitsforcompletionofindividualprocessingstepsand/orthetotalprocess,whereappropriate,andexpectedyieldrangesatappropriatephasesofprocessingortime;Whereappropriate,anyspecialnotationsandprecautionstofollow,orcross-referencestothese,andTheinstructionsforstorageoftheAPItoassureitssuitabilityforuse,includingthelabellingandpackagingmaterialsandspecialstorageconditionswithtimelimits,whereappropriate.
12.
Packagers/labellers,importers,agents,brokers,traders,distributors,wholesalersshouldmaintaincompletetraceabilityofAPIsthattheydistribute.
Documentsthatshouldberetainedandavailableinclude:12.
1nameidentityoforiginalfabricatorandpackager/labeller;12.
2addressoforiginalfabricatorandpackager/labeller;12.
3purchaseorders;12.
4billsoflading(transportationdocumentation);12.
5receiptdocuments;12.
6nameordesignationoftheAPIorintermediate;12.
7fabricator=sorpackager/labeller=sbatchnumber;12.
8transportationanddistributionrecords;12.
9allauthenticCertificatesofAnalysis,includingthoseoftheoriginalfabricator;12.
10retestorexpirydate.
13.
Thefabricator,packager/labeller,wholesaler,distributorreferredtoinparagraphC.
01A.
003(a),importerofanAPI,includinganypartyotherthantheoriginalfabricatorwhomaytradeand/ortakeHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final63possession,repackage,re-label,manipulate,orstoreanAPI,shouldaddthefollowinginformationtothedocumentationthataccompaniestheAPI:13.
1theestablishmentlicencenumber;iftheestablishmentdoesnothaveanestablishmentlicence,theyshouldaddtheirname,address,telephonenumber,faxnumberandemailaddress;13.
2theactivityincludingfabrication,packaging/labelling,wholesale,distributionorimportationandthedateonwhichtheactivitywasconducted;13.
3theexpirationdateand/orretestdate;and13.
4thelotnumberoftheAPI.
SamplesSectionC.
02.
025(1)EverydistributorreferredtoinparagraphC.
01A.
003(b)andimporterofadrugindosageformshallretaininCanadaasampleofeachlotorbatchofthepackaged/labelleddrugforoneyearaftertheexpirationdateofthedrugunlesstheirestablishmentlicencespecifiessomeotherperiod.
(2)Subjecttosubsection(4),thefabricatorofadrugindosageformshallretainasampleofeachlotorbatchofrawmaterialsusedinthefabricationfortwoyearsafterthematerialswerelastusedinthefabricationunlesstheirestablishmentlicencespecifiessomeotherperiod.
(3)Subjecttosubsection(4),thefabricatorofanactiveingredientshallretainasampleofeachlotorbatchofitforthefollowingperiod,unlesstheirestablishmentlicencespecifiessomeotherperiod:(a)inthecaseofanactiveingredientthathasaretestdate,threeyearsafterthelotorbatchhasbeencompletelydistributed;or(b)inanyothercase,oneyearaftertheexpirationdateofthelotorbatch.
(4)Ifafabricatorisrequiredtomaintainsamplesinrespectofthesameactiveingredientundersubsections(2)and(3),theyshallmaintainthemforthelongestperiodthatisapplicable.
SectionC.
02.
026ThesamplesreferredtoinsectionC.
02.
025shallbeinanamountthatissufficienttodeterminewhetherthedrugorrawmaterialcomplieswiththespecificationsforthatdrugorrawmaterial.
RationaleTheserequirementshelpensurethatresponsibleofficialsatfabricating,establishmentsandatHealthCanadahavereadyaccesstothosesamplesthatareessentialforre-examinationshouldaproductqualityconcernarise.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final64Interpretation1.
Arepresentativesampleshouldbetakenforthepurposeofperformingaretest.
2.
ThepackagingandholdingofretainedsamplesisforthepurposeofpotentialfutureevaluationofthequalityofbatchesofAPIsandnotforfuturestabilitytestingpurposes.
3.
AppropriatelyidentifiedretainedsamplesofeachAPIbatchshouldberetainedbythefabricatorofanAPIforoneyearaftertheexpirydateofthebatch,orforthreeyearsafterdistributionofthebatch,whicheveristhelonger.
ForAPIswithretestdates,similarretainedsamplesshouldberetainedforthreeyearsafterthebatchiscompletelydistributedbythefabricator.
3.
1Retentionsamplesmaybestoredatanothersitepursuanttoawrittenagreementclearlydescribingtherespectiveresponsibilitiesofeachparty.
4.
TheretainedsampleshouldbestoredinthesamepackagingsysteminwhichtheAPIisstoredorinonethatisequivalenttoormoreprotectivethanthemarketedpackagingsystem.
Sufficientquantitiesshouldberetainedtoconductatleasttwofullcompendialanalysesor,whenthereisnopharmacopoeialmonograph,twofullspecificationanalyses.
5.
Thesampleshouldbestoredundertheconditionsindicatedonthelabel.
6.
Retentionsamplesshouldbemaintainedinaccordancewithawrittenprocedure.
Retentionsamplesmaybestoredatanothersitepursuanttoawrittenagreementclearlydescribingtherespectiveresponsibilitiesofeachparty.
StabilitySectionC.
02.
027(1)EverydistributorreferredtoinparagraphC.
01A.
003(b)andimporterofadrugindosageformshallestablishtheperiodduringwhicheachdruginthepackageinwhichitissoldwillcomplywiththespecificationsforthatdrug.
(2)Everyfabricatorandimporterofanactiveingredientshallestablishtheperiodduringwhicheachdruginthepackageinwhichitissoldwillcomplywiththespecificationsforthatdrug.
RationaleThepurposeofthewrittenstabilityprogramistoascertaintheexpiryorretestdateofanAPI,thereforetodeterminehowlongtheAPIscanbeexpectedtoremainwithinspecificationsunderrecommendedstorageconditions.
TheexpiryorretestdateforanAPIshouldbebasedonwell-designedstabilitystudies.
TherequirementsforthestabilitystudiesareoutlinedinthevariousHealthCanada,andICHGuidelines.
InterpretationHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final651.
Whenanintermediateisintendedtobetransferredoutsidethecontrolofthefabricator'smaterialmanagementsystemandanexpiryorretestdateisassigned,supportingstabilityinformationshouldbeavailable(e.
g.
publisheddata,testresults).
2.
AnAPIexpiryorretestdateshouldbebasedonanevaluationofdataderivedfromstabilitystudies.
Commonpracticeistousearetestdate,notanexpirationdate.
3.
PreliminaryAPIexpiryorretestdatescanbebasedonpilotscalebatchesif(1)thepilotbatchesemployamethodofmanufactureandprocedurethatsimulatesthefinalprocesstobeusedonacommercialmanufacturingscale;and(2)thequalityoftheAPIrepresentsthematerialtobemadeonacommercialscale.
3.
1Acceleratedstabilitydataareconsideredtobepreliminaryinformationonly.
Theaccelerateddataaresupportedbylongtermtesting.
Whentheshelf-lifeisassignedbasedonaccelerateddataandextrapolatedlong-termdata,itshouldbeverifiedbyadditionallongtermstabilitydataasthesedatabecomeavailable.
4.
Stabilitysamplesshouldbestoredincontainersthatsimulatethemarketcontainer.
Forexample,iftheAPIismarketedinbagswithinfiberdrums,stabilitysamplescanbepackagedinbagsofthesamematerialandinsmaller-scaledrumsofsimilaroridenticalmaterialcompositiontothemarketdrums.
4.
1StabilitystudiestojustifyassignedexpirationorretestdatesshouldbeconductediftheAPIisrepackagedinadifferenttypeofcontainerthanthatusedbytheAPIfabricator.
5.
Normallythefirstthreecommercialproductionbatchesshouldbeplacedonthestabilitymonitoringprogramtoconfirmtheretestorexpirydate.
However,wheredatafrompreviousstudiesshowthattheAPIisexpectedtoremainstableforatleasttwoyears,fewerthanthreebatchescanbeused.
6.
Forimportedproducts,stabilitystudiesoriginatingfromforeignsitesareacceptableprovidedthatthedatameettherequirementsofthevariousHealthCanadaandICHguidelinesregardingstabilityandthatthesitecandemonstrateGMPcompliance.
7.
Whereappropriate,thestabilitystorageconditionsshouldbeconsistentwiththeICHguidelinesonstability.
8.
AnalyticaltestproceduresusedinstabilityevaluationarevalidatedinaccordancewiththeICHdocumententitled,ICHQ2(R1):ValidationofAnalyticalProcedures:TextandMethodology.
Assaysaretobestability-indicating,(e.
g.
,sufficientlyspecifictodetectandquantifydegradationproductsandtodistinguishbetweendegradedandnon-degradedmaterials).
Limitsforindividualspecified,unspecified,andtotaldegradationproductsareincluded.
SectionC.
02.
028(1)EverydistributorreferredtoinparagraphC.
01A.
003(b)andimporterofadrugindosageformshallmonitor,bymeansofacontinuingprogram,thestabilityofthedruginthepackageinwhichitissold.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final66(2)Everyfabricatorandimporterofanactiveingredientshallmonitor,bymeansofacontinuingprogram,thestabilityofthedruginthepackageinwhichitissold.
RationaleThepurposeofthewrittencontinuingstabilityprogramistomonitorthevalidityoftheAPIexpiryorretestdateonanon-goingbasis.
Interpretation1.
Stabilitysamplesshouldbestoredincontainersthatsimulatethemarketcontainer.
Forexample,iftheAPIismarketedinbagswithinfiberdrums,stabilitysamplescanbepackagedinbagsofthesamematerialandinsmaller-scaledrumsofsimilaroridenticalmaterialcompositiontothemarketdrums.
2.
Adocumented,on-goingtestingprogramshouldbedesignedtomonitorthestabilitycharacteristicsofAPIs,andtheresultsshouldbeusedtoconfirmappropriatestorageconditionsandretestorexpirydates.
3.
AtleastonebatchperyearofAPImanufactured(unlessnoneisproducedthatyear)shouldbeaddedtothestabilitymonitoringprogramandtestedatleastannuallytoconfirmthestability.
4.
ForAPIswithshortshelf-lives,testingshouldbedonemorefrequently.
Forexample,forthoseAPIswithshelf-livesofoneyearorless,stabilitysamplesshouldbeobtainedandshouldbetestedmonthlyforthefirstthreemonthsandatthreemonthintervalsafterthat.
WhendataexistthatconfirmthatthestabilityoftheAPIisnotcompromised,eliminationofspecifictestintervals(e.
g.
9monthtesting)canbeconsidered.
)5Whereappropriate,thestabilitystorageconditionsshouldbeconsistentwiththeICHguidelinesonstability.
6.
Anydifferencesintheprotocolforthecontinuingstabilityprogramandtheprotocolfortheformalstabilitystudiesshouldbescientificallyjustified.
7.
Worstcasesituationsshouldbeaddressedbythecontinuingstabilityprogram(e.
g.
,inclusionofreworkedorreprocessedlots).
8.
AnyconfirmedoutofspecificationresultorsignificantnegativetrendthatmayhaveanimpactonthequalityoftheAPIshouldbeassessedandmayrequirefurtherstabilitystudies.
9.
ForimportedAPIs,stabilitystudiesoriginatingfromforeignsitesareacceptable,providedthatthedatameettherequirementsofthevariousHealthCanadaandICHguidelinesregardingstabilityandthatthesitecandemonstrateGMPcompliance.
Itshouldbetheimporter'sresponsibilitytoobtainandmaintainuptodaterecordsassociatedwiththeongoingstabilityprogram.
SterileProductsSectionHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final67C.
02.
029InadditiontotheotherrequirementsofthisDivision,adrugthatisintendedtobesterileshallbefabricatedandpackaged/labelled(a)inseparateandenclosedareas;(b)underthesupervisionofpersonneltrainedinmicrobiology;and(c)byamethodscientificallyproventoensuresterility.
ThisguidelineappliestothemanufactureofsterileAPIsonlyuptothepointimmediatelypriortotheAPIbeingrenderedsterile.
ThesterilizationandasepticprocessingofsterileAPIsarenotcoveredbythisguidance,butshouldbeperformedinaccordancewiththeGoodManufacturingPracticesGuidelines,Edition2009,Version2(GUI-0001).
MedicalGasesSectionC.
02.
030Thisguidelinedoesnotapplytomedicalgases.
Theguidanceregardingthefabrication,packaging,labelling,testing,distribution,andimportationofmedicalgasesisdescribedintheguidelineGoodManufacturingPracticesforMedicalGases(GUI-0031).
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final68AppendixAAcronymsAI:ActiveIngredientAPI:ActivePharmaceuticalIngredientDIN:DrugIdentificationNumberGMP:GoodManufacturingPracticesHPFB:HealthProductsandFoodBranchICH:InternationalConferenceonHarmonisationICHQ7:GoodManufacturingPracticeGuideforActivePharmaceuticalIngredientsQ7MPD:MasterProductionDocumentsNOC:NoticeofComplianceOOS:OutofspecificationPIC/S:PharmaceuticalInspectionCooperation/SchemeWHO:WorldHealthOrganizationAppendixBGlossaryofTermsThefollowingdefinitionsapplytothetermsusedintheseguidelines;theyalsoapplytothetermsusedintheannexesunlessotherwisespecifiedtherein.
Definitionsquotedfromotherdocumentsareidentifiedinbracketsattheendofthedefinition.
AcceptanceCriteria(critèred'acceptation)-Numericallimits,ranges,orothersuitablemeasuresforacceptanceoftestresults.
(ICHQ7)ActiveIngredient(ingrédientactif)-Meansadrugthat,whenusedasarawmaterialinthefabricationofadrugindosageform,providesitsintendedeffect.
(Division1A,PartC,FoodandDrugRegulations)ActivePharmaceuticalIngredient(ingrédientpharmaceutiqueactif)-Meansanactiveingredientthatisusedinthefabricationofapharmaceutical.
(Division1A,PartC,FoodandDrugRegulations)AlternateSampleRetention(ASR)Site(sitealternatifpourlarétentiondeséchantillons)-AnalternatesitespecifiedonaDrugEstablishmentLicenceforthestorageofsamplespursuanttosectionC.
02.
025(1)oftheFoodandDrugRegulations.
(GUI-0001)APIEstablishmentLicence(licenced'etablissementpourlesIPA)–AlicenceissuedtoapersoninCanadatoconductlicensableactivitiesinabuildingwhichhasbeeninspectedandassessedasbeingincompliancewiththerequirementofDivision2oftheFoodandDrugRegulations.
APIStartingMaterial(Produitdedépartdel'IPA)–Arawmaterial,intermediate,oranAPIthatisusedintheproductionofanAPIandthatisincorporatedasasignificantstructuralfragmentintothestructureoftheAPI.
AnAPIStartingMaterialcanbeanarticleofcommerce,amaterialpurchasedfromoneormoresuppliersundercontractorcommercialagreement,orproducedin-house.
APIStartingMaterialsarenormallyofdefinedchemicalpropertiesandstructure.
(ICHQ7)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final69Batch(orLot)(lotdefabricationoulot)-Aspecificquantityofmaterialproducedinaprocessorseriesofprocessessothatitisexpectedtobehomogeneouswithinspecifiedlimits.
Inthecaseofcontinuousproduction,abatchmaycorrespondtoadefinedfractionoftheproduction.
Thebatchsizecanbedefinedeitherbyafixedquantityorbytheamountproducedinafixedtimeinterval.
(ICHQ7)BatchNumber(numérodelotdefabrication)-Auniquecombinationofnumbers,letters,and/orsymbolsthatidentifiesabatch(orlot)andfromwhichtheproductionanddistributionhistorycanbedetermined.
(ICHQ7)Bioburden(Chargemicrobienne)-Thelevelandtype(e.
g.
objectionableornot)ofmicro-organismsthatcanbepresentinrawmaterials,APIstartingmaterials,intermediatesorAPIs.
Bioburdenshouldnotbeconsideredcontaminationunlessthelevelshavebeenexceededordefinedobjectionableorganismshavebeendetected.
(ICHQ7)BiologicalDrug(droguebiologique)-AdrugthatislistedinScheduleDtotheFoodandDrugsAct.
BulkAPIs(IPAsenvrac)–AnAPIthatisnotinitsfinalshippingpackageconfiguration.
BulkProcessIntermediate(produitintermédiaireenvrac)-MeansanactiveingredientthatisusedinthefabricationofeitheradrugofbiologicaloriginthatislistedinScheduleCoradrugthatislistedinScheduleDtotheAct.
(Division1A,PartC,FoodandDrugRegulations)Calibration(étalonnage)-Thedemonstrationthataparticularinstrumentordeviceproducesresultswithinspecifiedlimitsbycomparisonwiththoseproducedbyareferenceortraceablestandardoveranappropriaterangeofmeasurements.
(ICHQ7)CampaignProduction(productionconsécutive)–Sequentialprocessingofmaterial,eithermorethanoneproductinamulti-productfacilityormorethanonelotofthesameproductinadedicatedfacility,overadefinedperiodoftime.
Campaignproductioncouldoccuratanypointinaproductionprocesswherecommonrooms/suitesand/orequipmentarereusedformultipleproducts/lots.
(GUI-0001)CertificateofAnalysis(CoA)(certificatd'analyse)-Adocumentcontainingthenameandaddressofthelaboratoryperformingthetest(s),nameandspecificationsofthematerial(s),test(s)performed,testmethod(s)used,actualnumericalresults,approvaldate(s),signatureofapprover,andanyothertechnicalinformationdeemednecessaryforitsproperuse.
(GUI-0001)CertificateofManufacture(certificatdefabrication)-Adocumentissuedbyavendortoadistributororimporterthatatteststhataspecificlotorbatchofdrughasbeenproducedinaccordancewithitsmasterproductiondocuments.
Suchcertificatesincludeadetailedsummaryofcurrentbatchdocumentation,withreferencetorespectivedatesofrevision,manufacture,andpackaging,andaresignedanddatedbythevendor'squalitycontroldepartment.
Changecontrol(contrledeschangements)-Awrittenprocedurethatdescribestheactiontobetakenifachangeisproposed(a)tofacilities,materials,equipment,and/orprocessesusedinthefabrication,packaging,andtestingofdrugs,or(b)thatmayaffecttheoperationofthequalityorsupportsystem.
(GUI-0001)ChangeoverProcedure(procéduredeconversion)-Alogicalseriesofvalidatedstepsthatensuresthepropercleaningofsuitesandequipmentbeforetheprocessingofadifferentproductbegins.
(GUI-0001)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final70ComputerizedSystem(systèmeinformatisé)-Consistsofallcomponents,includingbutnotlimitedtohardware,software,personnel,anddocumentation,necessarytocapture,process,transfer,store,display,andmanageinformation.
(GUI-0001)Concurrentvalidation(validationconcomitante):Aprocesswherecurrentproductionbatchesareusedtomonitorprocessingparameters.
Itgivesassuranceofthepresentbatchbeingstudied,andofferslimitedassuranceregardingconsistencyofqualityfrombatchtobatch.
(GUI-0029)Containment(confinement)-Totalisolationofoneormorestepsofamanufacturingprocesstopreventcross-contaminationoftheproduct,orstaff,fromallotherstepsoftheprocess.
(GUI-0001)Contamination(contamination)-Theundesiredintroductionofimpuritiesofachemicalormicrobiologicalnature,orofforeignmatter,intoorontoarawmaterial,intermediate,orAPIduringproduction,sampling,packagingorrepackaging,storageortransport.
(ICHQ7)Contractor(entrepreneur)-Legalentitycarryingoutactivitiesonbehalfofacompanypursuanttoawrittenagreement.
Thisincludesothersiteswithinthesamecorporatestructure.
(GUI-0001)Critical(critique)-Describesaprocessstep,processcondition,testrequirement,orotherrelevantparameteroritemthatmustbecontrolledwithinpredeterminedcriteriatoensurethattheAPImeetsitsspecification.
(ICHQ7)Cross-Contamination(contaminationcroisée)-Contaminationofamaterialorproductwithanothermaterialorproduct.
(ICHQ7)DesignQualification(DQ)(qualificationdeconception)-Documentedverificationthattheproposeddesignofthefacilities,equipment,orsystemsissuitablefortheintendedpurpose.
(ICHQ7)Deviation(déviation)-Departurefromanapprovedinstructionorestablishedstandard.
(ICHQ7)Director(directeur)-"TheAssistantDeputyMinister,HealthProductsandFoodBranch,oftheDepartmentofHealth.
"(A.
01.
010)Distributor(distributeur)orManufacturer(fabricant)-"Aperson,includinganassociationorpartnership,whoundertheirownname,orunderatrade,designorwordmark,tradenameorothername,wordormarkcontrolledbythem,sellsafoodordrug.
"(A.
01.
010)Divisions1Aand2to4applytothefollowingdistributors(C.
01A.
003):(a)adistributorofanactiveingredientorofadrugindosageformthatislistedinScheduleCtotheAct;and(b)adistributorofadrugforwhichthedistributorholdsthedrugidentificationnumber.
DosageForm(formeposologique)-Adrugproductthathasbeenprocessedtothepointwhereitisnowinaforminwhichitmaybeadministeredinindividualdoses.
(GUI-0001)Drug(drogue)-meansadrugindosageform,oradrugthatisabulkprocessintermediatethatcanbeusedinthepreparationofadruglistedinScheduleCtotheActorinScheduleDtotheActthatisofbiologicalorigin.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final71Itdoesnotincludeadilutedrugpremix,amedicatedfeedasdefinedinSection2oftheFeedsRegulations,1983,adrugthatisusedonlyforthepurposesofanexperimentalstudyinaccordancewithacertificateissuedunderSectionC.
08.
015oradruglistedinScheduleHtotheAct.
(C.
01A.
001(2))DrugEstablishmentLicence(licenced'établissementpourlesproduitspharmaceutiques):AlicenceissuedtoapersoninCanadatoconductlicensableactivitiesinabuildingwhichhasbeeninspectedandassessedasbeingincompliancewiththerequirementsofDivisions2to4oftheFoodandDrugRegulations.
DrugIdentificationNumber(numérod'identificationd'unedrogue):ADrugIdentificationNumber(DIN)isacomputer-generatedeightdigitnumberassignedbyHealthCanadatoadrugproductpriortobeingmarketedinCanada.
ItuniquelyidentifiesalldrugproductssoldinadosageforminCanadaandislocatedonthelabelofprescriptionandover-the-counterdrugproductsthathavebeenevaluatedandauthorizedforsaleinCanada.
ADINuniquelyidentifiesthefollowingproductcharacteristics:manufacturer;productname;activeingredient(s);strength(s)ofactiveingredient(s);pharmaceuticalform;routeofadministration.
(GUI-0001)ExpiryDate(orExpirationDate)–(datelimited'utilisation)Means(a)inthecaseofadrugindosageform,theearlierofthefollowingdates,expressedatminimumasayearandmonth:(i)thedateuptoandincludingwhichthedrugmaintainsitslabelledpotency,purityandphysicalcharacteristics,and(ii)thedateafterwhichthemanufacturerrecommendsthatthedrugnotbeused;and(b)inthecaseofanactiveingredient,whicheverofthefollowingdatesisapplicable,expressedatminimumasayearandmonth:(i)theretestdate,or(ii)thedateafterwhichthemanufacturerrecommendsthattheactiveingredientnotbeused.
(datelimited'utilisation)(C.
01.
001(1))Fabricate(fabricator)-"Toprepareandpreserveadrugforthepurposeofsale.
"(C.
01A.
001)Filling(remplissage)–Transferringabulkdrugintoitsfinalcontainerandenclosingitinthecontainer.
(GUI-0001)Import(importer)-"MeanstoimportintoCanadaadrugforthepurposeofsale"(C.
01A.
001)Impurity(impureté)-AnycomponentpresentintheintermediateorAPIthatisnotthedesiredentity.
(ICHQ7)ImpurityProfile(profild'impureté)-AdescriptionoftheidentifiedandunidentifiedimpuritiespresentinanAPI.
(ICHQ7)In-processControl(contrleencoursdefabrication):Checksperformedduringproductioninordertomonitorand,ifnecessary,toadjusttheprocesstoensurethattheintermediateorAPIconformstoitsspecifications.
Thecontroloftheproductionenvironmentorequipmentmayalsoberegardedasapartofin-processcontrol.
In-ProcessTesting(analyseencoursdefabrication)-Theexaminationortestingofanymaterialormixtureofmaterialsduringthemanufacturingprocess.
(GUI-0001)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final72InstallationQualification(IQ)(qualificationdel'installation)-Documentedverificationthattheequipmentorsystems,asinstalledormodified,complywiththeapproveddesign,themanufacturer'srecommendationsand/oruserrequirements.
(ICHQ7)Intermediate(produitintermédiaire)-AmaterialproducedduringstepsoftheprocessingofanAPIthatundergoesfurthermolecularchangeorpurificationbeforeitbecomesanAPI.
Intermediatesmayormaynotbeisolated.
(ICHQ7)Label(étiquette)-"Includesanylegend,word,ormarkattachedto,includedin,belongingto,oraccompanyinganyfood,drug,cosmetic,device,orpackage(Section2oftheAct).
Asdescribedinpackage/label,theactionoflabellingreferstoaffixingtheinnerorouterlabeltothedrug.
"(C.
01A.
001)Lot(lot)–RefertothedefinitionofBatch.
(ICHQ7)LotNumber(numérodelot)–.
"Anycombinationofletters,figures,orboth,bywhichanyfoodordrugcanbetracedinmanufactureandidentifiedindistribution.
"(A.
01.
010)Manufacture(manufacture)-Alloperationsofreceiptofmaterials,production,packaging,repackaging,labelling,relabelling,qualitycontrol,release,storage,anddistributionofAPIsandrelatedcontrols.
(ICHQ7)Manufacturer(fabricant)orDistributor(distributeur)–Refertodefinitionofdistributor.
MarketingAuthorization(autorisationdemiseenmarché)-AlegaldocumentissuedbyHealthCanada,authorizingthesaleofadrugindosageformoradevicebasedonthehealthandsafetyrequirementsoftheFoodandDrugActanditsassociatedRegulations.
ThemarketingauthorizationmaybeintheformofaNoticeofCompliance(NOC),DrugIdentificationNumber(DIN),adevicelicenceforclassesII,IIIandIVmedicaldevices,oranaturalproductnumber(NPN)orhomeopathicDIN(DIN-HM).
(GUI-0001)MasterFormula(formule-type)-Adocumentorsetofdocumentsspecifyingtherawmaterialswiththeirquantitiesandthepackagingmaterials,togetherwithdetailedprocessinginstructions,includingin-processcontrolsandprecautionsrequiredtoproduceaspecifiedquantityofanAPI.
MasterProductionDocuments(MPD)(document-typedeproduction)-Documentsthatincludespecificationsforrawmaterial,andforpackagingmaterial;masterformula(includingcompositionandinstructionsasdescribedinthedefinitionabove),samplingprocedures,andothercriticalprocessingrelatedstandardoperatingprocedures(SOPs),whetherornottheseSOPsarespecificallyreferencedinthemasterformula.
Material(matière)-Ageneraltermusedtodenoterawmaterials(startingmaterials,reagents,solvents),processaids,intermediates,APIsandpackagingandlabellingmaterials.
(ICHQ7)MedicinalIngredient(ingrédientmédicinal)-Refertothedefinitionofactivepharmaceuticalingredient.
MotherLiquor(liquide-mère)-Theresidualliquidwhichremainsafterthecrystallizationorisolationprocesses.
Themotherliquormaycontainunreactedmaterials,intermediates,levelsoftheAPIand/orimpurities.
Itmaybeusedforfurtherprocessing.
(ICHQ7)MRACountry(paysparticipantàunARM)-"AcountrythatisaparticipanttoamutualrecognitionagreementwithCanada.
"(C.
01A.
001)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final73MutualRecognitionAgreement(MRA)(accorddereconnaissancemutuelle(ARM))–"AninternationalagreementthatprovidesforthemutualrecognitionofcompliancecertificationforGoodManufacturingPracticesfordrugs.
"(C.
01A.
001)OperationalQualification(OQ)(qualificationopérationelle)-Documentedverificationthattheequipmentorsystems,asinstalledormodified,performasintendedthroughouttheanticipatedoperatingranges.
(ICHQ7)Package(emballer)-"Asdescribedinpackage/label,theactionofpackagingreferstoputtingadruginitsimmediatecontainer.
"(C.
01A.
001)Package/Label(emballer/étiqueter)-"Toputadruginitsimmediatecontainerortoaffixtheinnerorouterlabeltothedrug.
"(C.
01A.
001).
Thisincludestherepackagingandrelabellingofpreviouslypackagedandlabelleddrugs.
PackagingBatchRecord(registred'emballagedelotdefabrication)-Recordsdemonstratingthatthebatchofadrugwaspackagedinaccordancewiththeapprovedmasterproductiondocuments.
(GUI-0001)PackagingMaterial(matérield'emballage)–includesalabel.
(C.
02.
002)Note:Forthepurposeoftheseguidelines,thisdefinitionalsoincludes:Labels,printedpackagingmaterials,anymaterialintendedtoprotecttheintermediateorAPIduringstorageandtransportandthosecomponentsindirectcontactwiththefinalAPI.
PerformanceQualification(PQ)(qualificationderendement)-Documentedverificationthattheequipmentandancillarysystems,asconnectedtogether,canperformeffectivelyandreproduciblybasedontheapprovedprocessmethodandspecifications.
(ICHQ7)Pharmaceutical(produitpharmaceutique)-"AdrugotherthanadruglistedinScheduleCorDtotheAct.
"(C.
01A.
001).
Potency(teneur)-Theactivityoramountofactivemoiety,oranyformthereof,indicatedbylabelclaimtobepresent.
(GUI-0001)Procedure(procédure)–Adocumenteddescriptionoftheoperationstobeperformed,theprecautionstobetakenandmeasurestobeapplieddirectlyorindirectlyrelatedtothemanufactureofanintermediateorAPI.
(ICHQ7)ProcessAids(adjuvantdeprocédé)-Materials,excludingsolvents,usedasanaidinthemanufactureofanintermediateorAPIthatdonotthemselvesparticipateinachemicalorbiologicalreaction(e.
g.
filteraid,activatedcarbon,etc).
(ICHQ7)ProcessValidation(PV)(validationduprocédé)-Documentedevidencethattheprocess,operatedwithinestablishedparameters,canperformeffectivelyandreproduciblytoproduceanintermediateorAPImeetingitspredeterminedspecificationsandqualityattributes.
(ICHQ7)Production(production)-AlloperationsinvolvedinthepreparationofanAPI,fromreceiptofmaterials,throughprocessingandpackaging,tocompletionofthefinalAPI,includingstorage.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final74ProductionBatchRecord(fichedelotdefabrication)-RecordsdemonstratingthatthebatchofafinalAPIwasfabricatedinaccordancewiththeapprovedmasterproductiondocuments.
PurifiedWater(eaupurifiée)-AsdefinedinanystandardlistedinScheduleBtotheFoodandDrugsAct.
(GUI-0001)Purity(pureté)-TheextenttowhicharawmaterialorafinalAPIisfreefromundesirableoradulteratingchemical,biological,orphysicalentitiesasdefinedbyspecifications.
Qualification(qualification)-Actionofprovinganddocumentingthatequipmentorancillarysystemsareproperlyinstalled,workcorrectly,andactuallyleadtotheexpectedresults.
Qualificationispartofvalidation,buttheindividualqualificationstepsalonedonotconstituteprocessvalidation.
(ICHQ7)QualityAssurance(QA)(assurancequalité)-ThesumtotaloftheorganisedarrangementsmadewiththeobjectofensuringthatallAPIsareofthequalityrequiredfortheirintendeduseandthatqualitysystemsaremaintained.
(ICHQ7)QualityControl(QC)(contrledequalité)-Checkingortestingthatspecificationsaremet.
(ICHQ7)QualityRiskManagement(gestiondesrisquesàlaqualité)-Asystematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthemedicinalproduct.
Itcanbeappliedbothproactivelyandretrospectively(ICHQ9).
QualityUnit(unitédequalité)-AnorganizationalunitindependentofproductionwhichfulfillsbothQualityAssuranceandQualityControlresponsibilities.
ThiscanbeintheformofseparateQAandQCunitsorasingleindividualorgroup,dependinguponthesizeandstructureoftheorganization.
(ICHQ7)Quarantine(quarantaine)-Thestatusofmaterialsisolatedphysicallyorbyothereffectivemeanspendingadecisionontheirsubsequentapprovalorrejection.
(ICHQ7)RawMaterial(matièrepremière)-Ageneraltermusedtodenotestartingmaterials,reagents,andsolventsintendedforuseintheproductionofintermediatesorAPIs.
(ICHQ7)Reconciliation(bilancomparatif)-Acomparison,makingdueallowancefornormalvariation,betweentheamountofproductormaterialstheoreticallyproducedorusedandtheamountactuallyproducedorused.
(GUI-0001)Recovery(récupération)-Theintroductionofallorpartofpreviousbatchesoftherequiredqualityintoanotherbatchatadefinedstageofmanufacture.
(GUI-0001)ReferenceStandard,Primary(étalonderéférenceprimaire)-Asubstancethathasbeenshownbyanextensivesetofanalyticalteststobeauthenticmaterialthatshouldbeofhighpurity.
Thisstandardcanbe:(1)obtainedfromanofficiallyrecognisedsource,or(2)preparedbyindependentsynthesis,or(3)obtainedfromexistingproductionmaterialofhighpurity,or(4)preparedbyfurtherpurificationofexistingproductionmaterial.
(ICHQ7)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final75ReferenceStandard,Secondary(étalonderéférencesecondaire)-Asubstanceofestablishedqualityandpurity,asshownbycomparisontoaprimaryreferencestandard,usedasareferencestandardforroutinelaboratoryanalysis.
(ICHQ7)Repackaging/Relabelling(réemballer/réétiqueter)-Replacementofpackagingorlabellingofpreviouslypackagedandlabelledproducts.
(GUI-0001)Reprocessing(retraitement)-IntroducinganintermediateorAPI,includingonethatdoesnotconformtostandardsorspecifications,backintotheprocessandrepeatingacrystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps(e.
g.
,distillation,filtration,chromatography,milling)thatarepartoftheestablishedmanufacturingprocess.
Continuationofaprocessstepafteranin-processcontroltesthasshownthatthestepisincompleteisconsideredtobepartofthenormalprocess,andnotreprocessing.
(ICHQ7)RetestDate(datederéanalyse)-"Thedatewhenamaterialshouldbere-examinedtoensurethatitisstillsuitableforuse.
"(ICHQ7)Reworking(reprise)-SubjectinganintermediateorAPIthatdoesnotconformtostandardsorspecificationstooneormoreprocessingstepsthataredifferentfromtheestablishedmanufacturingprocesstoobtainacceptablequalityintermediateorAPI(e.
g.
,recrystallizingwithadifferentsolvent).
(ICHQ7)Sell(vendre)-"Offerforsale,exposeforsale,haveinpossessionforsale,anddistribute,regardlessofwhetherthedistributionismadeforconsideration.
"(Section2oftheFoodandDrugsAct)ShelfLife(duréedeconservation)-Thetimeintervalduringwhichadrugisexpectedtoremainwithintheapprovedspecificationprovidedthatitisstoredundertheconditionsdefinedonthelabelandintheproposedcontainersandclosure.
(GUI-0001)Signed(signature)-Therecordoftheindividualwhoperformedaparticularactionorreview.
Thisrecordcanbeinitials,fullhandwrittensignature,personalseal,orauthenticated,andsecureelectronicsignature.
(ICHQ7)Solvent(solvent)-AninorganicororganicliquidusedasavehicleforthepreparationofsolutionsorsuspensionsinthemanufactureofanintermediateorAPI.
(ICHQ7)Specifications(spécifications)-"Meansadetaileddescriptionofadrug,therawmaterialusedinadrug,orthepackagingmaterialforadrugandincludes:(a)astatementofallpropertiesandqualitiesofthedrug,rawmaterialorpackagingmaterialthatarerelevanttothemanufacture,packaging,anduseofthedrug,includingtheidentity,potency,andpurityofthedrug,rawmaterial,orpackagingmaterial,(b)adetaileddescriptionofthemethodsusedfortestingandexaminingthedrug,rawmaterial,orpackagingmaterial,and(c)astatementoftolerancesforthepropertiesandqualitiesofthedrug,rawmaterial,orpackagingmaterial.
"(C.
02.
002)StandardOperatingProcedure(SOP)-(procédureopératoirenormalisée(PON))-Awrittenproceduregivinginstructionsforperformingoperationsnotnecessarilyspecifictoagivenproductormaterialbutofamoregeneralnature(e.
g.
,equipmentoperation,maintenanceandcleaning;validation;cleaningofpremisesandHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final76environmentalcontrol;samplingandinspection).
CertainSOPsmaybeusedtosupplementproduct-specificmasterandbatchproductiondocuments.
(GUI-0001)System(système)-Aregulatedpatternofinteractingactivitiesandtechniquesthatareunitedtoformanorganizedwhole.
(GUI-0001)Test(analyser)-Toperformthetests,includinganyexaminations,evaluations,andassessments,asspecifiedintheDivision2oftheFoodandDrugRegulations.
(GUI-0001)Validation(validation)-Adocumentedprogramthatprovidesahighdegreeofassurancethataspecificprocess,method,orsystemwillconsistentlyproducearesultmeetingpre-determinedacceptancecriteria.
(ICHQ7)Vendor/Supplier(fournisseur)-Anypersonorcompanythatsellsorsuppliesgoodsorservicestoanothercompany.
Alsocalledsupplier.
VeterinaryDrugs(médicamentsvétérinaires)-Drugsthatareadministeredtofood-producingandcompanionanimals.
(GUI-0001)Wholesaler(grossiste)-"MeansapersonwhoisnotadistributordescribedinsectionC.
01A.
003andwhosellsanyofthefollowingdrugsotherthanatretailsale:(a)adrugindosageformthatislistedinScheduleCorDtotheActorinScheduleFtotheseRegulationsoracontrolleddrugasdefinedinsubsectionG.
01.
001(1);or(b)anactiveingredient;or(c)anarcoticasdefinedintheNarcoticControlRegulations.
"(C.
01A.
001(1))AsperthenewdefinitionofwholesalerinDivision1A,PartCoftheFoodandDrugRegulations,agents,brokers,tradersareconsideredwholesalers.
Yield,Expected(rendementprévu)-Thequantityofmaterialorthepercentageoftheoreticalyieldanticipatedatanyappropriatephaseofproductionbasedonpreviouslaboratory,pilotscale,ormanufacturingdata.
(ICHQ7)Yield,Theoratical(rendementthéorique)-Thequantitythatwouldbeproducedatanyappropriatephaseofproduction,baseduponthequantityofmaterialtobeused,intheabsenceofanylossorerrorinactualproduction.
(ICHQ7)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final77AppendixCICHQ7Guideline:Section18-SpecificGuidanceforAPIsManufacturedbyCellCulture/Fermentation18.
1General18.
10Section18isintendedtoaddressspecificcontrolsforAPIsorintermediatesmanufacturedbycellcultureorfermentationusingnaturalorrecombinantorganismsandthathavenotbeencoveredadequatelyintheprevioussections.
Itisnotintendedtobeastand-aloneSection.
Ingeneral,theGMPprinciplesintheothersectionsofthisdocumentapply.
Notethattheprinciplesoffermentationfor"classical"processesforproductionofsmallmoleculesandforprocessesusingrecombinantandnon-recombinantorganismsforproductionofproteinsand/orpolypeptidesarethesame,althoughthedegreeofcontrolwilldiffer.
Wherepractical,thissectionwilladdressthesedifferences.
Ingeneral,thedegreeofcontrolforbiotechnologicalprocessesusedtoproduceproteinsandpolypeptidesisgreaterthanthatforclassicalfermentationprocesses.
18.
11Theterm"biotechnologicalprocess"(biotech)referstotheuseofcellsororganismsthathavebeengeneratedormodifiedbyrecombinantDNA,hybridomaorothertechnologytoproduceAPIs.
TheAPIsproducedbybiotechnologicalprocessesnormallyconsistofhighmolecularweightsubstances,suchasproteinsandpolypeptides,forwhichspecificguidanceisgiveninthisSection.
CertainAPIsoflowmolecularweight,suchasantibiotics,aminoacids,vitamins,andcarbohydrates,canalsobeproducedbyrecombinantDNAtechnology.
ThelevelofcontrolforthesetypesofAPIsissimilartothatemployedforclassicalfermentation.
18.
12Theterm"classicalfermentation"referstoprocessesthatusemicroorganismsexistinginnatureand/ormodifiedbyconventionalmethods(e.
g.
irradiationorchemicalmutagenesis)toproduceAPIs.
APIsproducedby"classicalfermentation"arenormallylowmolecularweightproductssuchasantibiotics,aminoacids,vitamins,andcarbohydrates.
18.
13ProductionofAPIsorintermediatesfromcellcultureorfermentationinvolvesbiologicalprocessessuchascultivationofcellsorextractionandpurificationofmaterialfromlivingorganisms.
Notethattheremaybeadditionalprocesssteps,suchasphysicochemicalmodification,thatarepartofthemanufacturingprocess.
Therawmaterialsused(media,buffercomponents)mayprovidethepotentialforgrowthofmicrobiologicalcontaminants.
Dependingonthesource,methodofpreparation,andtheintendeduseoftheAPIorintermediate,controlofbioburden,viralcontamination,and/orendotoxinsduringmanufacturingandmonitoringoftheprocessatappropriatestagesmaybenecessary.
18.
14Appropriatecontrolsshouldbeestablishedatallstagesofmanufacturingtoassureintermediateand/orAPIquality.
WhilethisGuidestartsatthecellculture/fermentationstep,priorsteps(e.
g.
cellbanking)shouldbeperformedunderappropriateprocesscontrols.
ThisGuidecoverscellculture/fermentationfromthepointatwhichavialofthecellbankisretrievedforuseinmanufacturing.
18.
15Appropriateequipmentandenvironmentalcontrolsshouldbeusedtominimizetheriskofcontamination.
Theacceptancecriteriaforqualityoftheenvironmentandthefrequencyofmonitoringshoulddependonthestepinproductionandtheproductionconditions(open,closed,orcontainedsystems).
18.
16Ingeneral,processcontrolsshouldtakeintoaccount:MaintenanceoftheWorkingCellBank(whereappropriate);Properinoculationandexpansionoftheculture;HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final78Controlofthecriticaloperatingparametersduringfermentation/cellculture;Monitoringoftheprocessforcellgrowth,viability(formostcellcultureprocesses)andproductivitywhereappropriate;Harvestandpurificationproceduresthatremovecells,cellulardebrisandmediacomponentswhileprotectingtheintermediateorAPIfromcontamination(particularlyofamicrobiologicalnature)andfromlossofquality;Monitoringofbioburdenand,whereneeded,endotoxinlevelsatappropriatestagesofproduction;andViralsafetyconcernsasdescribedinICHGuidelineQ5AQualityofBiotechnologicalProducts:ViralSafetyEvaluationofBiotechnologyProductsDerivedfromCellLinesofHumanorAnimalOrigin.
18.
17Whereappropriate,theremovalofmediacomponents,hostcellproteins,otherprocess-relatedimpurities,product-relatedimpuritiesandcontaminantsshouldbedemonstrated.
18.
2CellBankMaintenanceandRecordKeeping18.
20Accesstocellbanksshouldbelimitedtoauthorizedpersonnel.
18.
21Cellbanksshouldbemaintainedunderstorageconditionsdesignedtomaintainviabilityandpreventcontamination.
18.
22Recordsoftheuseofthevialsfromthecellbanksandstorageconditionsshouldbemaintained.
18.
23Whereappropriate,cellbanksshouldbeperiodicallymonitoredtodeterminesuitabilityforuse.
18.
24SeeICHGuidelineQ5DQualityofBiotechnologicalProducts:DerivationandCharacterizationofCellSubstratesUsedforProductionofBiotechnological/BiologicalProductsforamorecompletediscussionofcellbanking.
18.
3CellCulture/Fermentation18.
30Whereasepticadditionofcellsubstrates,media,buffers,andgasesisneeded,closedorcontainedsystemsshouldbeusedwherepossible.
Iftheinoculationoftheinitialvesselorsubsequenttransfersoradditions(media,buffers)areperformedinopenvessels,thereshouldbecontrolsandproceduresinplacetominimizetheriskofcontamination.
18.
31WherethequalityoftheAPIcanbeaffectedbymicrobialcontamination,manipulationsusingopenvesselsshouldbeperformedinabiosafetycabinetorsimilarlycontrolledenvironment.
18.
32Personnelshouldbeappropriatelygownedandtakespecialprecautionshandlingthecultures.
18.
33Criticaloperatingparameters(forexampletemperature,pH,agitationrates,additionofgases,pressure)shouldbemonitoredtoensureconsistencywiththeestablishedprocess.
Cellgrowth,viability(formostcellcultureprocesses),and,whereappropriate,productivityshouldalsobemonitored.
Criticalparameterswillvaryfromoneprocesstoanother,andforclassicalfermentation,certainparameters(cellviability,forexample)maynotneedtobemonitored.
18.
34Cellcultureequipmentshouldbecleanedandsterilizedafteruse.
Asappropriate,fermentationequipmentshouldbecleaned,andsanitizedorsterilized.
18.
35CulturemediashouldbesterilizedbeforeusewhenappropriatetoprotectthequalityoftheAPI.
18.
36Thereshouldbeappropriateproceduresinplacetodetectcontaminationanddeterminethecourseofactiontobetaken.
ThisshouldincludeprocedurestodeterminetheimpactofthecontaminationontheHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final79productandthosetodecontaminatetheequipmentandreturnittoaconditiontobeusedinsubsequentbatches.
Foreignorganismsobservedduringfermentationprocessesshouldbeidentifiedasappropriateandtheeffectoftheirpresenceonproductqualityshouldbeassessed,ifnecessary.
Theresultsofsuchassessmentsshouldbetakenintoconsiderationinthedispositionofthematerialproduced.
18.
37Recordsofcontaminationeventsshouldbemaintained.
18.
38Shared(multi-product)equipmentmaywarrantadditionaltestingaftercleaningbetweenproductcampaigns,asappropriate,tominimizetheriskofcross-contamination.
18.
4Harvesting,IsolationandPurification18.
40Harvestingsteps,eithertoremovecellsorcellularcomponentsortocollectcellularcomponentsafterdisruption,shouldbeperformedinequipmentandareasdesignedtominimizetheriskofcontamination.
18.
41Harvestandpurificationproceduresthatremoveorinactivatetheproducingorganism,cellulardebrisandmediacomponents(whileminimizingdegradation,contamination,andlossofquality)shouldbeadequatetoensurethattheintermediateorAPIisrecoveredwithconsistentquality.
18.
42Allequipmentshouldbeproperlycleanedand,asappropriate,sanitizedafteruse.
MultiplesuccessivebatchingwithoutcleaningcanbeusedifintermediateorAPIqualityisnotcompromised.
18.
43Ifopensystemsareused,purificationshouldbeperformedunderenvironmentalconditionsappropriateforthepreservationofproductquality.
18.
44Additionalcontrols,suchastheuseofdedicatedchromatographyresinsoradditionaltesting,maybeappropriateifequipmentistobeusedformultipleproducts.
18.
5ViralRemoval/Inactivationsteps18.
50SeetheICHGuidelineQ5AQualityofBiotechnologicalProducts:ViralSafetyEvaluationofBiotechnologyProductsDerivedfromCellLinesofHumanorAnimalOriginformorespecificinformation.
18.
51Viralremovalandviralinactivationstepsarecriticalprocessingstepsforsomeprocessesandshouldbeperformedwithintheirvalidatedparameters.
18.
52Appropriateprecautionsshouldbetakentopreventpotentialviralcontaminationfrompre-viraltopost-viralremoval/inactivationsteps.
Therefore,openprocessingshouldbeperformedinareasthatareseparatefromotherprocessingactivitiesandhaveseparateairhandlingunits.
18.
53Thesameequipmentisnotnormallyusedfordifferentpurificationsteps.
However,ifthesameequipmentistobeused,theequipmentshouldbeappropriatelycleanedandsanitizedbeforereuse.
Appropriateprecautionsshouldbetakentopreventpotentialviruscarry-over(e.
g.
throughequipmentorenvironment)fromprevioussteps.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final80AppendixDICHQ7Guideline:Section19–APIsforUseinClinicalTrials19.
1General19.
10NotallthecontrolsintheprevioussectionsofthisGuideareappropriateforthemanufactureofanewAPIforinvestigationaluseduringitsdevelopment.
Section19providesspecificguidanceuniquetothesecircumstances.
19.
11ThecontrolsusedinthemanufactureofAPIsforuseinclinicaltrialsshouldbeconsistentwiththestageofdevelopmentofthedrugproductincorporatingtheAPI.
Processandtestproceduresshouldbeflexibletoprovideforchangesasknowledgeoftheprocessincreasesandclinicaltestingofadrugproductprogressesfrompre-clinicalstagesthroughclinicalstages.
OncedrugdevelopmentreachesthestagewheretheAPIisproducedforuseindrugproductsintendedforclinicaltrials,manufacturersshouldensurethatAPIsaremanufacturedinsuitablefacilitiesusingappropriateproductionandcontrolprocedurestoensurethequalityoftheAPI.
19.
2Quality19.
20AppropriateGMPconceptsshouldbeappliedintheproductionofAPIsforuseinclinicaltrialswithasuitablemechanismofapprovalofeachbatch.
19.
21Aqualityunit(s)independentfromproductionshouldbeestablishedfortheapprovalorrejectionofeachbatchofAPIforuseinclinicaltrials.
19.
22Someofthetestingfunctionscommonlyperformedbythequalityunit(s)canbeperformedwithinotherorganizationalunits.
19.
23Qualitymeasuresshouldincludeasystemfortestingofrawmaterials,packagingmaterials,intermediates,andAPIs.
19.
24Processandqualityproblemsshouldbeevaluated.
19.
25LabellingforAPIsintendedforuseinclinicaltrialsshouldbeappropriatelycontrolledandshouldidentifythematerialasbeingforinvestigationaluse.
19.
3EquipmentandFacilities19.
30Duringallphasesofclinicaldevelopment,includingtheuseofsmall-scalefacilitiesorlaboratoriestomanufacturebatchesofAPIsforuseinclinicaltrials,proceduresshouldbeinplacetoensurethatequipmentiscalibrated,cleanandsuitableforitsintendeduse.
19.
31Proceduresfortheuseoffacilitiesshouldensurethatmaterialsarehandledinamannerthatminimizestheriskofcontaminationandcross-contamination.
19.
4ControlofRawMaterials19.
40RawmaterialsusedinproductionofAPIsforuseinclinicaltrialsshouldbeevaluatedbytesting,orreceivedwithasupplier'sanalysisandsubjectedtoidentitytesting.
Whenamaterialisconsideredhazardous,asupplier'sanalysisshouldsuffice.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final8119.
41Insomeinstances,thesuitabilityofarawmaterialcanbedeterminedbeforeusebasedonacceptabilityinsmall-scalereactions(i.
e.
,usetesting)ratherthanonanalyticaltestingalone.
19.
5Production19.
50TheproductionofAPIsforuseinclinicaltrialsshouldbedocumentedinlaboratorynotebooks,batchrecords,orbyotherappropriatemeans.
Thesedocumentsshouldincludeinformationontheuseofproductionmaterials,equipment,processing,andscientificobservations.
19.
51Expectedyieldscanbemorevariableandlessdefinedthantheexpectedyieldsusedincommercialprocesses.
Investigationsintoyieldvariationsarenotexpected.
19.
6Validation19.
60ProcessvalidationfortheproductionofAPIsforuseinclinicaltrialsisnormallyinappropriate,whereasingleAPIbatchisproducedorwhereprocesschangesduringAPIdevelopmentmakebatchreplicationdifficultorinexact.
Thecombinationofcontrols,calibration,and,whereappropriate,equipmentqualificationassuresAPIqualityduringthisdevelopmentphase.
19.
61ProcessvalidationshouldbeconductedinaccordancewithSection12whenbatchesareproducedforcommercialuse,evenwhensuchbatchesareproducedonapilotorsmallscale.
19.
7Changes19.
70Changesareexpectedduringdevelopment,asknowledgeisgainedandtheproductionisscaledup.
Everychangeintheproduction,specifications,ortestproceduresshouldbeadequatelyrecorded.
19.
8LaboratoryControls19.
80WhileanalyticalmethodsperformedtoevaluateabatchofAPIforclinicaltrialsmaynotyetbevalidated,theyshouldbescientificallysound.
19.
81Asystemforretainingreservesamplesofallbatchesshouldbeinplace.
Thissystemshouldensurethatasufficientquantityofeachreservesampleisretainedforanappropriatelengthoftimeafterapproval,termination,ordiscontinuationofanapplication.
19.
82ExpiryandretestdatingasdefinedinSection11.
6appliestoexistingAPIsusedinclinicaltrials.
FornewAPIs,Section11.
6doesnotnormallyapplyinearlystagesofclinicaltrials.
19.
9Documentation19.
90AsystemshouldbeinplacetoensurethatinformationgainedduringthedevelopmentandthemanufactureofAPIsforuseinclinicaltrialsisdocumentedandavailable.
19.
91ThedevelopmentandimplementationoftheanalyticalmethodsusedtosupportthereleaseofabatchofAPIforuseinclinicaltrialsshouldbeappropriatelydocumented.
19.
92Asystemforretainingproductionandcontrolrecordsanddocumentsshouldbeused.
Thissystemshouldensurethatrecordsanddocumentsareretainedforanappropriatelengthoftimeaftertheapproval,termination,ordiscontinuationofanapplication.
HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final82AppendixEAnnexestotheCurrentEditionoftheseAPIGMPGuidelinesAnnexesareavailableonHealthCanada'swebsite:(http://www.
hc-sc.
gc.
ca/dhp-mps/compli-conform/gmp-bpf/docs/index-eng.
php).
1.
Annex1totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-SelectedCategoryIVMonographDrugs(GUI-0066)2.
Annex2totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-ScheduleDDrugs,BiologicalDrugs(GUI-0027)3.
Annex3totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-ScheduleCDrugs(GUI-0026)4.
Annex4totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-VeterinaryDrugs(GUI-0012)5.
Annex5totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-PositronEmittingRadiopharmaceuticals(PERs)(GUI-0071)6.
PIC/SAnnex11:ComputerisedSystems7.
Annex13totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-DrugsUsedinClinicalTrials(GUI-0036)8.
Annex14totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-ScheduleDDrugs,HumanBloodandBloodComponents(GUI-0032)9.
Annex17totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-GuidanceonParametricRelease(GUI-0046)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final83ReferencesJusticeCanadaActsandregulationsofCanadaareavailableonJusticeLawswebsite.
1.
FoodandDrugsAct2.
FoodandDrugRegulationsHealthCanadaGuidancedocumentsandQuestionsandAnswersthatrelatetoGMPsareavailableonHealthCanada'swebsite3.
GoodManufacturingPractices(GMP)Guidelines,Edition2009,Version2(GUI-0001)4.
GuidanceonEvidencetoDemonstrateDrugGMPComplianceofForeignSites(GUI-0080)5.
Annex3totheCurrentEditionoftheGoodManufacturingPracticesGuidelines-ScheduleCDrugs(GUI-0026)6.
Annex2totheCurrentEditionoftheGoodManufacturingPracticesGuidelinesScheduleDDrugs(BiologicalDrugs)(GUI-0027)7.
GoodManufacturingPracticesQuestionsandAnswers8.
ActivePharmaceuticalIngredientsQuestionsandAnswers9.
RiskClassificationofGMPObservations(GUI–0023)10.
GuidelinesforTemperatureControlofDrugProductsduringStorageandTransportation(GUI-0069)11.
ProductRecallProcedures12.
CleaningValidationGuidelines(GUI-0028)13.
ValidationDocumentationRequirementsandResponsibilitiesforDrugFabricators,Packagers/Labellers,DistributorsandImporters(GUI-0042)14.
ProcessValidationGuidelines:MoistHeatSterilizationforPharmaceuticals(GUI-0010)IrradiationSterilizationforPharmaceuticals(GUI-0009)HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final84GaseousSterilizationforPharmaceuticals(GUI-0007)AsepticProcessesforPharmaceuticals(GUI-0006)15.
ImportationandExportationQuestionsandAnswers16.
AlternateSampleRetentionSiteGuidelines(GUI-0014)DocumentsthatrelatetostabilityareavailableonHealthCanada'swebsiteintheDrugProductssectionunderApplicationandSubmissions.
17.
StabilityTestingofExistingDrugSubstancesandProducts(TPD)GuidancedocumentsdevelopedbytheInternationalConferenceonHarmonisation(ICH)andadoptedbyHealthCanadaareavailableonthewebintheDrugProductssectionunderICH(InternationalConferenceonHarmonisation).
18.
ICHQ1A(R2):StabilityTestingofNewDrugSubstancesandProducts19.
ICHQ1B:StabilityTesting:PhotostabilityTestingofNewDrugSubstancesandProducts20.
ICHQ2(R1):ValidationofAnalyticalProcedures:TextandMethodology21.
ICHQ7:GoodManufacturingPracticeGuideforActivePharmaceuticalIngredients22.
ICHQ8:PharmaceuticalDevelopment23.
ICHQ9:QualityRiskManagement24.
ICHQ10:PharmaceuticalQualitySystemHealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final85AppendixFCross-walkbetweenICHQ7andGUI-0001documentsInterpretationsoftheAPIGuideSectionofICHQ7SectionofGUI-0001QualityManagement4.
12.
10,2.
124.
14.
2notapplicable4.
24.
2.
1notapplicable4.
2.
14.
2.
1.
1notapplicable4.
2.
1.
14.
2.
1.
22.
114.
2.
1.
24.
2.
1.
32.
3.
104.
2.
1.
34.
2.
1.
4notapplicable4.
2.
1.
44.
2.
1.
5notapplicable4.
2.
1.
54.
2.
1.
62.
174.
2.
1.
64.
2.
1.
7notapplicable4.
2.
1.
74.
2.
1.
8notapplicable4.
2.
1.
84.
2.
1.
9notapplicable4.
2.
1.
94.
2.
1.
102.
17,partial2.
144.
2.
1.
104.
2.
1.
11notapplicable4.
2.
1.
114.
2.
1.
12notapplicable4.
2.
1.
124.
2.
1.
13notapplicable4.
2.
1.
134.
2.
1.
14notapplicable4.
2.
1.
144.
2.
1.
152.
15notapplicable4.
2.
2notapplicable4.
2.
24.
2.
2.
1notapplicable4.
2.
2.
14.
2.
2.
2notapplicable4.
2.
2.
24.
2.
2.
3notapplicable4.
2.
2.
34.
2.
2.
4notapplicable4.
2.
2.
44.
2.
2.
5notapplicable4.
2.
2.
54.
2.
2.
62.
164.
2.
2.
64.
2.
2.
7notapplicable4.
2.
2.
74.
2.
2.
8notapplicable4.
2.
2.
84.
2.
2.
9notapplicable4.
2.
2.
94.
2.
2.
10notapplicable4.
2.
2.
104.
2.
3notapplicable4.
2.
34.
2.
3.
1notapplicable4.
2.
3.
14.
2.
3.
1.
1notapplicable4.
2.
3.
1.
14.
2.
3.
1.
2notapplicable4.
2.
3.
1.
24.
2.
3.
1.
3notapplicable4.
2.
3.
1.
34.
2.
3.
1.
42.
414.
2.
3.
1.
44.
2.
3.
1.
5notapplicable4.
2.
3.
1.
54.
2.
3.
1.
6notapplicable4.
2.
3.
1.
64.
2.
3.
1.
7notapplicable4.
2.
3.
1.
7C.
02.
003–SaleandUseinFabrication1.
notapplicablenotapplicable2.
notapplicablenotapplicableC.
02.
004–Premises1.
4.
10C.
02.
004:1,11,Partial3,Partial3.
1,C.
02.
007:2.
9,Records:5.
42.
4.
70C.
02.
004:1,2.
1-2.
4,9,Partial3.
1,Records:5.
43.
4.
11C.
02.
004:2,2.
5,6.
1,6.
2,11,C.
02.
005:3.
3,3.
44.
4.
14C.
02.
004:Partial2.
2,2.
3,6.
1-6.
4,C.
02.
011:48,49HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final865.
4.
16C.
02.
004:Partial2.
3,10,C.
02.
011:126.
4.
24C.
02.
004:3.
57.
4.
20C.
02.
004:3.
6,7,C.
02.
007:2.
98.
4.
21C.
02.
004:3.
6,48.
14.
22notapplicable9.
4.
15C.
02.
004:510.
4.
13C.
02.
004:6,11,C.
02.
005:3.
311.
4.
50C.
02.
004:6.
512.
4.
23C.
02.
004:813.
4.
40C.
02.
004:11,11.
2.
1,C.
02.
005:3.
614.
4.
41C.
02.
004:11,11.
1,11.
2.
2,C.
02.
005:3.
615.
4.
43C.
02.
004:11.
2.
2,11.
4,C.
02.
011:Partial916.
4.
33C.
02.
005:3.
7C.
02.
005-Equipment1.
5.
10C.
02.
005:1,1.
1,1.
3,3.
3,5,Partial1.
2,Partial1.
5,Partial4.
2,Partial4.
3,Partial4.
42.
5.
11C.
02.
005:1,Partial1.
2,2,2.
1,2.
3,4.
1,4.
43.
5.
22C.
02.
005:1.
1,1.
2,1.
3,1.
4,2.
44.
5.
14C.
02.
005:2.
2,3.
25.
5.
15C.
02.
005:2.
4,2.
5,3.
25.
1notapplicableC.
02.
005:3.
16.
5.
13C.
02.
005:3.
57.
5.
16,5.
20C.
02.
005:4,Partial4.
28.
notapplicableC.
02.
005:5.
29.
5.
30,5.
34C.
02.
005:5.
1,5.
3,5.
4,C.
02.
011:139.
15.
31notapplicable9.
25.
33,5.
35notapplicable10.
Partial8.
10C.
02.
005:5.
1,C.
02.
011:2211.
5.
12C.
02.
005:5.
2,5.
3,C.
02.
011:35.
1012.
5.
40C.
02.
005:5.
3,C.
02.
015:Partial7.
513.
5.
41C.
02.
005:5.
314.
5.
42notapplicable15.
5.
43notapplicable16.
5.
44,5.
48notapplicable17.
5.
49notapplicable18.
12.
30C.
02.
005:5.
3C.
02.
006-Personnel1.
3.
10C.
02.
006:1,1.
1,1.
2,1.
3,1.
4,3,3.
1,3.
2,4,4.
1,4.
2,5,5.
1,5.
32.
notapplicableC.
02.
006:12.
1notapplicableC.
02.
006:1.
32.
2notapplicableC.
02.
006:1.
43.
3.
11C.
02.
006:5.
24.
Partial3.
12C.
02.
006:6,6.
14.
1Partial3.
12C.
02.
006:64.
2Partial3.
12C.
02.
006:6.
44.
3Partial3.
12C.
02.
006:6.
2,6.
64.
4notapplicableC.
02.
006:6.
34.
5notapplicableC.
02.
006:6.
55.
3.
30C.
02.
006:76.
2.
3C.
02.
011:Partial16.
12.
3.
1C.
02.
011:Partial16.
22.
3.
2C.
02.
011:Partial236.
32.
3.
3C.
02.
011:27.
106.
42.
3.
4C.
02.
011:56.
52.
3.
5C.
02.
004:1,2,3,9,11HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final87C.
02.
005:1,3,46.
62.
3.
6C.
02.
005:5.
1Records:2.
36.
72.
3.
7C.
02.
004:2C.
02.
005:4,5Records:2.
3,5.
4,6.
46.
82.
3.
8C.
02.
011:Partial36.
92.
3.
9C.
02.
011:46.
102.
3.
10C.
02.
004:Partial7C.
02.
005:Partial5.
372.
22C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
12.
22.
1C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
22.
22.
2C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
32.
22.
3C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
42.
22.
4C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
52.
22.
5C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
62.
22.
6C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
72.
22.
7C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
82.
22.
8C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
92.
22.
9C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
102.
22.
10C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
112.
22.
11C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
122.
22.
12C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
132.
22.
13C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
142.
22.
14C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
152.
22.
15C.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial17.
16notapplicableC.
02.
009:Partial1,7,C.
02.
011:3,4,5,19,C.
02.
012:3.
2C.
02.
014:2,2.
1,3,C.
02.
015:4,6,C.
02.
016:1,C.
02.
018:Partial1C.
02.
007-SanitationRationale4.
70C.
02.
007:31.
4.
71C.
02.
007:1,2,2.
1,2.
4,2.
101.
1notapplicableC.
02.
007:2.
91.
2notapplicableC.
02.
007:2.
52.
5.
24C.
02.
007:2.
33.
5.
25C.
02.
007:2.
4,3.
24.
4.
60C.
02.
007:2.
65.
12.
70C.
02.
007:3.
16.
12.
74C.
02.
007:3.
2,3.
47.
12.
75C.
02.
007:3.
38.
4.
72C.
02.
004:2HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final88C.
02.
007:2.
7,2.
89.
5.
21C.
02.
005:1,1.
1,1.
3,1.
4,1.
6,C.
02.
007:1,2.
2,2.
3,2.
4,2.
10,3.
2,Partial1.
210.
5.
23C.
02.
007:2.
3,2.
8,3.
5,Partial2.
711.
6.
20C.
02.
005:5.
512.
12.
76notapplicable13.
notapplicableC.
02.
007:5C.
02.
008-Sanitation1.
3.
20C.
02.
008:2.
1,Partial1,Partial2,Partial2.
4,Records:Partial5.
4,6.
41.
1notapplicableC.
02.
008:2.
52.
3.
24C.
02.
008:1.
3,1.
42.
1notapplicableC.
02.
008:1.
22.
2notapplicableC.
02.
008:1.
53.
3.
21C.
02.
008:2.
1,2.
73.
1notapplicableC.
02.
008:2.
64.
3.
22C.
02.
008:2.
25.
3.
23C.
02.
008:2.
3C.
02.
009–RawMaterialsTesting1.
6.
17C.
02.
009:1,C.
02.
018:1,Records:5.
12.
notapplicablenotapplicable3.
7.
12C.
02.
009:Partial14.
4.
30C.
02.
005:Partial3.
75.
4.
31C.
02.
009:Partial46.
4.
32C.
02.
009:Partial4,Partial4.
1,Partial4.
27.
4.
34C.
02.
005:Partial3.
78.
12.
80C.
02.
009:Partial5,C.
02.
018:29.
12.
81C.
02.
009:Partial5,C.
02.
018:210.
7.
50notapplicableC.
02.
010–RawMaterialsTesting1.
7.
11C.
02.
010:Partial12.
7.
30C.
02.
010:Partial1,C.
02.
017:Partial12.
1notapplicableC.
02.
010:33.
7.
31C.
02.
010:Partial1,Partial1.
3,C.
02.
017:Partial13.
1notapplicableC.
02.
010:1.
73.
2notapplicableC.
02.
010:1.
44.
7.
32notapplicable5.
7.
33C.
02.
009:Partial6,C.
02.
013:Partial3,C.
02.
015:46.
Partial7.
10C.
02.
011:Partial1,Partial177.
7.
13Records:5.
3,6.
38.
7.
14notapplicable9.
notapplicableC.
02.
010:1.
310.
notapplicableC.
02.
010:1.
811.
notapplicableC.
02.
010:412.
notapplicableC.
02.
010:513.
notapplicableC.
02.
010:613.
1notapplicableC.
02.
010:6.
113.
2notapplicableC.
02.
010:6.
213.
3notapplicableC.
02.
010:6.
313.
4notapplicableC.
02.
010:6.
4C.
02.
011–ManufacturingControl1.
notapplicableC.
02.
011:82.
Partial7.
10C.
02.
011:1,173.
12.
12C.
02.
011:23.
112.
60,13.
13C.
02.
011:4,C.
02.
015:64.
12.
20C.
02.
011:3HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final894.
112.
21C.
02.
011:Partial34.
212.
22notapplicable4.
312.
23notapplicable5.
Partial12.
30C.
02.
005:5.
36.
8.
15,8.
20C.
02.
011:5,19,35.
12,Partial417.
8.
14C.
02.
011:6,78.
8.
50C.
02.
005:2,3,C.
02.
011:Partial99.
notapplicableC.
02.
011:910.
9.
44C.
02.
011:1011.
8.
51C.
02.
004:3.
2,3.
3,3.
4,C.
02.
011:11,20,Partial9,Records:5.
4,6.
412.
8.
35C.
02.
011:1213.
8.
30notapplicable14.
8.
31notapplicable15.
8.
32notapplicable16.
8.
33notapplicable17.
8.
34notapplicable18.
8.
52C.
02.
004:3.
2,3.
3,3.
4,C.
02.
011:Partial919.
4.
42C.
02.
004:1,220.
5.
26C.
02.
005:3.
5,C.
02.
011:1421.
8.
16C.
02.
005:3.
5,C.
02.
011:14,3422.
7.
44C.
02.
011:1523.
8.
17C.
02.
011:1524.
7.
20C.
02.
011:16,17,1924.
17.
20C.
02.
011:1625.
7.
21C.
02.
011:16,17,1926.
7.
22C.
02.
011:16,17,1927.
8.
21C.
02.
011:4828.
10.
21C.
02.
011:48C.
02.
015:329.
10.
22C.
02.
015:3.
230.
7.
34C.
02.
004:6.
4,C.
02.
011:2031.
7.
35C.
02.
011:1732.
7.
23C.
02.
011:1433.
7.
24C.
02.
010:5,6,6.
1.
6.
2,6.
3,6.
4C.
02.
011:14,21.
5C.
02.
017:534.
7.
40C.
02.
004:4C.
02.
011:48C.
02.
017:Partial3,3.
1,3.
2,3.
4,3.
535.
7.
41notapplicable36.
7.
42notapplicable37.
7.
43notapplicable38.
Partial8.
10C.
02.
005:5.
1,C.
02.
011:2239.
8.
12C.
02.
011:2240.
8.
13notapplicable41.
2.
15C.
02.
011:35.
442.
6.
14C.
02.
011:35.
4Records:Interpretationparagraph43.
6.
10C.
02.
011:143.
16.
40C.
02.
011:2344.
6.
41,8.
20C.
02.
011:24,24.
1,24.
3,24.
4,24.
5,24.
7,24.
8,24.
9,25,25.
1,25.
2,27,27.
1,27.
3,27.
4,35.
7,Partial24.
645.
6.
50C.
02.
011:26,Records:2.
246.
6.
51C.
02.
011:26,27.
2,Records:2.
247.
6.
52C.
02.
011:27.
3to27.
10,35,35.
1to35.
4,Records:2.
248.
8.
11C.
02.
011:Partial21,Partial21.
4HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final9049.
8.
40notapplicable50.
8.
41notapplicable51.
8.
42notapplicable52.
8.
43C.
02.
011:2853.
8.
44notapplicable54.
8.
45notapplicable55.
8.
46notapplicable56.
8.
47C.
02.
027:Partial1.
557.
14.
40C.
02.
011:28.
15814.
41notapplicable59.
14.
42notapplicable60.
14.
43notapplicable61.
notapplicableC.
02.
011:2962.
9.
41C.
02.
011:29,3863.
9.
30C.
02.
011:Partial43,43.
164.
9.
44C.
02.
011:25.
4,3165.
9.
40C.
02.
011:25.
1,25.
5,29,35.
8,35.
13,38,45,46C.
02.
017:Partial3,Partial3.
1,Partial3.
2,Partial3.
4,Partial3.
566.
9.
34notapplicable67.
9.
35C.
02.
011:43,4768.
9.
21C.
02.
011:3369.
9.
22notapplicable70.
9.
42C.
02.
011:21,21.
1,21.
2,21.
3,5071.
9.
43C.
02.
011:21,21.
1to21.
4,Partial35.
772.
9.
46notapplicable73.
9.
45C.
02.
011:25.
6,35.
5,35.
6,35.
874.
9.
31C.
02.
011:35.
14,4275.
9.
32C.
02.
011:3976.
9.
33C.
02.
011:4077.
notapplicableC.
02.
011:4978.
notapplicableC.
02.
011:3578.
1notapplicableC.
02.
011:35.
178.
2notapplicableC.
02.
011:35.
378.
3notapplicableC.
02.
011:35.
478.
4notapplicableC.
02.
011:35.
878.
5notapplicableC.
02.
011:35.
978.
6notapplicableC.
02.
011:35.
1078.
7notapplicableC.
02.
011:35.
1178.
8notapplicableC.
02.
011:35.
1278.
9notapplicableC.
02.
011:3779.
2.
50C.
02.
011:51,51.
1,51.
2,51.
3,51.
4,51.
5,51.
6,51.
7C.
02.
015:4,C.
02.
028:180.
2.
51C.
02.
011:5581.
notapplicableC.
02.
011:5382.
notapplicableC.
02.
011:54C.
02.
012–ManufacturingControlRationale17.
40C.
02.
012:Interpretationparagraph1.
2.
18C.
02.
012:1.
42.
15.
13C.
02.
012:Partial1,Partial1.
10,Partial1.
11,1.
2Records:3.
23.
15.
14C.
02.
012:1.
3,1.
5,1.
9,Partial1Records:3.
23.
1notapplicableC.
02.
012:1.
13.
2notapplicableC.
02.
012:1.
43.
3notapplicableC.
02.
012:1.
104.
10.
24C.
02.
012:1.
6HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final91Records:2.
1,2.
1.
1,2.
1.
24.
115.
14C.
02.
012:1.
85.
10.
11C.
02.
012:1.
96.
17.
70C.
02.
012:1.
11Records:3.
17.
2.
40C.
02.
012:2,2.
1,2.
2,2.
47.
1notapplicableC.
02.
012:2.
38.
2.
41C.
02.
012:2.
1,2.
5,Records:2.
29.
Partial16.
10,17.
11C.
02.
012:3.
2.
210.
16.
11notapplicable11.
notapplicableC.
02.
012:3.
11.
1notapplicableC.
02.
012:3.
111.
216.
12C.
02.
012:3.
211.
2.
1notapplicableC.
02.
012:3.
2.
111.
2.
216.
13C.
02.
012:3.
2.
211.
2.
3notapplicableC.
02.
012:3.
2.
311.
2.
3.
1notapplicableC.
02.
012:3.
2.
3.
111.
2.
3.
2notapplicableC.
02.
012:3.
2.
3.
211.
2.
3.
3notapplicableC.
02.
012:3.
2.
3.
311.
2.
416.
14C.
02.
012:3.
2.
411.
2.
5notapplicableC.
02.
012:3.
2.
511.
2.
6notapplicableC.
02.
012:3.
2.
611.
3notapplicableC.
02.
012:3.
311.
4notapplicableC.
02.
012:3.
411.
4.
116.
16notapplicable11.
5notapplicableC.
02.
012:3.
511.
5.
1notapplicableC.
02.
012:3.
5.
111.
5.
2notapplicableC.
02.
012:3.
5.
2C.
02.
013–QualityControlDepartment1.
2.
20C.
02.
015:42.
2.
21,Partial7.
10,Partial11.
11C.
02.
011:1,17C.
02.
013:3C.
02.
014:3C.
02.
015:33.
2.
13notapplicable4.
11.
10C.
02.
013:2C.
02.
015:7,7.
1C.
02.
014–QualityControlDepartment1.
Partial2.
14,Partial2.
22C.
02.
014:12.
2.
17notapplicable3.
2.
22C.
02.
014:24.
10.
20notapplicable5.
notapplicableC.
02.
014:36.
2.
16,6.
53C.
02.
014:2.
1,2.
27.
14.
10,14.
50C.
02.
011:15C.
02.
014:5C.
02.
018:48.
14.
51C.
02.
014:48.
1notapplicableC.
02.
014:4.
19.
14.
30C.
02.
014:610.
14.
31C.
02.
014:6,6.
1to6.
711.
14.
32C.
02.
014:6,6.
1to6.
712.
14.
20C.
02.
014:7,7.
1-7.
5,7.
713.
14.
21notapplicable14.
14.
22C.
02.
014:7,7.
1to7.
7HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final9215.
notapplicablenotapplicableC.
02.
015–QualityControlDepartment1.
2.
18C.
02.
012:1.
42.
13.
10C.
02.
015:53.
13.
11C.
02.
014:4C.
02.
015:54.
13.
12C.
02.
015:55.
13.
13C.
02.
011:4C.
02.
015:55.
113.
16C.
02.
015:Partial65.
213.
15C.
02.
015:Partial65.
313.
14C.
02.
015:Partial66.
13.
17notapplicable7.
15.
10C.
02.
015:4Records:3.
1,3.
27.
117.
71notapplicable7.
217.
72notapplicable8.
15.
12C.
02.
015:5Records:3.
29.
11.
12C.
02.
009:Partial2,C.
02.
015:Partial3,C.
02.
016:Partial2,3,C.
02.
018:1.
210.
11.
14C.
02.
015:611.
6.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
16.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
26.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
36.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
46.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
56.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
66.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
76.
60C.
02.
014:1,C.
02.
015:1,Records:4.
211.
86.
60C.
02.
014:1,C.
02.
015:1,Records:4.
212.
11.
16notapplicable13.
notapplicableC.
02.
015:713.
1notapplicableC.
02.
015:7.
113.
1.
1notapplicableC.
02.
015:7.
1.
113.
1.
2notapplicableC.
02.
015:7.
1.
213.
2notapplicableC.
02.
015:7.
213.
3notapplicableC.
02.
015:7.
313.
4notapplicableC.
02.
015:7.
413.
5notapplicableC.
02.
015:7.
513.
6notapplicableC.
02.
015:7.
613.
7notapplicableC.
02.
015:7.
713.
7.
1notapplicableC.
02.
015:7.
7.
113.
7.
2notapplicableC.
02.
015:7.
7.
213.
7.
3notapplicableC.
02.
015:7.
7.
313.
7.
4notapplicableC.
02.
015:7.
7.
413.
7.
4.
1notapplicableC.
02.
015:7.
7.
4.
113.
7.
4.
2notapplicableC.
02.
015:7.
7.
4.
213.
7.
4.
3notapplicableC.
02.
015:7.
7.
4.
313.
7.
4.
4notapplicableC.
02.
015:7.
7.
4.
413.
8notapplicableC.
02.
015:7.
813.
92.
16,11.
15C.
02.
015:7.
913.
9.
1notapplicableC.
02.
015:7.
9.
113.
9.
2notapplicableC.
02.
015:7.
9.
213.
9.
3notapplicableC.
02.
015:7.
9.
313.
9.
4notapplicableC.
02.
015:7.
9.
4HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final9313.
9.
5notapplicableC.
02.
015:7.
9.
513.
9.
68.
36notapplicable14.
11.
17C.
02.
015:Partial7.
815.
11.
18C.
02.
015:Partial7.
816.
11.
19C.
02.
015:Partial7.
817.
6.
61Records:2.
317.
16.
61C.
02.
015:617.
26.
61C.
02.
005:5.
1C.
02.
015:Partial7.
417.
36.
61Records:Partial2.
4,2.
4.
117.
46.
61C.
02.
015:Partial7.
9Records:2.
318.
5.
45notapplicable19.
5.
46notapplicable20.
5.
47notapplicable21.
6.
72C.
02.
015:7.
9.
422.
notapplicableC.
02.
015:7.
1022.
1notapplicableC.
02.
015:7.
10.
122.
2notapplicableC.
02.
015:7.
10.
222.
3notapplicableC.
02.
015:7.
10.
322.
3.
1notapplicableC.
02.
015:7.
10.
3.
122.
3.
2notapplicableC.
02.
015:7.
10.
3.
222.
3.
3notapplicableC.
02.
015:7.
10.
3.
322.
3.
3.
1notapplicableC.
02.
015:7.
10.
3.
3.
122.
3.
3.
2notapplicableC.
02.
015:7.
10.
3.
3.
222.
3.
3.
3notapplicableC.
02.
015:7.
10.
3.
3.
322.
3.
3.
4notapplicableC.
02.
015:7.
10.
3.
3.
422.
3.
4notapplicableC.
02.
015:7.
10.
3.
423.
10.
23C.
02.
015:Partial3.
6C.
02.
016–PackagingMaterialTestingandC.
02.
017–PackagingMaterialTesting1.
9.
10notapplicable2.
notapplicableC.
02.
016:Partial12.
1notapplicableC.
02.
016:22.
2notapplicableC.
02.
016:32.
3notapplicableC.
02.
016:Partial12.
49.
21notapplicable2.
5.
notapplicablenotapplicable3.
notapplicableC.
02.
016:74.
notapplicableC.
02.
017:44.
16.
31,9.
36C.
02.
011:25.
3,Partial375.
9.
11C.
02.
016:Partial46.
notapplicableC.
02.
016:47.
9.
20notapplicable8.
9.
21notapplicable9.
notapplicableC.
02.
016:510.
notapplicableC.
02.
017:110.
17.
31C.
02.
010:1C.
02.
017:Partial1C.
02.
018–FinishedProductsTesting1.
11.
20notapplicable2.
11.
12,Partial6.
17C.
02.
018:12.
1notapplicableC.
02.
018:1.
23.
11.
13,11.
23C.
02.
015:6C.
02.
018:1.
14.
12.
80C.
02.
018:2HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final945.
Partial12.
81C.
02.
018:Partial26.
notapplicableC.
02.
018:37.
11.
21notapplicable8.
11.
22notapplicable9.
11.
41C.
02.
011:Partial21.
410.
11.
40notapplicable11.
11.
42notapplicable12.
11.
43notapplicable13.
11.
44notapplicable14.
Partial11.
15C.
02.
018:4C.
02.
019:Partial5C.
02.
019–FinishedProductsTesting1.
notapplicableC.
02.
019:12.
notapplicablenotapplicable3.
notapplicablenotapplicableC.
02.
020toC.
02.
024–Records1.
notapplicablePartialRecordsInterpretationParagraph2.
17.
60notapplicable3.
notapplicablePartialRecordsInterpretationParagraph3.
16.
11notapplicable3.
2Partial6.
10PartialRecordsInterpretationParagraph3.
3notapplicablePartialRecordsInterpretationParagraph3.
46.
12notapplicable4.
6.
15,6.
16PartialRecordsInterpretationParagraph4.
116.
15notapplicable5.
notapplicableRecords:15.
16.
18PartialRecordsInterpretationParagraph6.
6.
14PartialRecordsInterpretationParagraph7.
notapplicableRecords:Partial2.
3,87.
16.
13Records:5.
57.
2notapplicableRecords:2.
3.
17.
36.
21notapplicable7.
45.
32C.
02.
005:5.
17.
5notapplicableRecords:7,7.
17.
63.
31Records:Partial2.
3.
27.
7notapplicableRecords:5.
47.
86.
71notapplicable7.
9notapplicableRecords:3.
27.
10notapplicableRecords:2.
47.
10.
1notapplicableRecords:2.
4.
17.
1110.
10C.
02.
004:4,C.
02.
015:2,C.
02.
025/C.
02.
026:2.
28.
notapplicableRecords:2.
28.
16.
70notapplicable8.
2notapplicableRecords:2.
2.
18.
3notapplicableRecords:2.
2.
29.
notapplicableRecords:3,4,89.
1notapplicableRecords:3.
19.
1.
1notapplicableRecords:3.
1.
19.
1.
2notapplicableRecords:3.
1.
29.
1.
314.
52notapplicable9.
2Partial15.
10Records:4.
1,4.
29.
2.
115.
11notapplicable10.
notapplicableRecords:5,610.
16.
17Records:5.
1,6.
110.
26.
30,9.
12Records:2.
2.
1,5.
3,6.
3HealthCanada/HealthProductsandFoodBranchInspectorateGoodManufacturingPractices(GMP)forActivePharmaceuticalIngredients(API)(GUI-0104)-Final9510.
36.
30Records:6.
210.
3.
1Partial11.
11Records:2.
2.
1,5.
2,6.
211.
6.
13Records:2,1011.
16.
40,6.
41Records:2.
112.
17.
20notapplicable12.
117.
20notapplicable12.
217.
20notapplicable12.
317.
20notapplicable12.
417.
20notapplicable12.
517.
20notapplicable12.
617.
20notapplicable12.
717.
20notapplicable12.
817.
20notapplicable12.
917.
20notapplicable12.
1017.
20notapplicable13.
notapplicablenotapplicable13.
1notapplicablenotapplicable13.
2notapplicablenotapplicable13.
3notapplicablenotapplicable13.
4notapplicablenotapplicableC.
02.
025andC.
02.
026–Samples1.
11.
63notapplicable2.
11.
70notapplicable3.
11.
71notapplicable4.
11.
72C.
02.
025:2.
1,35.
notapplicableC.
02.
025:1.
26.
notapplicableC.
02.
025:1.
3C.
02.
027–Stability1.
11.
60C.
02.
027:12.
11.
61Records:2.
4,2.
4.
1,C.
02.
027:Partial1.
13.
11.
62C.
02.
027:Partial13.
1notapplicableC.
02.
027:1.
14.
11.
52C.
02.
027:1.
24.
1notapplicablenotapplicable5.
11.
53C.
02.
027:Partial1.
36.
notapplicableC.
02.
027:1.
47.
11.
56C.
02.
027:Partial1.
48.
Partial11.
51C.
02.
027:1.
7C.
02.
028–Stability1.
11.
52C.
02.
027:1.
22.
11.
50Records:2.
4,2.
4.
1C.
02.
028:13.
11.
54C.
02.
028:1.
24.
11.
55notapplicable5.
11.
56RationaleParagraph6.
notapplicableC.
02.
028:1.
17.
notapplicableC.
02.
028:1.
38.
notapplicableC.
02.
028:1.
49.
notapplicableC.
02.
028:1.
5