NAFDAC GOOD MANUFACTURING PRACTICE · PDF filenafdac good manufacturing practice guidelines...

NAFDAC

GOOD MANUFACTURINGPRACTICE GUIDELINES FORPHARMACEUTICAL PRODUCTS

2016

NAFDAC GOOD MANUFACTURING PRACTICE

GUIDELINES FOR PHARMACEUTICAL PRODUCTS

2016

FO RY FC ON OE DG AA NL DA N D

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NAFDAC

NAFDAC G

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paths2Partnership for Transforming Health System II

...improving pathway to health UKfrom the British people

aid

NAFDAC

GOOD MANUFACTURING

PRACTICE GUIDELINES FOR

PHARMACEUTICAL PRODUCTS

2016

FO RY FC ON OE DG AA NL DA N DO RI UT

GAN

NAFDAC

For all enquiries or comments, write to:

The Director General,Attention: The Director, Drug Evaluation and ResearchNational Agency for Food and Drug Administration and Control,Plot 2032, Olusegun Obasanjo WayWuse Zone 7, Abuja, Nigeria

[email protected]

TABLE OFCONTENTS

3NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016

INTRODUCTION............................................................................................... 6

PHARMACEUTICAL QUALITY SYSTEM.................................................. 8

PERSONNEL.......................................................................................................17

PREMISES AND EQUIPMENT...................................................................... 23

QUALIFICATION AND VALIDATION....................................................... 33

DOCUMENTATION......................................................................................... 41

PRODUCTION.................................................................................................... 62

MATERIALS MANAGEMENT....................................................................... 73

QUALITY CONTROL....................................................................................... 83

CONTRACT MANUFACTURE AND ANALYSIS...................................... 95

COMPLAINTS AND PRODUCT RECALL ................................................ 97

SELF-INSPECTION............................................................................................100

REFERENCES......................................................................................................100

GLOSSARY.............................................................................................................103

TAB

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ACRONYMNS

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API Active Pharmaceutical Ingredients CAPA Corrective And Preventive Action DFID UK Department for International Development DQ Design Qualification FAT Factory Acceptance Test FEFO First -Expired, First--Out FRS Functional Requirement Specification GCP Good Clinical Practice GLP

Good Laboratory Practice

GMP

Good Manufacturing Practice

HVAC

Heating, Ventilation and Air -Conditioning

ICH

International Conference on Harmonization

IMP

Investigational Medicinal Products INN

International Non-proprietary Name

IQ

Installation Qualification ISO

International Standards Organization

NAFDAC

National Agency for Food and Drug Administration and ControlNIS

Nigerian Industrial Standard

OOS

Out-Of--Specification OOT

Out-Of -Trend

OQ

Operational Qualification

PAT

Process Analytical Technology

PATHS 2

Partnership for Transforming Health Systems

PLC

Programmable Logic Controllers

PPQ

Process Performance Qualification

PQS

Pharmaceutical Quality System

QA

Quality Assurance

QC

Quality Control

QRM

Quality Risk Management

SAT

Site Acceptance Test

SMT

Site Master File

SOP

Standard Operating Procedure

TSE

Transmissible Spongiform Encephalopathy

URS

User Requirement Specification

VMP

Validation Master Plan

WHO World Health Organization

NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016

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The National Agency for Food and Drug Administration and Control (NAFDAC) appreciates the efforts put in the development of these guidelines. However, it would not have been possible without the kind support and help of many individuals and organizations.

The Agency is grateful to the Director-General (NAFDAC), Dr. Paul Orhii JD, MD, PhD, OON for providing focused leadership in pharmaceutical regulation in Nigeria.

The Agency acknowledges the UK Department for International Development (DFID) and Partnership for Transforming Health Systems (PATHS 2) for providing the needed finances to develop this important guide to manufacturers.The technical support of the World Health Organization is specially acknowledged. In particular, the WHO Representative in Nigeria, Dr. Rui Vaz who provided the needed leadership and Dr. Ogori Taylor for her resilience in ensuring the development of this guide.

The enormous intellectual and experiential contributions of the key officers of the Drug Evaluation & Research Directorate of NAFDAC to the production of this guide are also acknowledged.

Mrs. Titilope O. OwolabiDirector, Drug Evaluation & ResearchNAFDAC

ACKNWOLEDGEMENTS


INTRODUCTION

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GoodManufacturingPractice(GMP)isthatpartofqualityassurancewhichensuresthatpharmaceuticalproductsareconsistentlyproducedandcontrolledtothequalitystandardsappropriatetotheirintendeduseandasrequiredbytheirmarketingauthorisations.Itensuresthatpharmaceuticalproductsaremanufacturedsothattheyarefitfortheirintendeduse,complywiththerequirementsofthemarketingauthorisationsanddonotplacethepopulaceatrisk.

TheNationalAgencyforFoodandDrugAdministrationandControl(NAFDAC)ACTCapN1,LFN2004empowerstheAgencytocontrolandregulatethemanufacture,importation,exportation,distribution,advertisement,saleanduseofitsregulatedproducts.ThismandaterequiresthattheAgencyensuresthequality,safetyandefficacyofallregulatedproducts.TheAgency,thereforehasdevelopedNAFDACGoodManufacturingPracticeRegulationswhichstipulatetheminimumstandardsthatmanufacturersarerequiredtoadheretoensurethequalityofpharmaceuticalproducts.

TheseguidelinesareintendedtohelpallstakeholderscomplywiththeprovisionsoftheNAFDACGoodManufacturingPracticeRegulationsforpharmaceuticalproducts. Theregulationscontaingoodmanufacturingpractice requirements for methods, facilities and controls for themanufacture, processing, packaging, or holding of a pharmaceuticalproductforhumanoranimaluse.Theregulationsaremeanttoensurethatpharmaceuticalproductsmeettherequirementsofsafety,qualityandefficacytheypurportorarerepresentedtopossess.

Theseguidelinesapplytopharmaceutical,biological,andveterinaryproductsasrequiredbytheirmarketingauthorisations.Theyarealsorelevantforpharmaceuticalmanufacturingprocesses,suchasthoseundertakeninhospitals.Theseguidelinesarenotapplicabletothecompoundingofapharmaceuticalproductbyaregisteredpharmacistinagovernmentorprivatehealthinstitutioninordertofillaprescription.

Theattainmentofthisqualityobjectiveistheresponsibilityoftopmanagementandrequirestheparticipationandcommitmentofallstaffmembersinthedifferentdepartmentsandatalllevelswithinthe


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organisationaswellastheirsuppliers.

Thisdocumentistobeusedinconjunctionwithotherexistingrelevantpharmaceuticalproductstatutesinthecountry.Thegoodpracticesoutlinedbelowaretobeconsideredgeneralguides,andtheymaybeadaptedtomeetindividualneedsaslongastheindustryachievescompliancewithregulatoryobjectives.Asnewtechnologybecomesavailable,operationalproceduresandequipmentstandardsintheindustrymayvaryfromthosedescribedinthisdocument.Materialsand/ormethodsotherthanthosespecifiedintheguidelinesmaybeusedbymanufacturers,iftheycanprovidesoundandscientificevidencethatclearlydemonstratescompliancewiththeregulatoryobjectives.

AllstakeholdersareencouragedtosendtheircommentstotheAgencyduringtheuseoftheseguidelinesinordertoimprovefutureeditions.


CHAPTER

PHARMACEUTICALQUALITY SYSTEM1C

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Qualitymanagementinthepharmaceuticalindustry:philosophyand

essentialelements1.1. Inthepharmaceuticalindustryatlarge,qualitymanagementis

usuallydefinedastheaspectofthemanagementfunctionthatdeterminesandimplementsthe“qualitypolicy”,i.e.theoverallintentionanddirectionofanorganizationregardingquality,asformallyexpressedandauthorizedbytopmanagement.Thebasicelementsofqualitymanagementare:

a. Anappropriateinfrastructureor“qualitysystem”,encompassingthe

organizationalstructure,procedures,processesandresources;

b. Systematicactionsnecessarytoensureadequateconfidencethata

product(orservice)willsatisfygivenrequirementsforquality.

1.2. Thetotalityoftheseactionsistermedqualityassurance(QA).Withinanorganization,QAservesasamanagementtool.Incontractualsituations,QAalsoservestogenerateconfidenceinthesupplier.TheconceptsofQA,GMP,QCandqualityriskmanagement(QRM)areinterrelatedaspectsofqualitymanagementandshouldbetheresponsibilityofallpersonnel.Theyaredescribedhereinordertoemphasizetheirrelationshipandtheirfundamentalimportancetotheproductionandcontrolofpharmaceuticalproducts.

PharmaceuticalqualitysystemPrinciple1.3. Themanufacturermustassumeresponsibilityforthequalityofthe

pharmaceuticalproductstoensurethattheyarefitfortheirintendeduse,complywiththerequirementsofthemarketingauthorizationanddonotplacepatientsatriskduetoinadequatesafety,qualityorefficacy.

1.4. Theattainmentofthisqualityobjectiveistheresponsibilityoftopmanagementandrequirestheparticipationandcommitmentofstaffinmanydifferentdepartmentsandatalllevelswithinthecompany,thecompany'ssuppliersandthedistributors.Toachievethisqualityobjectivereliablytheremustbeacomprehensivelydesignedandcorrectlyimplementedpharmaceuticalqualitysystem(PQS)


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incorporatingGMPandQRM

1.5. TopmanagementhastheultimateresponsibilitytoensureaneffectivePQSisinplace,isadequatelyresourced,andthatroles,responsibilities,andauthoritiesaredefined,communicatedandimplementedthroughouttheorganization.Topmanagement'sleadershipandactiveparticipationinthePQSisessential.ThisleadershipshouldensurethesupportandcommitmentofstaffatalllevelsandsiteswithintheorganizationtothePQS.

1.6. Qualitymanagementisawide-rangingconceptcoveringallmattersthatindividuallyorcollectivelyinfluencethequalityofaproduct.Itisthetotalityofthearrangementsmadewiththeobjectofensuringthatpharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.Qualitymanagement,therefore,incorporatesGMPandotherfactors,includingthoseoutsidethescopeofthisguide,suchasproductdesignanddevelopment.GMPappliestothelife-cyclestagesfromthemanufactureofinvestigationalmedicinalproducts,technologytransfer,andcommercialmanufacturing,throughtoproductdiscontinuation.ThePQScanextendtothepharmaceuticaldevelopmentlife-cyclestageandshouldfacilitateinnovationandcontinualimprovementandstrengthenthelinkbetweenpharmaceuticaldevelopmentandmanufacturingactivities.AllpartsofthePQSshouldbeadequatelyresourcedandmaintained,includingbeingprovidedwithsufficientcompetentpersonnel,suitablepremises,equipmentandfacilities.

1.7. ThePQSappropriatetothemanufactureofpharmaceuticalproducts

shouldensurethat:

a. Productrealizationisachievedbydesigning,qualifying,

planning,implementing,maintainingandcontinuously

improvingasystemthatallowstheconsistentdeliveryof

productswithappropriatequalityattributes;

b. Productandprocessknowledgeismanagedthroughoutall

lifecyclestages;

c. Pharmaceuticalproductsaredesignedanddevelopedinaway

thattakesaccountoftherequirementsofGMPandother

associatedcodessuchasthoseofGoodLaboratoryPractice

(GLP)andGoodClinicalPractice(GCP);

d. Productionandcontroloperationsareclearlyspecifiedina

writtenformandGMPrequirementsareadopted;


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e. Managerialresponsibilitiesareclearlyspecifiedinjob

descriptions;

f. Arrangementsaremadeforthemanufacture,supplyanduse

ofthecorrectstartingandpackagingmaterials,theselection

andmonitoringofsuppliersandforverifyingthateach

deliveryisthecorrectmaterialfromtheapprovedsupply

chain;

g. Allnecessarycontrolsonstartingmaterials,intermediate

products,andbulkproductsandotherin-processcontrols,

calibrationsandvalidationsarecarriedout;

h. Thefinishedproductiscorrectlyprocessedandchecked

accordingtodefinedprocedures;

i. Pharmaceuticalproductsarenotsoldorsuppliedbeforethe

authorizedpersonshavecertifiedthateachproductionbatch

hasbeenproducedandcontrolledinaccordancewiththe

requirementsofthemarketingauthorizationandanyother

regulationsrelevanttotheproduction,controlandreleaseof

pharmaceuticalproducts(see2.13to2.16);

j. Processesareinplacetoassurethemanagementof

outsourcedactivities;

k. Satisfactoryarrangementsexisttoensure,asfaraspossible,

thatthepharmaceuticalproductsarestored,distributedand

subsequentlyhandledsuchthatqualityismaintained

throughouttheirshelf-life;

l. Thereisaprocedureforself-inspectionand/orqualityaudit

thatregularlyappraisestheeffectivenessandapplicabilityof

thePQS;

m. Productandprocessesaremonitoredandtheresultstaken

intoaccountinbatchrelease,intheinvestigationofdeviations

andwithaviewtotakingpreventiveactiontoavoidpotential

deviationsoccurringinfuture;

n. Arrangementsareinplacefortheprospectiveevaluationand

approvalofplannedchangesandtheirapprovalpriorto

implementationtakingintoaccountregulatorynotification

andapprovalwhererequired.Afterimplementationofany

change,anevaluationisundertakentoconfirmthatthe

qualityobjectiveswereachievedandthattherewasno


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unintendedadverseimpactonproductquality;

o. Regularreviewsofthequalityofpharmaceuticalproductsare

conductedwiththeobjectiveofverifyingtheconsistencyof

theprocessandidentifyingwherethereisaneedfor

improvement;

p. Astateofcontrolisestablishedandmaintainedbydeveloping

andusingeffectivemonitoringandcontrolsystemsfor

processperformanceandproductquality;

q. Continualimprovementisfacilitatedthroughthe

implementationofqualityimprovementsappropriatetothe

currentlevelofprocessandproductknowledge;

r. ThereisasystemforQRM;

s. Deviations,suspectedproductdefectsandotherproblemsare

reported,investigatedandrecorded.Anappropriatelevelof

rootcauseanalysisisappliedduringsuchinvestigations.The

mostlikelyrootcause(s)shouldbeidentifiedandappropriate

correctiveactionsand/orpreventiveactions(CAPAs)should

beidentifiedandtaken.TheeffectivenessofCAPAsshouldbe

monitored.

1.8. Thereshouldbeperiodicmanagementreviewsoftheoperationofthe

PQS,withtheinvolvementoftopmanagement,toidentify

opportunitiesforcontinualimprovementofproducts,processesand

thesystemitself.Unlessotherwisejustified,suchreviewsshouldbe

conductedatleastannually.

1.9. ThePQSshouldbedefinedanddocumented.Aqualitymanualshould

beestablishedandshouldcontainadescriptionofthequality

managementsystemincludingmanagementresponsibilities.

GoodManufacturingPractice(GMP)forPharmaceuticalProducts

1.10. Goodmanufacturingpracticeisthatpartofqualityassurancewhich

ensuresthatpharmaceuticalproductsareconsistentlyproducedand

controlledtothequalitystandardsappropriatetotheirintendeduse

andasrequiredbytheclinicaltrialauthorisation,marketing

authorisation,orproductspecification.Goodmanufacturingpractice

isconcernedwithbothproductionandqualitycontrol.

1.11. GMPappliestothelife-cyclestagesfromthemanufactureof

investigationalpharmaceuticalproducts,technologytransfer,and

commercialmanufacturing,throughtoproductdiscontinuation.GMP


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isaimedprimarilyatmanagingandminimizingtherisksinherentin

pharmaceuticalmanufacturetoensurethequality,safetyandefficacy

ofproducts.

1.12. ThebasicrequirementsofGMParethat:

a. Allmanufacturingprocessesareclearlydefined,systematically

reviewedforassociatedrisksinthelightofscientificknowledge

andexperienceandshowntobecapableofconsistently

manufacturingpharmaceuticalproductsoftherequiredquality

andcomplyingwiththeirspecifications;

b. Criticalstepsofmanufacturingprocessesandsignificantchanges

totheprocessarevalidated;

c. AllnecessaryfacilitiesforGMPareprovidedincluding:

i. Appropriatelyqualifiedandtrainedpersonnel;

ii. Adequatepremisesandspace;

iii. Suitableequipmentandservices;

iv. Appropriatematerials,containersandlabels;

v. Approvedproceduresandinstructions;

vi. Suitablestorageandtransport;

vii. Adequatepersonnel,laboratoriesandequipmentfor

in-processcontrols;

1.13. Instructionsandproceduresarewritteninaninstructionalformin

clearandunambiguouslanguage,specificallyapplicabletothe

facilitiesprovided;

1.14. Operatorsaretrainedtocarryoutprocedurescorrectly;

1.15. Recordsaremade,manuallyand/orbyrecordinginstruments,during

manufacturewhichdemonstratethatallthestepsrequiredbythe

definedproceduresandinstructionswereinfacttakenandthatthe

quantityandqualityoftheproductwasasexpected.Anysignificant

deviationsarefullyrecordedandinvestigated;withtheobjectiveof

determiningtherootcauseandensuringappropriatecorrectiveand

preventiveactionsareimplemented;

1.16. Recordsofmanufactureincludingdistributionwhichenablethe

completehistoryofabatchtobetraced,areretainedina

comprehensibleandaccessibleform;


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1.17. Theproperstorageanddistributionoftheproductsminimizesany

risktotheirqualityandtakesaccountofGoodDistributionPractice

(GDP);

1.18. Asystemisavailabletorecallanybatchofproductfromsaleor

supply;

1.19. Complaintsaboutmarketedproductsareexamined,thecausesof

qualitydefectsinvestigatedandappropriatemeasurestakenin

respectofthedefectiveproductsandtopreventre-occurrence.

QualityControl(QC)

1.20. QualityControlisthatpartofGoodManufacturingPracticewhichis

concernedwithsampling,specificationsandtesting,andwiththe

organisation,documentationandreleaseprocedureswhichensure

thatthenecessaryandrelevanttestsareactuallycarriedoutandthat

materialsarenotreleasedforuse,norproductsreleasedforsaleor

supply,untiltheirqualityhasbeenadjudgedtobesatisfactory.

1.21. ThebasicrequirementsofQualityControlarethat:

a. Adequatefacilities,trainedpersonnelandapproved

proceduresareavailableforsampling,inspectingandtesting

startingmaterials,packagingmaterials,intermediate,bulk,

andfinishedproducts,andwhereappropriateformonitoring

environmentalconditionsforGMPpurposes;

b. Samplesofstartingmaterials,packagingmaterials,

intermediate,bulkandfinishedproductsaretakenby

personnelandbymethodsapprovedbyqualitycontrol;

c. Testmethodsarevalidated;

d. Recordsaremademanuallyand/orbyrecordinginstruments,

whichdemonstratethatalltherequiredsampling,inspecting

andtestingprocedureswereactuallycarriedout.Any

deviationsarefullyrecordedandinvestigated;

e. Thefinishedproductscontainactiveingredientscomplying

withthequalitativeandquantitativecompositionofthe

marketingauthorisation,areofthepurityrequired,andare

enclosedwithintheirpropercontainersandcorrectly

labelled;

f. Recordsaremadeoftheresultsofinspectionandthattesting

ofmaterials,intermediate,bulk,andfinishedproductsis


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1 formallyassessedagainstspecification.Productassessmentincludes

areviewandevaluationofrelevantproduction

documentationandanassessmentofdeviationsfrom

specifiedprocedures;

g. Nobatchofproductisreleasedforsaleorsupplypriorto

certificationbyanauthorisedpersonthatitisinaccordance

withtherequirementsoftherelevantauthorisations;

h. Sufficientretentionsamplesofstartingmaterialsand

productsareretainedtopermitfutureexaminationofthe

productifnecessaryandthattheproductisretainedinits

finalpackunlessexceptionallylargepacksareproduced.

QualityRiskManagement(QRM)

1.22. QRMistheoverallandcontinuingprocessofappropriatelymanaging

riskstoproductqualitythroughouttheproduct'slife-cycleinorderto

optimizeitsbenefit–riskbalance.Itisasystematicprocessforthe

assessment,control,communicationandreviewofriskstothequality

ofthepharmaceuticalproduct.Itcanbeappliedbothproactivelyand

retrospectively.

1.23. QRMprinciplescanbeappliedbypharmaceuticalmanufacturersin

thedesign,development,manufactureanddistribution,i.e.thelife-

cycleofapharmaceuticalproduct.QRMshouldbeanintegralelement

ofthepharmaceuticalqualitysystem.

1.24. QRMshouldensurethat:

a. Theevaluationoftherisktoqualityisbasedonscientific

knowledge,experiencewiththeprocessandultimatelylinks

totheprotectionofthepatient;and

b. Thelevelofeffort,formalityanddocumentationoftheQRM

processiscommensuratewiththelevelofrisk.

1.25. Inadditiontothetwoprinciplesabove,thefollowingprinciplesare

alsopartoftheQRMmethodology:

a. Whenapplied,processesusingQRMmethodologiesshouldbe

dynamic,iterativeandresponsivetochange.

b. Thecapabilityforcontinualimprovementshouldbe

embeddedintheQRMprocess.

Qualityriskmanagementprocess


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11.26. QRMactivitiesshouldbeperformedusingsystematicprocesses

designedtocoordinate,facilitateandimprovescience-baseddecision-

makingwithrespecttorisk.Thepossiblestepstobetakenin

initiatingandplanningaQRMprocessmightincludethefollowing:

a. Definetheproblemand/orriskquestion,includingpertinent

assumptionsidentifyingthepotentialforrisk;

b. Assemblebackgroundinformationand/ordataonthe

potentialhazard,harmorhumanhealthimpactrelevantto

theriskassessment;

c. Identifyaleaderandthenecessaryresources;

d. Specifyatimeline,thedeliverables,andanappropriatelevel

ofdecision-makingfortheriskmanagementprocess.Internal

SOPsshoulddefinesteps,stakeholders,rolesand

responsibilities.

PersonnelinvolvedinQRM

1.27. Themanufacturershouldensurethatpersonnelwithappropriate

product-specificknowledgeandexpertiseareavailabletoensure

effectiveplanningandcompletionofQRMactivities.Thismaybebest

accomplishedbyassemblingamultidisciplinaryteam.Thepersonnel

appointedshouldbeableto:

a. Conductariskanalysis;

b. Identifyandanalysepotentialrisks;

c. Evaluaterisksanddeterminewhichonesshouldbecontrolled

andwhichonescanbeaccepted;

d. Recommendandimplementadequateriskcontrolmeasures;

e. Deviseproceduresforriskreview,monitoringand

verification;

f. Considertheimpactofriskfindingsonrelatedorsimilar

productsand/orprocesses.

g. DefineanddocumentQRMactivities.

Knowledgeoftheproductandprocess

1.28. QRMshouldbebasedonknowledgeoftheproductorprocesses

concernedaccordingtothestageoftheproductlife-cycle.Aflow

diagrammaybehelpful,coveringalloperationsandcontrolsinthe

processunderevaluation.WhenapplyingQRMtoagivenoperation,

thestepsprecedingandfollowingthatoperationshouldalsobe

considered.Ablock-typediagrammaybesufficientlydescriptive.


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1 Amendmentstotheflowdiagrammaybemadewhereappropriate,and

shouldbedocumented.

ProductQualityReview

1.29. Regularperiodicorrollingqualityreviewsofalllicensed

pharmaceuticalproductsshouldbeconductedwiththeobjectiveof

verifyingtheconsistencyoftheexistingprocess,theappropriateness

ofcurrentspecificationsforbothstartingmaterialsandfinished

productstohighlightanytrendsandtoidentifyproductandprocess

improvements.Suchreviewsshouldnormallybeconductedand

documentedannually,takingintoaccountpreviousreviews,and

shouldincludeatleast:

a. Areviewofstartingmaterialsincludingpackagingmaterials

usedintheproduct,especiallythosefromnewsourcesandin

particularthereviewofsupplychaintraceabilityofactive

substances.

b. Areviewofcriticalin-processcontrolsandfinishedproduct

results.

c. Areviewofallbatchesthatfailedtomeetestablished

specification(s)andtheirinvestigation.

d. Areviewofallsignificantdeviationsornon-conformances,

theirrelatedinvestigations,andtheeffectivenessofresultant

correctiveandpreventiveactions(CAPA)taken.

e. Areviewofallchangesmadetotheprocessesoranalytical

methods;

f. AreviewofMarketingAuthorisationvariations

submitted/granted/refused

g. Areviewoftheresultsofthestabilitymonitoringprogramme

andanyadversetrends.

h. Areviewofallquality-relatedreturns,complaintsandrecalls

andtheinvestigationsperformedatthetime.

i. Areviewofadequacyofanyotherpreviouscorrectiveactions

onproductprocessorequipment;

j. Fornewmarketingauthorisationsandvariationstomarketing

authorisations,areviewofpost-marketingcommitments.


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CHAPTER

PERSONNEL2Principle

2.1. Theestablishmentandmaintenanceofasatisfactorysystemof

qualityassuranceandthecorrectmanufactureandcontrolof

pharmaceuticalproductsandactiveingredientsrelyuponpeople.For

thisreasontheremustbesufficientqualifiedpersonneltocarryout

allthetasksforwhichthemanufacturerisresponsible.

2.2. Individualresponsibilitiesshouldbeclearlydefinedandunderstood

bythepersonsconcernedandrecordedaswrittendescriptions.

General

2.3. Themanufacturershouldhaveanorganisationalchart.Personnelin

responsiblepositionsshouldhavespecificdutiesrecordedinwritten

jobdescriptionsandadequateauthoritytocarryouttheir

responsibilities.Theirdutiesmaybedelegatedtodesignateddeputies

ofsatisfactoryqualification.Thereshouldbenogapsorunexplained

overlapsintheresponsibilitiesofthosepersonnelconcernedwiththe

applicationofgoodmanufacturingpractice.

2.4. Themanufacturershouldhaveadequatenumberofpersonnelwith

thenecessaryqualificationsandpracticalexperience.The

responsibilitiesplacedonanyoneindividualshouldnotbeso

extensiveastopresentanyrisktoquality.

2.5. AllpersonnelshouldbeawareoftheprinciplesofGMPthataffect

themandreceiveinitialandcontinuingtraining,includinghygiene

instructionsrelevanttotheirneeds.

2.6. Allpersonnelshouldbemotivatedtosupporttheestablishmentand

maintenanceofhighqualitystandards.

2.7. Stepsshouldbetakentopreventunauthorizedpeoplefromentering

production,storageandQCareas.Personnelwhodonotworkin

theseareasshouldnotusethemasapassageway.

Keypersonnel


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2.8. InimplementingGMP,keypersonnelaretheheadofProduction,the

headofQualityAssurance,and/ortheheadofQualityControl.The

qualityunittypicallycomprisesthequalityassuranceandquality

controlfunctions.Insomecases,thesecouldbecombinedinone

department.Thesekeypostsshouldbeoccupiedbyfull-time

personnel.Theheadsofproductionandqualityunitshouldbe

independentofeachother.Inlargeorganizations,itmaybenecessary

todelegatesomeofthefunctions;however,theresponsibilitycannot

bedelegated.

a. Theheadoftheproductionunitforpharmaceuticalproducts

mustbearegisteredpharmacistinNigeria.

b. Keypersonnelresponsibleforsupervisingthequalityunitfor

pharmaceuticalproductsshouldpossessthequalificationsof

ascientificeducationandpracticalexperience.Their

educationalqualificationsshouldbeinanyofthefollowing

disciplines:

i. Chemistry(analyticalororganic)orbiochemistry;

ii. Chemicalengineering;

iii. Microbiology;

iv. Pharmaceuticalsciencesandtechnology;

v. Pharmacologyandtoxicology;

vi. Physiology;or

vii. Otherrelatedsciences.

2.9. Theyshouldalsohaveadequatepracticalexperienceinthe

manufactureandqualityassuranceofpharmaceuticalproducts.The

scientificeducationandpracticalexperienceofsuchpersonsshould

besuchastoenablethemexerciseindependentprofessional

judgment,basedontheapplicationofscientificprinciplesand

understandingofthepracticalproblemsencounteredinthe

manufactureandQAofpharmaceuticalproducts.

2.10. Theheadsoftheproductionandthequalityunitgenerallyhavesome

shared,orjointlyexercised,responsibilitiesrelatingtoquality.These

mayinclude:

a. Authorizationofwrittenproceduresandotherdocuments,

includingamendments;


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b. Monitoringandcontrolofthemanufacturingenvironment;

c. Planthygiene;

d. Processvalidationandcalibrationofanalyticalapparatus;

e. Training,includingtheapplicationandprinciplesofQA;

f. Approvalandmonitoringofsuppliersofmaterials;

g. Approvalandmonitoringofcontractmanufacturers;

h. Designationandmonitoringofstorageconditionsfor

materialsandproducts;

i. Performanceandevaluationofin-processcontrols;

j. Retentionofrecords;

k. MonitoringofcompliancewithGMPrequirements;and

l. Inspection,investigationandtakingofsamplesinorderto

monitorfactorsthatmayaffectproductquality.

2.11. Theheadofproductiongenerallyhasthefollowingresponsibilities:

a. Ensurethatproductsaremanufacturedandstoredaccording

totheappropriatedocumentationinordertoobtainthe

requiredquality;

b. Approvetheinstructionsrelatingtoproductionoperations,

includingthein-processcontrols,andtoensuretheirstrict

implementation;

c. Ensurethattheproductionrecordsareevaluatedandsigned

byadesignatedpersonbeforetheyaresenttothequality

unit;

d. Checkthemaintenanceofthedepartment,facilities,premises

andequipment;

e. Ensurethattheappropriateprocessvalidationsand

calibrationsofcontrolequipmentareperformedandrecorded

andthereportsmadeavailable;

f. Ensurethattherequiredinitialandcontinuingtrainingof

productionpersonneliscarriedoutandadaptedaccordingto

need.


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2 2.12. Theheadofthequalityunitgenerallyhasthefollowing

responsibilities:

a. Approvesorrejectsstartingmaterials,packagingmaterials,

andintermediate,bulkandfinishedproductsinrelationwith

theirspecifications;

b. Evaluatesbatchrecords;

c. Ensuresthatallnecessarytestingiscarriedout;

d. Approvessamplinginstructions,specifications,testmethods

andotherQCprocedures;

e. Approvesandmonitorsanalysescarriedoutundercontract;

f. Checksthemaintenanceofthedepartment,facilities,

premisesandequipment;

g. Ensuresthattheappropriatevalidations,includingthoseof

analyticalprocedures,andcalibrationsofcontrolequipment

arecarriedout;

h. Ensuresthattherequiredinitialandcontinuingtrainingof

qualityunitpersonneliscarriedoutandadaptedaccordingto

need.

i. Establishes,implementsandmaintainsthequalitysystem;

j. Supervisestheregularinternalauditsorself-inspections;

k. Participatesinexternalaudit(supplieraudit);

l. Participatesinvalidationprogrammes

2.13. Theauthorizedpersonisresponsibleforcompliancewithtechnicalor

regulatoryrequirementsrelatedtothequalityoffinishedproducts

andtheapprovalofthereleaseofthefinishedproductforsaleor

supply.

2.14. Assessmentoffinishedproductsshouldembraceallrelevantfactors,

includingtheproductionconditions,theresultsofin-processtesting,

themanufacturing(includingpackaging)documentation,compliance

withthespecificationforthefinishedproduct,andanexaminationof

thefinishedpack.

2.15. Nobatchofproductistobereleasedforsaleorsupplypriorto

certificationbytheauthorizedperson.

2.16. Theauthorizedpersonresponsibleforapprovingabatchforrelease


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shouldalwaysensurethatthefollowingrequirementshavebeenmet:

a. Themarketingauthorizationandthemanufacturing

authorizationrequirementsfortheproducthavebeenmetfor

thebatchconcerned;

b. TheprinciplesandguidelinesofGMPhavebeenfollowed;

c. Theprincipalmanufacturingandtestingprocesseshavebeen

validated,ifdifferent;

d. Allthenecessarychecksandtestshavebeenperformedand

accounttakenoftheproductionconditionsand

manufacturingrecords;

e. Anyplannedchangesordeviationsinmanufacturingor

qualitycontrolhavebeennotifiedinaccordancewithawell-

definedreportingsystembeforeanyproductisreleased.Such

changesmayneednotificationto,andapprovalbytheAgency;

f. Anyadditionalsampling,inspection,testsandcheckshave

beencarriedoutorinitiated,asappropriate,tocoverplanned

changesanddeviations;

g. AllnecessaryproductionandQCdocumentationhavebeen

completedandendorsedbysupervisorstrainedin

appropriatedisciplines;

h. Appropriateaudits,self-inspectionsandspot-checksare

carriedoutbyexperiencedandtrainedstaff;

i. Approvalhasbeengivenbytheheadofthequalityunit;

j. Allrelevantfactorshavebeenconsidered,includinganynot

specificallyassociatedwiththeoutputbatchdirectlyunder

review(e.g.subdivisionofoutputbatchesfromacommon

input,factorsassociatedwithcontinuousproductionruns)

k. Thefunctionoftheapprovalofthereleaseofafinishedbatch

oraproductcanbedelegatedtoadesignatedpersonwith

appropriatequalificationsandexperiencewhowillrelease

theproductinaccordancewithanapprovedprocedure.This

isnormallydonebythequalityunitbymeansofbatchreview

l. Ensuringthatthestabilityoftheactivepharmaceutical

ingredientsandproductsismonitored;

m. Participatingintheinvestigationofcomplaintsrelatedtothe


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2 qualityoftheproduct;

n. ParticipationinQRMprogrammes.

2.17. OtherdutiesofQCaresummarizedinChapter8“QualityControl”.

Training

2.18. Themanufacturershouldprovidetraininginaccordancewitha

writtenprogrammeforallpersonnelwhosedutiestaketheminto

manufacturingareasorintocontrollaboratories(includingthe

technical,maintenanceandcleaningpersonnel)andforother

personnelasrequired.

2.19. BesidesbasictrainingonthetheoryandpracticeofGMP,newly

recruitedpersonnelshouldreceivetrainingappropriatetotheduties

assignedtothem.Continuingtrainingshouldalsobegiven,andits

practicaleffectivenessperiodicallyassessed.Approvedtraining

programmesshouldbeavailable.Trainingrecordsshouldbekept.

2.20. Personnelworkinginareaswherecontaminationisahazard,e.g.

cleanareasorareaswherehighlyactive,toxic,infectiousor

sensitizingmaterialsarehandled,shouldbegivenspecifictraining.

2.21. TheconceptofQAandallthemeasureswhichaiditsunderstanding

andimplementationshouldbefullydiscussedduringthetraining

sessions.

2.22. Visitorsoruntrainedpersonnelshouldpreferablynotbetakeninto

theproductionandQCareas.Ifthisisunavoidable,theyshouldbe

givenrelevantinformationinadvance(particularlyaboutpersonal

hygiene)andtheprescribedprotectiveclothing.Theyshouldbe

closelysupervised.

2.23. Consultantsandcontractstaffshouldbequalifiedfortheservices

theyprovide.Evidenceofthisshouldbeincludedinthetraining

records.

Recordsshouldbemaintainedstatingthename,address,and

qualificationsofanyconsultantsandthetypeofservicetheyprovide.

Personalhygiene

2.24. Allpersonnel,priortoandduringemployment,shouldundergo

healthexaminations.Personnelconductingvisualinspectionsshould

alsoundergoperiodiceyeexaminations.


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CHAPTER

PREMISES ANDEQUIPMENT3

Principle

3.1. Premisesandequipmentshouldbelocated,designed,constructed,

adaptedandmaintainedtosuittheoperationstobecarriedout.Their

layoutanddesignshouldaimtominimizetheriskoferrorsand

permiteffectivecleaningandmaintenanceinordertoavoidcross-

contamination,build-upofdustordirtand,ingeneral,anyadverse

effectonthequalityofproducts.

Premises

General

3.2. Premisesshouldbesituatedinanenvironmentwhich,when

consideredtogetherwithmeasurestoprotectthemanufacture,

presentsminimalriskofcausingcontaminationofmaterialsor

products.

3.3. Premisesshouldbedesignedtoensurethelogicalflowofmaterials

andpersonnel.

3.4. Premisesshouldbedesignedandequippedsoastoaffordmaximum

protectionagainsttheentryofinsectsorotheranimals.Thereshould

beproceduresforrodentandpestcontrol.

3.5. Premisesusedforthemanufactureoffinishedproductsshouldbe

suitablydesignedandconstructedtofacilitategoodsanitation.

3.6. Premisesforthepackagingofpharmaceuticalproductsshouldbe

specificallydesignedandlaidoutsoastoavoidmix-ups,

contaminationorcross-contamination.

3.7. Premisesshouldbecarefullymaintained,ensuringthatrepairand

maintenanceoperationsdonotpresentanyhazardtothequalityof

products.

3.8. Premisesshouldbecleanedand,whereapplicable,disinfected

accordingtodetailedwrittenproceduresandcleaningrecordsshould

bemaintained.

3.9. Wheredustisgenerated(e.g.duringsampling,weighing,mixingand


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processingoperations,packagingofpowder),measuresshouldbetakento

avoidcross-contaminationandfacilitatecleaning.

3.10. Lighting,temperature,humidityandventilationshouldbe

appropriateandsuchthattheydonotadverselyaffect,directlyor

indirectly,eitherthepharmaceuticalproductsduringtheir

manufactureandstorage,ortheaccuratefunctioningofequipment.

3.11. Stepsshouldbetakeninordertopreventtheentryofunauthorized

persons.Production,storageandqualitycontrolareasshouldnotbe

usedasarightofwaybypersonnelwhodonotworkinthem.

3.12. Premisesshouldpreferablybelaidoutinsuchawayastoallowthe

productiontotakeplaceinareasconnectedinalogicalorder

correspondingtothesequenceoftheoperationsandtothe

cleanlinesslevelsrequired.

3.13. Theadequacyoftheworkingandin-processstoragespaceshould

permittheorderlyandlogicalpositioningofequipmentandmaterials

soastominimizetheriskofconfusionbetweendifferent

pharmaceuticalproductsortheircomponents,toavoidcross-

contamination,andtominimizetheriskofomissionorwrong

applicationofanyofthemanufacturingorcontrolsteps.

3.14. Wherestartingandprimarypackagingmaterialsandintermediateor

bulkproductsareexposedtotheenvironment,interiorsurfaces

(walls,floorsandceilings)shouldbesmoothandfreefromcracksand

openjoints,shouldnotshedparticulatematter,andshouldpermit

easyandeffectivecleaningand,ifnecessary,disinfection.

3.15. Pipework,lightfittings,ventilationpointsandotherservicesshould

bedesignedandsitedtoavoidthecreationofrecessesthatare

difficulttoclean.Asfaraspossible,formaintenancepurposes,they

shouldbeaccessiblefromoutsidethemanufacturingareas.

3.16. Drainsshouldbeofadequatesize,designedandequippedtoprevent

back-flow.Openchannelsshouldbeavoidedwherepossible,butif

theyarenecessarytheyshouldbeshallowtofacilitatecleaningand

disinfection.

3.17. Thereshouldbedefinedareasofadequatesizeorothercontrolled

systemstopreventcontaminationormix-upsforthefollowing:

a. Receipt,identification,sampling,storage,andquarantineof

materials,pharmaceuticalproductcontainers,closures,and

labelling,pendingtheappropriatesampling,testing,or


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examinationbyqualitycontrolbeforereleaseformanufacturingor

packaging;

b. Holdingrejectedmaterials,pharmaceuticalproduct

containers,closures,andlabellingbeforedisposition(e.g.

return,reprocessingordestruction);

c. Storageofreleasedmaterials,pharmaceuticalproduct

containers,closures,andlabelling;

d. Storageofin-processmaterials;

e. Manufacturingandprocessingoperations;

f. Packagingandlabellingoperations;

g. Quarantinestoragebeforereleaseorrejectionof

pharmaceuticalproducts;

h. Storageofpharmaceuticalproductsafterrelease;

i. Controlandlaboratoryoperations;

j. Asepticprocessing,whichincludesasappropriate:i. Floors,walls,andceilingsofsmooth,hardsurfaces

thatcanbeeasilycleanedanddisinfectedorsterilizedroutinely;

ii. Temperatureandhumiditycontrolsiii. Anairsupplyfilteredthroughhigh-efficiency

particulateairfiltersunderpositivepressure,regardlessofwhetherflowislaminarornon-laminar;

iv. Asystemformonitoringenvironmentalconditionsv. Asystemforcleaninganddisinfectingtheroomand

equipmenttoproduceasepticconditions;vi. Asystemforpreventiveandbreakdownmaintenance

ofallequipmentusedtocontrolandmonitortheasepticconditions.

Dedicatedfacilities

3.18. Inordertominimizetheriskofaseriousmedicalhazardduetocross-

contamination,dedicatedandself-containedfacilitiesmustbe

availablefortheproductionofparticularpharmaceuticalproducts,

suchashighlysensitizingmaterials(e.g.β-lactams)orbiological

preparations(e.g.livemicroorganisms).Theproductionofcertain

otherhighlyactiveproductssuchassomeantibiotics,hormones,

cytotoxicsubstancesandcertainnon-pharmaceuticalproductsshould


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notbeconductedinthesamefacility.Themanufactureoftechnicalpoisons,

suchaspesticidesandherbicides,shouldnotbeallowedinpremises

usedforthemanufactureofpharmaceuticalproducts.

Productionarea

3.19. Productionareasshouldbewelllit,particularlywherevisualon-line

controlsarecarriedout.

3.20. Productionareasshouldbeeffectivelyventilated,withaircontrol

facilities(includingfiltrationofairtoasufficientleveltoprevent

contaminationandcrosscontaminationaswellascontrolof

temperatureandwherenecessaryhumidity)appropriatetothe

productshandled,totheoperationsundertakenandtotheexternal

environment.Theseareasshouldberegularlymonitoredduringboth

productionandnon-productionperiodstoensurecompliancewith

theirdesignspecifications.

3.21. In-processcontrolsmaybecarriedoutwithintheproductionarea

providedtheydonotposeanyriskto-production.

Weighingareas

3.22. Theweighingofstartingmaterialsandtheestimationofyieldby

weighingshouldbecarriedoutinseparateweighingareasdesigned

forthatuse,forexample,withprovisionsfordustcontrol.Suchareas

maybepartofeitherstorageorproductionareas.

QualityControlAreas

3.23. QualityControllaboratoriesshouldbeseparatedfromproduction

areas.Areaswherebiological,microbiologicalorradioisotopetest

methodsareemployedshouldbeseparatedfromeachother.

3.24. QualityControllaboratoriesshouldbedesignedtosuittheoperations

tobecarriedoutinthem.Sufficientspaceshouldbegiventoavoid

mixupsandcross-contamination.Thereshouldbeadequateand

suitablestoragespaceforsamples,referencestandards(ifnecessary,

withcooling),solvents,reagentsandrecords.

3.25. Aseparateroommaybeneededforinstrumentstoprotectthem

againstelectricalinterference,vibration,contactwithexcessive

moistureandotherexternalfactorsorwhereitisnecessarytoisolate

theinstruments.

3.26. Thedesignofthelaboratoriesshouldtakeintoaccountthesuitability

ofconstructionmaterials,preventionoffumesandventilation.There

shouldbeseparateairsupplytolaboratoriesandproductionareas.


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3Separateair-handlingunitsandotherprovisionsareneededforbiological,

microbiologicalandradioisotopelaboratories.

StorageAreas

3.27. Storageareasshouldbeofsufficientcapacitytoalloworderlystorage

ofthevariouscategoriesofmaterialsandproductswithproper

separationandsegregation:startingandpackagingmaterials,

intermediates,bulkandfinishedproducts,productsinquarantine,

andreleased,rejected,returnedorrecalledproducts.

3.28. Storageareasshouldbedesignedoradaptedtoensuregoodstorage

conditions.Inparticular,theyshouldbeclean,dry,sufficientlylitand

maintainedwithinacceptabletemperaturelimits.Wherespecial

storageconditionsarerequired(e.g.temperature,humidity)these

shouldbeprovided,controlled,monitoredandrecordedwhere

appropriate.

3.29. Receivinganddispatchbaysshouldbeseparatedandshouldprotect

materialsandproductsfromtheweather.Receivingareasshouldbe

designedandequippedtoallowcontainersofincomingmaterialsto

becleaned,ifnecessary,beforestorage.

3.30. Wherequarantinestatusisensuredbystorageinseparateareas,

theseareasshouldbeclearlymarkedandtheiraccessrestrictedto

authorizedpersonnel.Anysystemreplacingthephysicalquarantine

shouldgiveequivalentsecurity.

3.31. Segregatedandsecureareasshouldbeprovidedforthestorageof

rejected,recalled,orreturnedmaterialsorproducts.

3.32. Thereshouldbeaseparatesamplingareaforstartingmaterialsto

preventcontaminationorcrosscontamination.

3.33. Printedpackagingmaterialsareconsideredcriticaltotheconformity

ofthepharmaceuticalproductandspecialattentionshouldbepaidto

samplingandthesafeandsecurestorageofthesematerials.

3.34. Highlyactiveandradioactivematerials,narcotics,otherdangerous

medicines,andsubstancespresentingspecialrisksofabuse,fireor

explosionshouldbestoredinsafeandsecureareas.

Ancillaryareas

3.35. Restandrefreshmentroomsshouldbeseparatefrommanufacturing

andcontrolareas.

3.36. Adequate,cleanwashingandtoiletfacilitiesshouldbeprovidedfor


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3 personnel.

3.37. Washingfacilitiesprovidedshouldbeequippedwithhotandcold

water,soapordetergent,airdriersorsingle-servicetowels,and

disinfectants.Cleantoiletfacilitiesshouldbeeasilyaccessibleto

workingareasandshouldbeadequatelyseparatedfromproduction

areas.

3.38. Facilitiesforchangingandstoringclothesandforwashingandtoilet

purposesshouldbeeasilyaccessibleandappropriateforthenumber

ofusers.Toiletsshouldnotcommunicatedirectlywithproductionor

storageareas.

3.39. Maintenanceworkshopsshouldbeseparatedfromproductionareas.

Wheneverpartsandtoolsarestoredintheproductionarea,they

shouldbekeptinroomsorlockersreservedforthatuse.

3.40. Animalhousesshouldbewellisolatedfromotherareas,with

separateentrance(animalaccess)andair-handlingfacilities.

Lighting

3.41. Adequatelightingshouldbeprovidedinallareasandshouldbe

appropriatetofacilitatecleaning,maintenance,dispensingandother

operationsthatmayimpactproductquality.

Heating,VentilationandAir-Conditioning(HVAC)

3.42. Adequateventilation,airfiltration,airheating,coolingandexhaust

systemsshouldbeprovidedwhereappropriate.Thesesystemsshould

bedesignedandconstructedtominimizerisksofcontaminationand

crosscontaminationaswellasprotecttheintegrityofstarting

materials,packagingmaterials,intermediatesandfinishedproducts.

3.43. Equipmentforadequatecontrolofairpressure,micro-organisms,

dust,humidity,andtemperatureshouldbeprovidedwhen

appropriateforthemanufacture,processing,packaging,orholdingof

apharmaceuticalproduct.

3.44. Airfiltrationsystems,includingpre-filtersandparticulatematterair

filters,shouldbeusedwhenappropriateonairsuppliestoproduction

andsamplingareas.

3.45. Whereairisre-circulatedtoproductionareas,appropriatemeasures

shouldbetakentocontrolre-circulationofdustfromproduction.In

areaswhereaircontaminationoccursduringproduction,there

shouldbeadequateexhaustsystemsorothersystemsadequateto


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3controlcontaminants.

3.46. Themanufacture,processingandpackagingofhighlysensitizing

materialssuchasβ-lactamsorbiologicalpreparationssuchaslive

microorganisms,highlyactiveproductssuchassomeantibiotics,

hormones,cytotoxicsubstancesandtechnicalpoisonssuchas

pesticidesandherbicidesshouldbecarriedoutindedicatedfacilities

topreventcrosscontamination.

Watersupplyandplumbing

3.47. Waterusedinthemanufactureofpharmaceuticalproductsshouldbe

suitableforitsintendeduse.

3.48. Unlessotherwisejustified,processwatershouldataminimummeet

NigerianIndustrialStandard(NIS)fordrinking(potable)waterquality.

Water not meeting such standards should not be permitted in the

potablewatersystem.

3.49. Where drinking (potable) water is insufficient to ensure

pharmaceutical product quality, stricter chemical and/or

microbiologicalwaterqualityspecificationsarerequired.Appropriate

specificationforphysical/chemicalattributes, totalmicrobialcounts,

objectionableorganismsandendotoxinsshouldbeestablished.

3.50. Wherewater used in the process is treated by themanufacturer to

achieveadefinedquality,thetreatmentprocessshouldbevalidatedand

monitoredwithappropriateactionlimits.

3.51. Potablewatershouldbesuppliedundercontinuouspositivepressurein

aplumbingsystemfreeofdefectsthatcouldcontributecontamination

toanypharmaceuticalproduct.

3.52. Drainsshouldbeofadequatesizeand,whereconnecteddirectlytoa

sewer,shouldbeprovidedwithanairbreakoranyothermechanical

devicetopreventback-siphonage.

3.53. Opendrainsshouldbeavoided;whereunavoidable,shouldbeeasily

accessibleandshallowforeasycleaninganddisinfection.

3.54. Permanently installed pipework should be appropriately identified.

This can be accomplished by identifying individual lines,

documentation, computer control systems, or alternative means.

Pipeworkshouldbelocatedtoavoidrisksofcontamination.

Sewageandrefuse


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3 3.55. Sewage, refuse, and other wastes in and from the building and

immediate premises should be disposed of in a safe and sanitary

manner.

3.56. Containersandorpipesforwastematerialsshouldbeclearlyidentified

Sanitation

3.57. Anybuildingusedinthemanufacture,processing,packagingorholding

of a pharmaceutical product should be maintained in a clean and

sanitary condition. There should be standard operating procedures

assigning responsibility for sanitation and describing in sufficient

detail,thecleaningschedules,methods,equipment,andmaterialstobe

usedincleaningthebuildingsandfacilities;andshouldbefollowed.

3.58. Thebuildingshouldbefreeofinfestationbyrodents,birds,insects,and

othervermin.

3.59. There should be standard operating procedures for use of suitable

rodenticides,insecticides,fungicides,fumigatingagents,cleaningand

sanitizing agents. Such standard operating procedures should be

designed to protect personnel and prevent the contamination of

equipment, materials, pharmaceutical product containers, closures,

packaging,labellingmaterials,orpharmaceuticalproductsandshould

be followed.Rodenticides, insecticides,and fungicidesshouldnotbe

usedunlessregisteredinaccordancewiththeFoodandDrugActand

thePesticideRegistrationRegulationsoftheAgency.

Equipment

3.60. Equipmentshouldbelocated,designed,constructed,adaptedand

maintainedtosuittheoperationstobecarriedout.Thelayoutand

designofequipmentmustaimtominimizetheriskoferrorsand

permiteffectivecleaningandmaintenanceinordertoavoidcross-

contamination,build-upofdustordirt,and,ingeneral,anyadverse

effectonthequalityofproducts.

3.61. Equipmentshouldbeinstalledinsuchawayastominimizeanyrisk

oferrororcontamination.

3.62. Productionequipmentshouldnotpresentanyhazardtotheproducts.

Thepartsoftheproductionequipmentthatcomeintocontactwith

theproductmustnotbereactive,additive,adsorptiveorabsorptiveto

anextentthatwouldaffectthequalityoftheproductandthuspresent

anyhazard.

3.63. Manufacturingequipmentshouldbedesignedsothatitcanbeeasily


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3andthoroughlycleaned.Itshouldbecleanedaccordingtodetailedwritten

proceduresandstoredonlyinacleananddrycondition.

3.64. Repairandmaintenanceoperationsshouldnotpresentanyhazardto

thequalityoftheproducts.

3.65. Washing,cleaninganddryingequipmentshouldbechosenandused

soasnottobeasourceofcontamination.

3.66. Balancesandmeasuringequipmentofanappropriaterangeand

precisionshouldbeavailableforproductionandcontroloperations.

3.67. Productionequipmentshouldbethoroughlycleanedaccordingtoa

fixedschedule.

3.68. Laboratoryequipmentandinstrumentsshouldbesuitedtothe

testingproceduresundertaken.

3.69. Measuring,weighing,recordingandcontrolequipmentshouldbe

calibratedbycertifiedbodiesandcheckedatdefinedintervalsby

appropriatemethods.Adequaterecordsshouldbemaintained

3.70. Fixedpipeworkshouldbeclearlylabelledtoindicatethecontents

and,whereapplicable,thedirectionofflow.

3.71. Allservicepipeworkanddevicesshouldbeadequatelymarkedand

specialattentionpaidtotheprovisionofnon-interchangeable

connectionsoradaptorsfordangerousgasesandliquids.

3.72. Closedequipmentshouldbeusedwheneverappropriate.Whereopen

equipmentisusedorequipmentisopened,precautionsshouldbe

takentominimizecontamination.

3.73. Non-dedicatedequipmentusedfortheproductionofdifferent

pharmaceuticalproductsshouldbecleanedaccordingtovalidated

cleaningprocedurestopreventcross-contamination.

3.74. Defectiveequipmentshouldberemovedfromproductionandquality

controlareas.Ifthisisnotpossible,itshouldbeclearlylabelledas

defectivetopreventuse.

3.75. Currentdrawingsofcriticalequipmentandsupportsystemsshould

bemaintained.

Cleaningandmaintenance

3.76. Anybuildingusedinthemanufacture,processing,packaging,or


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3 holdingofapharmaceuticalproductshouldbemaintainedinagoodstateof

repair.

3.77. Repairandmaintenanceoperationsshouldnotpresentanyhazardto

thequalityofproducts.

3.78. Schedulesandprocedures(includingassignmentsofresponsibilities)

shouldbeestablishedforthepreventivemaintenanceofequipment

3.79. Equipmentandutensilsshouldbecleaned,maintained,andsanitizedat

appropriate intervals to prevent malfunction or contamination that

would alter the safety, identity, strength, quality, or purity of the

pharmaceutical product beyond the official or other established

specifications.

3.80. Standardoperatingproceduresshouldbeestablishedandfollowedfor

cleaningandmaintenanceofequipment,includingutensils,usedinthe

manufacture, processing, packaging, or holding of a pharmaceutical

product. These procedures should include, but are not necessarily

limitedto,thefollowing:

a. Assignmentofresponsibilityforcleaningandmaintaining

equipment;

b. Maintenanceandcleaningschedules,including,where

appropriate,sanitizingschedules;

c. Adescriptioninsufficientdetailofthemethods,equipment,

andmaterialsused(includingdilutionofcleaningagents)in

cleaningandmaintenanceoperations,

d. Whereappropriate,instructionsfordisassemblingand

reassemblingequipmenttoensurepropercleaningand

maintenanceshouldbeprovided;

e. Instructionsfortheremovalorobliterationofpreviousbatch

identification;

f. Instructionsfortheprotectionofcleanequipmentfrom

contaminationpriortouse;

g. Inspectionofequipmentforcleanlinessimmediatelybefore

use.

h. Properrecordsshouldbekeptofmaintenance,cleaning,

sanitizing,andinspectionasdescribedinChapter5


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CHAPTER

QUALIFICATION ANDVALIDATION4

QualificationandvalidationPrinciple

4.1. ItisarequirementofGMPthatmanufacturersidentifywhatvalidationworkisneededtoprovethatthecriticalaspectsoftheirparticularoperationsarecontrolled.Significantchangestothefacilities,theequipmentandtheprocesses,whichmayaffectthequalityoftheproduct,shouldbevalidated.Ariskassessmentapproachshouldbeusedtodeterminethescopeandextentofvalidation.

General

4.2. Thekeyelementsofaqualificationandvalidationprogrammeofacompanyshouldbeclearlydefinedanddocumentedinavalidationmasterplan.

4.3. Qualificationandvalidationshouldestablishandprovidedocumentaryevidencethat:

a. Thepremises,supportingutilities,equipmentandprocesseshavebeendesignedinaccordancewiththerequirementsforGMP(designqualification{DQ});

b. Thepremises,supportingutilitiesandequipmenthavebeenbuiltandinstalledincompliancewiththeirdesignspecifications(installationqualification{IQ});

c. Thepremises,supportingutilitiesandequipmentoperateinaccordancewiththeirdesignspecifications(operationalqualification{OQ});

d. Aspecificprocesswillconsistentlyproduceaproductmeetingitspredeterminedspecificationsandqualityattributes(ProcessValidation{PV}alsocalledProcessPerformanceQualification{PPQ}).

4.4. Anyaspectofoperation,includingsignificantchangestothe


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premises,facilities,equipmentorprocesses,whichmayaffectthequalityoftheproduct,directlyorindirectly,shouldbequalifiedandvalidated.Qualificationandvalidationshouldnotbeconsideredasone-offexercises.Anon-goingprogrammeshouldfollowtheirfirstimplementationandshouldbebasedonaperiodicreview.

4.5. Thecommitmenttomaintaincontinuedvalidationstatusshouldbestatedintherelevantcompanydocumentation,suchasthequalitymanualorvalidationmasterplan.

4.6. Theresponsibilityofperformingvalidationshouldbeclearlydefined.

4.7. ValidationstudiesareanessentialpartofGMPandshouldbeconductedinaccordancewithpredefinedandapprovedprotocols.

4.8. Awrittenreportsummarizingtheresultsrecordedandtheconclusionsreachedshouldbepreparedandstored.

4.9. Processesandproceduresshouldbeestablishedonthebasisoftheresultsofthevalidationperformed.

4.10. Particularattentionshouldbepaidtothevalidationofprocesses,analyticaltestmethods,automatedsystemsandcleaningprocedures.

Planningforvalidation

4.11. Allvalidationactivitiesshouldbeplanned.ThekeyelementsofavalidationprogrammeshouldbeclearlydefinedanddocumentedinaValidationMasterPlan(VMP).

4.12. TheVMPshouldbeasummarydocumentwhichisbrief,conciseandclear.

4.13. TheVMPshouldcontainatleastthefollowing:

a. Validationpolicy;

b. Organizationalstructureofvalidationactivities;

c. Summaryoffacilities,systems,equipmentandprocessestobevalidated;

d. Documentationformat:theformattobeusedforprotocolsandreports;


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e. Planningandscheduling;

f. Changecontrol;

g. Referencetoexistingdocuments.

4.14. Incaseoflargeprojectsliketheconstructionofanewfacility,oftenthebestapproachistocreateaseparateVMP,(insuchsituationstheVMPshouldbepartofthetotalprojectmanagement.)

Documentation

4.15. Writtenprotocolthatspecifieshowqualificationandvalidationwillbeconductedshouldbeestablished.Theprotocolshouldbereviewedandapproved.Theprotocolshouldspecifycriticalstepsandacceptancecriteria.

4.16. Areportthatcross-referencesthequalificationand/orvalidationprotocolshouldbeprepared,summarizingtheresultsobtained,commentingonanydeviationsobserved,anddrawingthenecessaryconclusions,includingrecommendingchangesnecessarytocorrectdeficiencies.Anychangestotheplanasdefinedintheprotocolshouldbedocumentedwithappropriatejustification.

4.17. Aftercompletionofasatisfactoryqualification,aformalreleaseforthenextstepinqualificationandvalidationshouldbemadeasawrittenauthorization.

Qualification

Qualificationprerequisites

Userrequirementspecification(URS)

4.18. Thisdocumentdescribeswhattheequipmentisintendedtodoandalltheessentialrequirementssuchasproductionrates,operatingrangesetc.Theuserusuallydevelopsthisdocumentanditlinkstotheperformancequalificationdocumentwhichtestsforeachoftherequirements.

FunctionalRequirementSpecification(FRS)

4.19. Thisdocumentdescribesthedetailedfunctionalityoftheequipment.Thesupplierusuallydevelopsthisdocumentandthisdocumentlinkstotheoperationalqualificationdocument


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whichtestsforeachfunction.

FactoryAcceptanceTest(FAT)

4.20. FATisatestconductedtodetermineiftherequirementofthespecificationofthecontractaremetandthisisusuallyconductedinthefacilityofthesupplier.

SiteAcceptanceTest(SAT)

4.21. SATisatestconductedtodetermineiftherequirementsofthespecificationofthecontractaremetandthisisusuallyconductedinthefacilityoftheuser.Itisdonebeforecommissioning.

Designqualification

4.22. Thefirstelementofthevalidationofnewfacilities,systemsorequipmentwillbedesignqualification(DQ).

4.23. ThecomplianceofthedesignwithGMPshouldbedemonstratedanddocumented.

Installationqualification

4.24. Installationqualification(IQ)shouldbeperformedonnewormodifiedfacilities,systemsandequipment.

4.25. IQshouldinclude,butnotbelimitedtothefollowing:

a. Installationofequipment,piping,servicesandinstrumentationcheckedtocurrentengineeringdrawingsandspecifications;

b. Collectionandcollationofsupplieroperatingandworkinginstructionsandmaintenancerequirements;

c. Calibrationrequirements;

d. Verificationofmaterialsofconstruction.

Operationalqualification

4.26. Operationalqualification(OQ)shouldfollowinstallationqualification.

4.27. OQshouldinclude,butnotbelimitedtothefollowing:

a. Teststhathavebeendevelopedfromknowledgeofprocesses,systemsandequipment;


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b. Teststoincludeaconditionorasetofconditionsencompassingupperandloweroperatinglimits,sometimesreferredtoas“worstcase”conditions.

4.28. Thecompletionofasuccessfuloperationalqualificationshouldallowthefinalizationofcalibration,operatingandcleaningprocedures,operatortrainingandpreventivemaintenancerequirements.Itshouldpermitaformal"release"ofthefacilities,systemsandequipment.

Performancequalification

4.29. Performancequalification(PQ)shouldfollowsuccessfulcompletionofinstallationqualificationandoperationalqualification.

4.30. PQshouldinclude,butnotbelimitedtothefollowing:

a. Tests,usingproductionmaterials,qualifiedsubstitutesorsimulatedproduct,thathavebeendevelopedfromknowledgeoftheprocessandthefacilities,systemsorequipment;

b. Teststoincludeaconditionorsetofconditionsencompassingupperandloweroperatinglimits.

4.31. AlthoughPQisdescribedasaseparateactivity,itmayinsomecasesbeappropriatetoperformitinconjunctionwithOQ.

Qualificationofestablished(in-use)facilities,systemsandequipment

4.32. Evidenceshouldbeavailabletosupportandverifytheoperatingparametersandlimitsforthecriticalvariablesoftheoperatingequipment.Additionally,thecalibration,cleaning,preventivemaintenance,operatingproceduresandoperatortrainingproceduresandrecordsshouldbedocumented.

ProcessvalidationGeneral

4.33. Therequirementsandprinciplesforprocessvalidationareapplicabletothemanufactureofpharmaceuticaldosageforms.Theycovertheinitialvalidationofnewprocesses,subsequentvalidationofmodifiedprocessesandre-validation.

4.34. Processvalidationshouldnormallybecompletedpriortothe


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distributionandsaleofthepharmaceuticalproduct(prospectivevalidation).Inexceptionalcircumstances,wherethisisnotpossible,itmaybenecessarytovalidateprocessesduringroutineproduction(concurrentvalidation).Processesinuseforsometimeshouldalsobevalidated(retrospectivevalidation).Retrospectivevalidationisnotpermittedintheproductionofparenteralpreparations.

4.35. Facilities,systemsandequipmenttobeusedshouldhavebeenqualifiedandanalyticaltestingmethodsshouldbevalidatedorverifiedasappropriate.Personneltakingpartinthevalidationprogrammeshouldhavebeenappropriatelytrained.

4.36. Facilities,systems,equipmentandprocessesshouldbeperiodicallyevaluatedtoverifythattheyarestilloperatinginavalidmanner.

Prospectivevalidation

4.37. Prospectivevalidationshouldinclude,butnotbelimitedtothefollowing:

a. Shortdescriptionoftheprocess;

b. Summaryofthecriticalprocessingstepstobeinvestigated;

c. Listoftheequipment/facilitiestobeused(includingmeasuring/monitoring/recordingequipment)togetherwithitscalibrationstatus;

d. Finishedproductspecificationsforrelease;

e. Listofanalyticalmethods,asappropriate;

f. Proposedin-processcontrolswithacceptancecriteria;

g. Additionaltestingtobecarriedout,withacceptancecriteriaandanalyticalvalidation,asappropriate;

h. Samplingplan;

i. Methodsforrecordingandevaluatingresults;

j. Functionsandresponsibilities;

k. Proposedtimetable.

4.38. Usingthisdefinedprocess(includingspecifiedmaterials)a


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seriesofbatchesofthefinalproductmaybeproducedunderroutineconditions.Intheory,thenumberofprocessrunscarriedoutandobservationsmadeshouldbesufficienttoallowthenormalextentofvariationandtrendstobeestablishedandtoprovidesufficientdataforevaluation.

4.39. Inkeepingwithprinciplesofqualityriskmanagement,theseguidelinesrecommendthatprocessvalidationembracestheproductlife-cycleconceptwhichinvolvesthegenerationandevaluationofdatathroughouttheprocessfromdevelopmenttofullscaleproduction.

4.40. Batchesmadeforprocessvalidationshouldbethesamesizeastheintendedindustrialscalebatches.

4.41. Ifitisintendedthatvalidationbatchesbesoldorsupplied,theconditionsunderwhichtheyareproducedshouldcomplyfullywiththerequirementsofGoodManufacturingPractice,includingthesatisfactoryoutcomeofthevalidationexercise,andwiththemarketingauthorization.

Concurrentvalidation

4.42. Inexceptionalcircumstancesitmaybeacceptablenottocompleteavalidationprogrammebeforeroutineproductionstarts.

4.43. Thedecisiontocarryoutconcurrentvalidationmustbejustified,documentedandapprovedbyauthorisedpersonnel.

4.44. Documentationrequirementsforconcurrentvalidationarethesameasspecifiedforprospectivevalidation.

Retrospectivevalidation

4.45. Retrospectivevalidationisonlyacceptableforwell-establishedprocessesandwillbeinappropriatewheretherehavebeenrecentchangesinthecompositionoftheproduct,operatingproceduresorequipment.

4.46. Validationofsuchprocessesshouldbebasedonhistoricaldata.Thestepsinvolvedrequirethepreparationofaspecificprotocolandthereportingoftheresultsofthedatareview,leadingtoaconclusionandarecommendation.

4.47. Thesourceofdataforthisvalidationshouldinclude,butnotbe


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limitedtobatchprocessingandpackagingrecords,processcontrolcharts,maintenancelogbooks,recordsofpersonnelchanges,processcapabilitystudies,finishedproductdata,includingtrendcardsandstoragestabilityresults.

4.48. Batchesselectedforretrospectivevalidationshouldberepresentativeofallbatchesmadeduringthereviewperiod,includinganybatchesthatfailedtomeetspecifications,andshouldbesufficientinnumbertodemonstrateprocessconsistency.Additionaltestingofretainedsamplesmaybeneededtoobtainthenecessaryamountortypeofdatatoretrospectivelyvalidatetheprocess.

4.49. Forretrospectivevalidationgenerally,datafromtentothirtyconsecutivebatchesshouldbeexaminedtoassessprocessconsistency.

Cleaningvalidation

4.50. Cleaningvalidationshouldbeperformedinordertoconfirmtheeffectivenessofacleaningprocedure.Therationaleforselectinglimitsofcarryoverofproductresidues,cleaningagentsandmicrobialcontaminationshouldbelogicallybasedonthematerialsinvolved.Thelimitsshouldbeachievableandverifiable.

4.51. Validatedanalyticalmethodshavingsensitivitytodetectresiduesorcontaminantsshouldbeused.Thedetectionlimitforeachanalyticalmethodshouldbesufficientlysensitivetodetecttheestablishedacceptableleveloftheresidueorcontaminant.

4.52. Normally,onlycleaningproceduresforproductcontactsurfacesoftheequipmentneedtobevalidated.Considerationshouldbegiventonon-contactparts.Theintervalsbetweenuseandcleaningaswellascleaningandre-useshouldbevalidated.Cleaningintervalsandmethodsshouldbedetermined.

4.53. Forcleaningproceduresforproductsandprocesseswhicharesimilar,itisconsideredacceptabletoselectarepresentativerangeofsimilarproductsandprocesses.Asinglevalidationstudyutilizinga“worstcase”approachcanbecarriedoutwhichtakesaccountofthecriticalissues.

4.54. Typically,threeconsecutiveapplicationsofthecleaning


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CHAPTER

DOCUMENTATION5DOCUMENTATION

Principle

5.1. Gooddocumentationisanessentialpartofthequalityassurancesystemand,assuch,

shouldexistforallaspectsofGMP.Itsaimsaretodefinethespecificationsand

proceduresforallmaterialsandmethodsofmanufactureandcontrol;toensurethat

allpersonnelconcernedwithmanufactureknowwhattodoandwhentodoit;to

ensurethatauthorizedpersonshavealltheinformationnecessarytodecidewhether

ornottoreleaseabatchofapharmaceuticalproductforsale;toensuretheexistence

ofdocumentedevidence,traceability,andtoproviderecordsandanaudittrailthat

willpermitinvestigation.Itensurestheavailabilityofthedataneededforvalidation,

reviewandstatisticalanalysis.

5.2. Thevarioustypesofdocumentsandmediausedshouldbefullydefinedinthe

manufacturer'sPQS.Documentationmayexistinavarietyofforms,includingpaper-

based,electronicorphotographicmedia.Themainobjectiveofthesystemof

documentationutilisedmustbetoestablish,control,monitorandrecordallactivities

whichdirectlyorindirectlyimpactonallaspectsofthequalityofpharmaceutical

products.

5.3. ThePharmaceuticalQualitySystemshouldincludesufficientinstructionaldetailto

facilitateacommonunderstandingoftherequirements,inadditiontoprovidingfor

sufficientrecordingofthevariousprocessesandevaluationofanyobservations,so

thatongoingapplicationoftherequirementsmaybedemonstrated.Thedesignand

useofdocumentsdependuponthemanufacturer.Insomecasessomeorallofthe

documentsdescribedbelowmaybebroughttogether,buttheywillusuallybe

separate.

General

5.4. Documentsshouldbedesigned,prepared,reviewed,anddistributedwithcare.They

shouldcomplywiththerelevantpartsofProductSpecificationFiles,Manufacturing

andMarketingAuthorizationdossiers,asappropriate.

5.5. Documentscontaininginstructionsshouldbeapproved,signedanddatedby

appropriateandauthorisedpersons.


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5 5.6. Documentsshouldhaveunambiguouscontents;thetitle,natureandpurposeshould

beclearlystatedandbeuniquelyidentifiable.Theeffectivedateshouldbedefined.

Nodocumentshouldbechangedwithoutauthorizationandapproval.

5.7. Documentscontaininginstructionsshouldbelaidoutinanorderlyfashionand

shouldbeeasytocheck.Thestyleandlanguageofdocumentsshouldfitwiththeir

intendeduse.StandardOperatingProcedures,WorkInstructionsandMethodsshould

bewritteninanimperativemandatorystyle.

5.8. Reproduceddocumentsshouldbeclearandlegible.Thereproductionofworking

documentsfrommasterdocumentsmustnotallowanyerrortobeintroduced

throughthereproductionprocess.

5.9. Documentsshouldberegularlyreviewedandkeptuptodate.Whenadocumenthas

beenrevised,asystemshouldexisttopreventinadvertentuseofthesuperseded

version.Supersededdocumentsshouldberetainedforaspecificperiodoftime.

5.10. Documentsshouldnotbehand-written;although,wheredocumentsrequirethe

entryofdata,theseentriesshouldbeclear,legibleandindelible.Sufficientspace

shouldbeprovidedforsuchentries.

5.11. Anyalterationmadetoadocumentshouldbesignedanddated;thatalteration

shouldbedoneinsuchawayastopermitthereadingoftheoriginalinformation.

Whereappropriate,thereasonforthealterationshouldberecorded.

5.12. Recordsshouldbemadeorcompletedwhenanyactionistakenandinsuchaway

thatallsignificantactivitiesconcerningthemanufactureofpharmaceuticalproducts

aretraceable.Recordsshouldberetainedforatleastoneyearaftertheexpirydateof

thefinishedproduct.

5.13. Data(andrecordsforstorage)mayberecordedbyelectronicdataprocessing

systemsorbyphotographicorotherreliablemeans.Masterformulaeanddetailed

SOPsrelatingtothesysteminuseshouldbeavailableandtheaccuracyoftherecords

shouldbechecked.Ifdocumentationishandledbyelectronicdata-processing

methods,onlyauthorizedpersonsshouldbeabletoenterormodifydatainthe

computersystem,andthereshouldbearecordofchangesanddeletions;access

shouldberestrictedbypasswordsorothermeansandtheentryofcriticaldata

shouldbeindependentlychecked.Batchrecordsstoredelectronicallyshouldbe

protectedbyback-uptransferonmagnetictape,microfilm,electronicdiscs,paper

printoutsorothermeans.Itisparticularlyimportantthat,duringtheperiodof

retention,thedataarereadilyavailable.

5.14. Complexsystemsneedtobeunderstood,welldocumented,validated,andadequate

controlsshouldbeinplace.

5.15. Manydocuments(instructionsand/orrecords)mayexistinhybridforms,i.e.some


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5elementsaselectronicandothersaspaperbased.Relationshipsandcontrolmeasuresfor

masterdocuments,officialcopies,datahandlingandrecordsneedtobestatedfor

bothhybridandhomogenoussystems.

5.16. Appropriatecontrolsforelectronicdocumentssuchastemplates,forms,andmaster

documentsshouldbeimplemented.Appropriatecontrolsshouldbeinplaceto

ensuretheintegrityoftherecordthroughouttheretentionperiod.

5.17. Itshouldbeclearlydefinedwhichrecordisrelatedtoeachmanufacturingactivity

andwherethisrecordislocated.Securecontrolsmustbeinplacetoensurethe

integrityoftherecordthroughouttheretentionperiodandvalidatedwhere

appropriate.

5.18. Specificrequirementsapplytobatchdocumentationwhichmustbekeptforoneyear

afterexpiryofthebatchtowhichitrelatesoratleastfiveyearsaftercertificationof

thebatchbytheauthorizedPerson,whicheveristhelonger.

5.19. Forinvestigationalpharmaceuticalproducts(clinicaltrials),thebatchdocumentation

mustbekeptforatleastfiveyearsafterthecompletionorformaldiscontinuationof

thelastclinicaltrialinwhichthebatchwasused.

5.20. Forothertypesofdocumentation,theretentionperiodwilldependonthebusiness

activitywhichthedocumentationsupports.Criticaldocumentation,includingraw

data(forexamplerelatingtovalidationorstability),whichsupportsinformationin

theMarketingAuthorisationshouldberetainedwhilsttheauthorisationremainsin

force.Itmaybeconsideredacceptabletoretirecertaindocumentation(e.g.rawdata

supportingvalidationreportsorstabilityreports)wherethedatahasbeen

supersededbyafullsetofnewdata.Justificationforthisshouldbedocumentedand

shouldtakeintoaccounttherequirementsforretentionofbatchdocumentation;for

example,inthecaseofprocessvalidationdata,theaccompanyingrawdatashouldbe

retainedforaperiodatleastaslongastherecordsforallbatcheswhosereleasehas

beensupportedonthebasisofthatvalidationexercise.

5.21. Thefollowingsectiongivessomeexamplesofrequireddocuments.The

pharmaceuticalqualitysystemshoulddescribealldocumentsrequiredtoensure

productqualityandpatientsafety.

RequiredGMPdocumentation(bytype)

5.22. TherearetwoprimarytypesofdocumentationusedtomanageandrecordGMP

compliance:Instructions(directions,requirements)andRecords/Reports.

Appropriategooddocumentationpracticeshouldbeappliedwithrespecttothetype

ofdocument.

5.23. Suitablecontrolsshouldbeimplementedtoensuretheaccuracy,integrity,availability

andlegibilityofdocuments.Instructiondocumentsshouldbefreefromerrorsand


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5 availableinwriting.Theterm'written'meansrecorded,ordocumentedonmediafromwhich

datamayberenderedinahumanreadableform.

Instructions(DirectionsorRequirements):

5.24. Labels:Adocumentwhichisusedtoidentifyacontainer,product,equipmentor

locationprovidinginformationontheitem'sorigin,contents,use,destinationor

status.

5.25. Labelsappliedtocontainers,equipmentorpremisesshouldbeclear,unambiguous

andinthecompany'sagreedformat.Itisoftenhelpfulinadditiontothewordingon

thelabelstousecolourstoindicatestatus(e.g.quarantined,accepted,rejected,and

clean).

5.26. Allfinishedpharmaceuticalproductsshouldbeidentifiedbylabelling,asrequiredby

theAgency.

5.27. Forreferencestandards,thelabeland/oraccompanyingdocumentshouldindicate

potencyorconcentration,dateofmanufacture,expirydate,datetheclosurewasfirst

opened,storageconditionsandcontrolnumber,asappropriate.

5.28. Specifications:Describeindetailtherequirementswithwhichtheproductsor

materialsusedorobtainedduringmanufacturehavetoconform.Theyserveasa

basisforqualityevaluation.

5.29. Thereshouldbeappropriatelyauthorizedanddatedspecifications,includingtestson

identity,content,purityandquality,forstartingandpackagingmaterialsandfor

finishedproducts;whereappropriate,theyshouldalsobeavailableforintermediate

orbulkproducts.Specificationsforwater,solventsandreagents(e.g.acidsandbases)

usedinproductionshouldbeincluded.

5.30. Eachspecificationshouldbeapproved,signed,dated,andmaintainedbyquality

control.

5.31. Periodicrevisionsofthespecificationsmaybenecessarytocomplywithneweditions

ofcompendia.

5.32. Testingproceduresdescribedindocumentsshouldbevalidatedinthecontextof

availablefacilitiesandequipmentbeforetheyareadoptedforroutinetesting.

5.33. Pharmacopoeias,referencestandards,referencespectraandotherreference

materialsshouldbeavailableintheQClaboratory

Specificationsforstartingandpackagingmaterials

5.34. Specificationsforstartingandprimaryorprintedpackagingmaterialsshouldinclude

orprovidereferenceto,ifapplicable:

a. Adescriptionofthematerials,including:


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5i. Thedesignatedname(ifapplicable,theInternationalNon

ProprietaryName(INN)andtheinternalcodereference;

ii. Thereference,ifany,toapharmacopoeialmonograph;

iii. Theapprovedsuppliersandtheoriginalproducerofthematerial;

iv. Aspecimenofprintedmaterials;

b. Directionsforsamplingandtesting;

c. Qualitativeandquantitativerequirementswithacceptancelimits;

d. Storageconditionsandprecautions;

e. Themaximumperiodofstoragebeforere-examination.

5.35. Packagingmaterialshouldconformtospecifications,andshouldbecompatiblewith

thematerialand/orwiththepharmaceuticalproductitcontains.

5.36. Thematerialshouldbeexaminedforcompliancewiththespecification,andfor

defectsaswellasforthecorrectnessofidentitymarkings.

5.37. Documentsdescribingtestingproceduresshouldstatetherequiredfrequencyforre-

assayingeachstartingmaterial,asdeterminedbyitsstability.

Specificationsforintermediateandbulkproducts

5.38. Specificationsforintermediateandbulkproductsshouldbeavailableforcritical

stepsorifthesearepurchasedordispatched,orifdataobtainedfromthe

intermediateproductareusedfortheevaluationofthefinishedproduct.The

specificationsshouldbesimilartospecificationsforstartingmaterialsorforfinished

products,asappropriate.

Specificationsforfinishedproducts

5.39. Specificationsforfinishedproductsshouldincludeorprovidereferenceto:

a. Thedesignatednameoftheproductandthecodereferencewhere

applicable;

b. Thedesignatedname(s)oftheactiveingredient(s)(ifapplicable,withthe

INN(s));

c. Theformulaorareferencetotheformula;

d. Adescriptionofthepharmaceuticalformandpackagedetails;

e. Directionsforsamplingandtestingorareferencetoprocedures;

f. Thequalitativeandquantitativerequirements,withtheacceptancelimits;

g. Thestorageconditionsandanyspecialhandlingprecautions,where


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5 applicable;

h. Theshelf-life.

5.40. ManufacturingFormulae,Processing,PackagingandTestingInstructions:

Providethedetailsforallthestartingmaterials,equipmentandcomputerized

systems(ifany)tobeusedandspecifyallprocessing,packaging,samplingand

testinginstructions.In-processcontrolsandprocessanalyticaltechnologiestobe

employedshouldbespecifiedwhererelevant,togetherwithacceptancecriteria.

5.41. Approved,writtenMasterFormulaandProcessingInstructionsshouldexistforeach

productandbatchsizetobemanufactured.

5.42. TheMasterFormulashouldinclude:

a. Thenameoftheproduct,withaproductreferencecoderelatingtoits

specification;

b. Adescriptionofthepharmaceuticaldosageform,strengthoftheproduct

andbatchsize;

c. Alistofallstartingmaterialstobeused(ifapplicablewiththeINNs),with

theamountofeachdescribed;mentionshouldbemadeofanysubstance

thatmaydisappearinthecourseofprocessing;

d. Astatementoftheexpectedfinalyieldwiththeacceptablelimits,andof

relevantintermediateyields,whereapplicable.

5.43. Theprocessinginstructionsshouldinclude:

a. Astatementoftheprocessinglocationandtheprincipalequipmenttobe

used;

b. Themethodsorreferencetothemethods,tobeusedforpreparingthe

criticalequipmente.g.cleaning(especiallyafterachangeinproduct),

assembling,calibrating,sterilisinganduse;

c. Checksthattheequipmentandworkstationareclearofpreviousproducts,

documentsormaterialsnotrequiredfortheplannedprocess,andthat

equipmentiscleanandsuitableforuse;

d. Detailedstepwiseprocessinginstructions(e.g.checksonmaterials,pre-

treatments,sequenceforaddingmaterials,criticalprocessparameterssuch

astime,temperatureetc.);

e. Theinstructionsforanyin-processcontrolswiththeirlimits;

f. Wherenecessary,therequirementsforbulkstorageoftheproducts;

includingthecontainer,labellingandspecialstorageconditionswhere

applicable;


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5g. Anyspecialprecautionstobeobserved.

PackagingInstructions

5.44. Approvedpackaginginstructionsforeachproduct,packsizeandtypeshouldexist.

Theseshouldinclude,orhaveareferencetothefollowing:

a. Nameoftheproduct;includingthebatchnumberofbulkandfinished

product;

b. Descriptionofitspharmaceuticalformandstrengthwhereapplicable;

c. Thepacksizeexpressedintermsofthenumber,weightorvolumeofthe

productinthefinalcontainer;

d. Acompletelistofallthepackagingmaterialsrequired,includingquantities,

sizesandtypes,withthecodeorreferencenumberrelatingtothe

specificationsofeachpackagingmaterial;

e. Whereappropriate,anexampleorreproductionoftherelevantprinted

packagingmaterials,andspecimensindicatingwheretoapplybatchnumber

references,andshelflifeoftheproduct;

f. Checksthattheequipmentandworkstationareclearofpreviousproducts,

documentsormaterialsnotrequiredfortheplannedpackagingoperations

(lineclearance),andthatequipmentiscleanandsuitableforuse;

g. Specialprecautionstobeobserved,includingacarefulexaminationofthe

areaandequipmentinordertoascertainthelineclearancebeforeandafter

packagingoperations;

h. Adescriptionofthepackagingoperation,includinganysignificant

subsidiaryoperations,andequipmenttobeused;

i. Detailsofin-processcontrolswithinstructionsforsamplingandacceptance

limits.

Batchmanufacturing/processingrecords

5.45. Abatchprocessingrecordshouldbekeptforeachbatchprocessed.Itshouldbe

basedontherelevantpartsofthecurrentlyapprovedspecificationsontherecord.

Themethodofpreparationofsuchrecordsshouldbedesignedtoavoiderrors.

(Copyingorvalidatedcomputerprogrammesarerecommended.Transcribingfrom

approveddocumentsshouldbeavoided.)

5.46. Beforeanyprocessingbegins,acheckshouldbemadethattheequipmentandwork

stationareclearofpreviousproducts,documents,ormaterialsnotrequiredforthe

plannedprocess,andthattheequipmentiscleanandsuitableforuse.Thischeck

shouldberecorded.


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5 5.47. Duringprocessing,thefollowinginformationshouldberecordedatthetimeeach

actionistaken,andaftercompletion,therecordshouldbedatedandsignedbythe

personresponsiblefortheprocessingoperations:

a. Thenameoftheproduct;

b. Thenumberofthebatchbeingmanufactured;

c. Datesandtimesofcommencement,ofsignificantintermediatestages,and

ofcompletionofproduction;

d. Thenameofthepersonresponsibleforeachstageofproduction;

e. Theinitialsoftheoperator(s)ofdifferentsignificantstepsofproduction

and,whereappropriate,oftheperson(s)whocheckedeachofthese

operations(e.g.weighing);

f. Thebatchnumberand/oranalyticalcontrolnumberandthequantityof

eachstartingmaterialactuallyweighed(includingthebatchnumberand

amountofanyrecoveredorreprocessedmaterialadded);

g. Anyrelevantprocessingoperationoreventandthemajorequipmentused;

h. Thein-processcontrolsperformed,theinitialsoftheperson(s)carrying

themout,andtheresultsobtained;

i. Theamountofproductobtainedatdifferentandpertinentstagesof

manufacture(yield),togetherwithcommentsorexplanationsforsignificant

deviationsfromtheexpectedyield;

j. Notesonspecialproblemsincludingdetails,withsignedauthorizationfor

anydeviationfromthemasterformula(manufacturingformulaand

processinginstruction).

k. Approvalbythepersonresponsiblefortheprocessingoperations

5.48. Note:Whereavalidatedprocessiscontinuouslymonitoredandcontrolled,then

automaticallygeneratedreportsmaybelimitedtocompliancesummariesand

exception/out-of-specification(OOS)datareports.

Batchpackagingrecords

5.49. Abatchpackagingrecordshouldbekeptforeachbatchorpartbatchprocessed.It

shouldbebasedontherelevantpartsoftheapprovedpackaginginstructions,andthe

methodofpreparingsuchrecordsshouldbedesignedtoavoiderrors.(Copyingor

validatedcomputerprogrammesarerecommended.Transcribingfromapproved

documentsshouldbeavoided.)

5.50. Beforeanypackagingoperationbegins,checksshouldbemadethattheequipment

andworkstationareclearofpreviousproducts,documentsormaterialsnotrequired


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5fortheplannedpackagingoperations,andthatequipmentiscleanandsuitableforuse.These

checksshouldberecorded.

5.51. Thefollowinginformationshouldberecordedatthetimeeachactionistaken,and

thedateandthepersonresponsibleshouldbeclearlyidentifiedbysignatureor

electronicpassword:

a. Thenameoftheproduct,thebatchnumberandthequantityofbulk

producttobepacked,aswellasthebatchnumberandtheplannedquantity

offinishedproductthatwillbeobtained,thequantityactuallyobtainedand

thereconciliation;

b. Thedate(s)andtime(s)ofthepackagingoperations;

c. Thenameoftheresponsiblepersoncarryingoutthepackagingoperation;

d. Theinitialsoftheoperatorsofthedifferentsignificantsteps;

e. Thechecksmadeforidentityandconformitywiththepackaging

instructions,includingtheresultsofin-processcontrols;

f. Detailsofthepackagingoperationscarriedout,includingreferencesto

equipmentandthepackaginglinesused,and,whennecessary,the

instructionsforkeepingtheproductunpackedorarecordofreturning

productthathasnotbeenpackagedtothestoragearea;

g. Samplesoftheprintedpackagingmaterialsused,includingspecimens

bearingtheapprovalfortheprintingofandregularcheck(where

appropriate)ofthebatchnumber,expirydate,andanyadditional

overprinting;

h. Notesonanyspecialproblems,includingdetailsofanydeviationfromthe

packaginginstructions,withwrittenauthorizationbyanappropriate

person;

i. Thequantitiesandreferencenumberoridentificationofallprinted

packagingmaterialsandbulkproductissued,used,destroyedorreturnedto

stockandthequantitiesofproductobtainedtopermitadequate

reconciliation.

5.52. StandardOperatingProcedures(SOPs):givedirectionsforperformingcertain

operations.

5.53. SOPsandassociatedrecordsofactionstakenshouldbeavailableforbutnotlimited

to:

a. Equipmentassemblyandvalidation;

b. Analyticalapparatusandcalibration;


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5 c. Maintenance,cleaningandsanitization;

d. Personnelmattersincludingqualification,training,clothingandhygiene;

e. Environmentalmonitoring;

f. Pestcontrol;

g. Complaints;

h. Recalls;

i. Returns;

j. Changecontrol;

k. Investigationsintodeviationsandnon-conformances;

l. Internalquality/GMPcomplianceaudits;

m. Summariesofrecordswhereappropriate(e.g.productqualityreview);

n. Supplieraudits

o. TechnologyTransfer.

5.54. ThereshouldbeSOPsandrecordsforthereceiptofeachdeliveryofstartingmaterial

andprimaryandprintedpackagingmaterial.

5.55. Therecordsofthereceiptsshouldinclude:

a. Thenameofthematerialonthedeliverynoteandthecontainers;

b. The“in-house”nameand/orcodeofmaterialifdifferentfrom(a);

c. Thedateofreceipt;

d. Thesupplier'snameand,ifpossible,manufacturer'sname;

e. Themanufacturer'sbatchorreferencenumber;

f. Thetotalquantityandnumberofcontainersreceived;

g. Thebatchnumberassignedafterreceipt;

h. Anyrelevantcomment(e.g.stateofthecontainers).

5.56. ThereshouldbeSOPsfortheinternallabelling,quarantineandstorageofstarting

materials,packagingmaterialsandothermaterials,asappropriate.

5.57. SOPsshouldbeavailableforeachinstrumentandpieceofequipment(e.g.use,

calibration,cleaning,maintenance)andplacedincloseproximitytotheequipment.

5.58. ThereshouldbeSOPsforsampling,whichspecifytheperson(s)authorizedtotake

samples.


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55.59. Thesamplinginstructionsshouldinclude:

a. Themethodofsamplingandthesamplingplan;

b. Theequipmenttobeused;

c. Anyprecautionstobeobservedtoavoidcontaminationofthematerialor

anydeteriorationinitsquality;

d. Theamount(s)ofsample(s)tobetaken;

e. Instructionsforanyrequiredsubdivisionofthesample;

f. Thetypeofsamplecontainer(s)tobeused;andwhethertheyarefor

asepticsamplingorfornormalsampling,andlabelling;

g. Anyspecificprecautionstobeobserved,especiallyinregardtothesampling

ofsterileornoxiousmaterial.

5.60. ThereshouldbeanSOPdescribingthedetailsofthebatch(lot)numberingsystem,

withtheobjectiveofensuringthateachbatchofintermediate,bulkorfinished

productisidentifiedwithaspecificbatchnumber.

5.61. TheSOPsforbatchnumberingthatareappliedtotheprocessingstageandtothe

respectivepackagingstageshouldberelatedtoeachother.

5.62. TheSOPforbatchnumberingshouldensurethatthesamebatchnumberswillnotbe

usedrepeatedly;thisappliesalsotoreprocessing.

5.63. Batch-numberallocationshouldbeimmediatelyrecorded,e.g.inalogbook.The

recordshouldincludeatleastthedateofallocation,productidentityandsizeof

batch.

5.64. Thereshouldbewrittenproceduresfortestingmaterialsandproductsatdifferent

stagesofmanufacture,describingthemethodsandequipmenttobeused.Thetests

performedshouldberecorded.

5.65. Analysisrecordsshouldincludeatleastthefollowingdata:

a. Thenameofthematerialorproductand,whereapplicable,dosageform;

b. Thebatchnumberand,whereappropriate,themanufacturerand/or

supplier;

c. Referencestotherelevantspecificationsandtestingprocedures;

d. Testresults,includingobservationsandcalculations,andreferencetoany

specifications(limits);

e. Date(s)andreferencenumber(s)oftesting;

f. Theinitialsofthepersonswhoperformedthetesting;


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5 g. Thedateandinitialsofthepersonswhoverifiedthetestingandthe

calculations,whereappropriate;

h. Aclearstatementofreleaseorrejection(orotherstatusdecision)andthe

datedsignatureofthedesignatedresponsibleperson.

5.66. Writtenreleaseandrejectionproceduresshouldbeavailableformaterialsand

products,andinparticularforthereleaseforsaleofthefinishedproductbyan

authorizedperson.Allrecordsshouldbeavailabletotheauthorisedperson.Asystem

shouldbeinplacetoindicatespecialobservationsandanychangestocriticaldata.

5.67. Recordsshouldbemaintainedofthedistributionofeachbatchofaproductinorder,

e.g.tofacilitatetherecallofthebatchifnecessary.

5.68. Recordsshouldbekeptformajorandcriticalequipment,asappropriate,ofany

validations,calibrations,maintenance,cleaning,orrepairoperations,includingdates

andtheidentityofthepeoplewhocarriedouttheseoperations.

5.69. Theuseofmajorandcriticalequipmentandtheareaswhereproductshavebeen

processedshouldbeappropriatelyrecordedinchronologicalorder.

5.70. Logbooksshouldbekeptformajororcriticalanalyticaltesting,production

equipmentandareaswhereproducthasbeenprocessed.Theyshouldbeusedto

recordinchronologicalorder,asappropriate,anyuseofthearea,

equipment/method,calibrations,maintenance,cleaningorrepairoperations,

includingthedatesandidentityofpeoplewhocarriedouttheseoperations.

5.71. Thereshouldbewrittenproceduresassigningresponsibilityforcleaningand

sanitationanddescribinginsufficientdetailthecleaningschedules,methods,

equipmentandmaterialstobeusedandfacilitiesandequipmenttobecleaned.Such

writtenproceduresshouldbefollowed.

5.72. AninventoryofallSOPsandotherdocumentswithinthequalitymanagementsystem

shouldbemaintained.

5.73. Protocols:Thesegiveinstructionsforperformingandrecordingcertaindiscreet

operations.

5.74. Contracts:Thesearewrittenagreementsbetweencontractgiversandacceptorsfor

outsourcedactivities.

Record/Reporttype:

5.75. Records:Theseprovideevidenceofvariousactionstakentodemonstrate

compliancewithinstructions,e.g.activities,events,investigations,andinthecaseof

manufacturedbatchesahistoryofeachbatchofproduct,includingitsdistribution.

Recordsincludetherawdatawhichisusedtogenerateotherrecords.Forelectronic

recordsregulatedusersshoulddefinewhichdataaretobeusedasrawdata.Atleast,


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5alldataonwhichqualitydecisionsarebasedshouldbedefinedasrawdata.

LaboratoryRecords

5.76. Laboratoryrecordsshouldincludecompletedataderivedfromalltestsnecessaryto

ensurecompliancewithestablishedspecificationsandstandards,including

examinationsandassays,asfollows:

a. Adescriptionofthesamplereceivedfortestingwithidentificationofsource

(thatis,locationfromwheresamplewasobtained),quantity,batchnumberor

otherdistinctivecode,datesamplewastakenanddatesamplewasreceived

fortesting.

b. Astatementofeachmethodusedinthetestingofthesample.Thestatement

shouldindicatethelocationofdatathatestablishthatthemethodsusedinthe

testingof the samplemeetproper standardsof accuracyand reliability as

appliedtotheproducttested.Wherethemethodemployedisinthecurrent

editionofarecognizedstandardreference(e.g.BritishPharmacopoeia,United

States Pharmacopoeia, International Pharmacopoeia), and the referenced

methodisnotmodified,astatementindicatingthemethodandreferencewill

suffice.Thesuitabilityofalltestingmethodsusedshouldbeverifiedunder

actualconditionsofuse.

c. Astatementof theweightormeasureofsampleusedforeachtest,where

appropriate.

d. Acompleterecordofalldatasecuredinthecourseofeachtest,includingall

graphs, charts, and spectra from laboratory instrumentation, properly

identified to showthe specificmaterial,pharmaceuticalproduct container,

closure,in-processmaterial,orpharmaceuticalproduct,andbatchtested.

e. Arecordofallcalculationsperformedinconnectionwiththetest,including

unitsofmeasure,conversionfactors,andequivalencyfactors.

f. A statement of the results of tests and how the results compare with

establishedstandardsofidentity,strength,quality,andpurityforthematerial,

pharmaceutical product container, closure, in-process material, or

pharmaceuticalproducttested.

g. Theinitialsorsignatureofthepersonwhoperformseachtestandthedate(s)

thetestswereperformed.

h. Theinitialsorsignatureofasecondpersonshowingthattheoriginalrecords

have been reviewed for accuracy, completeness, and compliance with

establishedstandards.

5.77. Completerecordsofanymodificationofanestablishedmethodemployedintesting


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5 shouldbemaintained.Suchrecordsshouldincludethereasonforthemodificationanddatato

verifythatthemodificationproducedresultsthatareatleastasaccurateandreliablefor

thematerialbeingtestedastheestablishedmethod.

5.78. Complete records of all out-of-specification (OOS) and out-of -trend (OOT)

investigationsshouldbemaintained.

5.79. Completerecordsofanytestingandstandardizationoflaboratoryreferencestandards,

reagents,andstandardsolutionsshouldbemaintained.

5.80. Complete records of the periodic calibration of laboratory instruments, apparatus,

gauges,andrecordingdevicesshouldbemaintained.

5.81. CompleterecordsofallstabilitytestingperformedasdescribedinStabilityStudies

8.55to8.73shouldbemaintained.

Distributionrecords

5.82. Distributionrecordsshouldcontainthefollowing:

a. Name,strengthanddosageformoftheproduct

b. Descriptionofthedosageform,

c. Nameandaddressoftheconsignee,

d. Dateandquantityshipped,

e. Batchorcontrolnumberofthepharmaceuticalproduct.

f. DateofManufactureandExpirationdate.

5.83. CertificatesofAnalysis:Theseprovideasummaryoftestresultsonsamplesof

productsormaterialstogetherwiththeevaluationforcompliancetoastated

specification.

5.84. Alternativelythecertificationmaybebased,in-wholeorin-part,ontheassessmentof

realtimedata(summariesandexceptionreports)frombatchrelatedprocess

analyticaltechnology(PAT),parametersormetricsaspertheapprovedmarketing

authorisationdossier.

5.85. Reports:Thesedocumenttheconductofparticularexercises,projectsor

investigations,togetherwithresults,conclusionsandrecommendations.

SiteMasterFile(SMF):

Introduction

5.86. TheSiteMasterFile(SMF)isadocumentwhichdescribestheGMPrelatedactivities

ofthemanufacturerataparticularsite.

5.87. TheSMFispreparedbythepharmaceuticalmanufacturerandshouldcontainspecific


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informationaboutthequalitymanagementpoliciesandactivitiesofthesite,theproduction

and/orqualitycontrolofpharmaceuticalmanufacturingoperationscarriedoutatthe

namedsiteandanycloselyintegratedoperationsatadjacentandnearbybuildings.If

onlypartofapharmaceuticaloperationiscarriedoutonthesite,asitemasterfile

needsonlytodescribethoseoperations,e.g.analysis,packaging,etc.

5.88. WhensubmittedtotheAgency,theSMFshouldprovideclearinformationonthe

manufacturer'sGMPrelatedactivitiesthatcanbeusefulingeneralsupervisionandin

theefficientplanningandundertakingofGMPinspections.

5.89. Asitemasterfileshouldcontainadequateinformationbut,asfaraspossible,not

exceed25-30A4pagesplusappendices.Simpleplans,outlinedrawingsorschematic

layoutsarepreferredinsteadofnarratives.

5.90. TheSMFfileshouldbeapartofdocumentationbelongingtothequalitymanagement

systemofthemanufacturerandkeptupdatedaccordingly.TheSMFshouldhavean

editionnumber,thedateitbecomeseffectiveandthereviewdate.Itshouldbesubject

toregularreviewstoensurethatitisuptodateandrepresentativeofcurrent

activities.Eachappendixcanhaveanindividualeffectivedate,allowingfor

independentupdating.

ContentsofSiteMasterFile

5.91. TheSMFshouldcontainatleastthefollowing:

a. GeneralInformationontheManufacturer

i. Nameandofficialaddressofthemanufacturer;

ii. Namesandstreetaddressesofthesite,buildingsandproduction

unitslocatedonthesite;

iii. Phone(officeandmobile)numbersande-mailaddressofthe

manufacturer

iv. A24-hourtelephonenumber(s)ofthecontactpersonnelinthe

caseofproductdefectsorrecalls.

b. Authorizedpharmaceuticalmanufacturingactivitiesofthesite.

i. Abriefdescriptionofmanufacture,import,export,distribution

andotheractivitiesasauthorizedbytheAgencyincludingforeign

authoritieswithauthorizeddosageforms/activities,respectively;

wherenotcoveredbythemanufacturingauthorization.

ii. Typeofproductscurrentlymanufacturedon-sitewherenot

coveredbythemanufacturingauthorizationinAppendix1should

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iii. ListofGMPinspectionsofthesitewithinthelast5years;

includingdatesandname/countryoftheCompetentAuthority

havingperformedtheinspection.AcopyofthecurrentGMP

certificateshouldbeattachedasAppendix3ifavailable.

c. Anyothermanufacturingactivitiescarriedoutonthesite

i. Descriptionofnon-pharmaceuticalactivitieson-site,ifany.

QualityManagementSystemoftheManufacturer

5.92. Descriptionofthequalitymanagementsystem

a. Briefdescriptionofthequalitymanagementsystemsrunbythecompany

andreferencetothestandardsused(e.g.ICHQ10,ISO9001);

b. Responsibilitiesrelatedtothemaintainingofqualitysystemincludingtop

management;

c. Informationofactivitiesforwhichthesiteisaccreditedandcertified,

includingdatesandcontentsofaccreditations,namesofaccreditingbodies.

5.93. Releaseprocedureforfinishedproducts

a. Name(s)ofauthorisedperson(s)responsibleforbatchcertificationand

releaseprocedures

b. Detaileddescriptionofqualificationrequirements(educationandwork

experience)oftheauthorisedperson(s)responsibleforbatchcertification

andreleaseprocedures;

c. Generaldescriptionofbatchcertificationandreleaseprocedure;

d. Roleofauthorisedpersoninquarantineandreleaseoffinishedproducts

andinassessmentofcompliancewiththemarketingauthorization;

e. StatementonwhetherthecontrolstrategyemploysProcessAnalytical

Technology(PAT)and/orRealTimeReleaseorParametricRelease;

5.94. Managementofsuppliersandcontractors

a. Abriefsummaryoftheestablishment/knowledgeofsupplychainandthe

externalauditprogram;

b. Briefdescriptionofthequalificationsystemofcontractors,manufacturers

ofactivepharmaceuticalingredients(API)andothercriticalmaterials

suppliers;

c. Measurestakentoensurethatproductsmanufacturedarecompliantwith

TransmissibleSpongiformEncephalopathy(TSE)guidelines.


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d. Measuresadoptedwherecounterfeit/falsifiedproducts,bulkproducts(e.g.

unpackedtablets),activepharmaceuticalingredientsorexcipientsare

suspectedoridentified.

e. Useofoutsidescientific,analyticalorothertechnicalassistanceinrelation

tomanufactureandanalysis;

f. Listofcontractmanufacturersandlaboratoriesincludingtheaddressesand

contactinformationandflowchartsofsupply-chainsforoutsourced

manufacturingandQualityControlactivities;e.g.sterilizationofprimary

packagingmaterialforasepticprocesses,testingofstartingmaterialsetc.,

shouldbepresentedinAppendix4

g. Briefoverviewoftheresponsibilitysharingbetweenthecontractgiverand

acceptorwithrespecttocompliancewiththeMarketingAuthorization.

5.95. QualityRiskManagement(QRM)

a. BriefdescriptionofQRMmethodologiesusedbythemanufacturer;

b. ScopeandfocusofQRMincludingbriefdescriptionofanyactivitieswhich

areperformedatcorporatelevel,andthosewhichareperformedlocally.

AnyapplicationoftheQRMsystemtoassesscontinuityofsupplyshouldbe

mentioned;

5.96. ProductQualityReviews

a. Briefdescriptionofmethodologiesused

5.97. Personnel

a. Organizationalchartshowingthearrangementsforqualitymanagement,

productionandqualitycontrolpositions/titlesinAppendix5includingtop

managementandauthorizedperson.

b. Numberofemployeesengagedinthequalitymanagement,production,

qualitycontrol,storageanddistributionrespectively;

PremisesandEquipment

5.98. Premises

a. Shortdescriptionofplant;sizeofthesiteandlistofbuildings.Ifthe

productionfordifferentmarkets,i.e.forlocalandforeigncountriestakes

placeindifferentbuildingsonthesite,thebuildingsshouldbelistedwith

destinedmarketsidentified;

b. Simpleplanordescriptionofmanufacturingareaswithindicationofscale

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c. Lay-outsandflowchartsoftheproductionareas(inappendix6)showing

theroomclassificationandpressuredifferentialsbetweenadjoiningareas

andindicatingtheproductionactivities(i.e.compounding,filling,storage,

packaging,etc.)intherooms.;

d. Lay-outsofwarehousesandstorageareas,withspecialareasforthestorage

andhandlingofhighlytoxic,hazardousandsensitizingmaterialsindicated,

ifapplicable;

e. Briefdescriptionofspecificstorageconditionsifapplicable,butnot

indicatedonthelay-outs;

f. Briefdescriptionofheating,ventilationandairconditioning(HVAC)

systems

g. Principlesfordefiningtheairsupply,temperature,humidity,pressure

differentialsandairchangerates,policyofairrecirculation;

h. Briefdescriptionofwatersystems

i. Qualityreferencesofwaterproduced

j. Schematicdrawingsofthesystemsinappendix7

k. Briefdescriptionofotherrelevantutilities,suchassteam,compressedair,

nitrogen,etc.

5.99. Equipment

a. Listingofmajorproductionandcontrollaboratoryequipmentwithcritical

piecesofequipmentidentifiedshouldbeprovidedinappendix8.

5.100. PreventivemaintenanceandCalibration

a. Descriptionofpreventivemaintenanceandcalibrationsystem,

responsibilitiesandrecordingsystem

5.101. QualificationandValidation

a. Briefdescriptionofthecompany'sgeneralpolicyforqualificationand

validation

5.102. Cleaningandsanitation

a. Briefdescriptionofcleaningandsanitationmethodsofproductcontact

surfaces(i.e.manualcleaning,automaticClean-in-Place,etc.).

b. Cleaningvalidationpolicyofthecompanyandmethodofevaluationofthe

effectivenessofcleaning;principlesforestablishingallowableresidue

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c. Cleaningagentsandqualityofwaterusedforcleaning

d. Arrangementsforthehandlingofspillagesofpotent/toxicsubstances

whereapplicable

5.103. GMPcriticalcomputerizedsystems

a. DescriptionofGMPcriticalcomputerizedsystems(excludingequipment

specificProgrammableLogicControllers(PLCs)

5.104. Documentation

a. Descriptionofdocumentationsystem(i.e.electronic,manual);

b. Whendocumentsandrecordsarestoredorarchivedoff-site(including

pharmacovigilancedata,whenapplicable):Listoftypesof

documents/records;Nameandaddressofstoragesiteandanestimateof

timerequiredforretrievingdocumentsfromtheoff-sitearchive.

5.105. Production

a. Typeofproductsmanufacturedincludinglistofdosageformsofboth

humanandveterinaryproductswhicharemanufacturedonthe

site(appendices1and2)

b. ListofdosageformsofInvestigationalMedicinalProducts(IMP)

manufacturedforanyclinicaltrialsonthesite,andwhendifferentfromthe

commercialmanufacturing,informationofproductionareasandpersonnel

c. Toxicorhazardoussubstanceshandled(e.g.withhighpharmacological

activityand/orwithsensitizingproperties);

d. Producttypesmanufacturedinadedicatedfacilityoronacampaignbasis,if

applicable;

e. ProcessAnalyticalTechnology(PAT)applications,ifapplicable:general

statementoftherelevanttechnology,andassociatedcomputerizedsystems;

5.106. Processvalidation

a. Briefdescriptionofgeneralpolicyforprocessvalidation;

b. Policyforreprocessing;

5.107. Materialmanagementandwarehousing

a. Arrangementsforthehandlingofstartingmaterials,packagingmaterials,

bulkandfinishedproductsincludingsampling,quarantine,releaseand

storage

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5.108. QualityControl(QC)

a. Descriptionofthequalitycontrolactivitiescarriedoutonthesiteinterms

ofphysical,chemical,andmicrobiologicalandbiologicaltesting.

Distribution,Complaints,ProductDefectsandRecalls

5.109. Distribution(undertheresponsibilityofthemanufacturer)

a. Typesofcompanies(wholesalelicenceholders,establishmentlicence

holders,etc.)andlocations(withinNigeria,othercountriesetc.)towhich

theproductsareshippedfromthesite;

b. Descriptionofthesystemusedtoverifythateachcustomer/recipientis

legallyentitledtoreceivepharmaceuticalproductsfromthemanufacturer

c. Briefdescriptionofthesystemtoensureappropriateenvironmental

conditionsduringtransit,e.g.temperaturemonitoring/control;

d. Arrangementsforproductdistributionandmethodsbywhichproduct

traceabilityismaintained;

e. Measurestakentopreventmanufacturers'productsfromenteringthe

illegalsupplychain.

5.110. Complaints,productdefectsandrecalls

a. Briefdescriptionofthesystemforhandlingcomplaints,productdefectsand

recalls

5.111. Self-Inspections

b. Shortdescriptionoftheself-inspectionsystemwithfocusoncriteriaused

forselectionoftheareastobecoveredduringplannedinspections,practical

arrangementsandfollow-upactivities5.112. QualityManual:Adocumentproducedbyamanufacturerthatdetailshowits

qualitymanagementsystemoperates.5.113. Thisshouldcontainatleastthefollowing:

a. Qualitypolicyb. Qualityobjectivesc. Administrative structured. Organization and management e. Documentation and change controlf. Records g. Material management h. Production processesi. Laboratory controlj. Personnelk. Management review and internal auditl. Non-conformances/CAPAm. Complaints and recall


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n. Contract manufacturing and analysis o. Self-inspection

Appendix 1

Appendix 2

Appendix 3

Appendix 4

Appendix 5

Appendix 6

Appendix 7

Appendix 8

Copy of valid manufacturing authorization

List of dosage forms manufactured including the INN-names or common name (as available) of active pharmaceutical ingredients (API) used

List of contract manufacturers and laboratories including the addresses and contact information, and

-charts of the supply chains for these outsourced activities

Organizational charts

Lay outs of production areas including material and

processes of each product type (dosage form)

Schematic drawings of water systems

List of major production and laboratory equipment

Appendices


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CHAPTER

PRODUCTION6Principle

6.1. Productionoperationsmustfollowclearlydefinedprocedures;theymust

complywiththeprinciplesofgoodmanufacturingpracticeinordertoobtain

productsoftherequisitequalityandbeinaccordancewiththerelevant

manufacturingandmarketingauthorizations.

General

6.2. Productionshouldbeperformedandsupervisedbycompetentpersons.

6.3. Allhandlingofmaterialsandproducts,suchasreceiptandquarantine,

sampling,storage,labelling,dispensing,processing,packaging,releasingand

distributionshouldbedoneinaccordancewithwrittenproceduresor

instructionsandrecorded.

6.4. Anydeviationfrominstructionsorproceduresshouldbeavoidedasfaras

possible.Ifdeviationsoccur,theyshouldbedoneinaccordancewithan

approvedprocedure.Theauthorizationofthedeviationshouldbeapproved

inwritingbyadesignatedperson,withtheinvolvementofthequalityunit.

6.5. Allincomingmaterialsshouldbecheckedtoensurethattheconsignment

correspondstotheorder.Containersshouldbecleanedwherenecessaryand

labelledwiththeprescribeddata.

6.6. Damagetocontainersandanyotherproblemwhichmightadverselyaffect

thequalityofamaterialshouldbeinvestigated,recordedandreportedtothe

qualityunit.

6.7. Incomingmaterialsandfinishedproductsshouldbephysicallyor

administrativelyquarantinedimmediatelyafterreceiptorprocessing,until

theyhavebeenreleasedforuseordistribution.

6.8. Intermediateandbulkproductspurchasedassuchshouldbehandledon

receiptasthoughtheywerestartingmaterials.

6.9. Allmaterialsandproductsshouldbestoredundertheappropriate

conditionsestablishedbythemanufacturerandinanorderlyfashionto

permitbatchsegregationandstockrotation.

6.10. Checksonyields,andreconciliationofquantities,shouldbecarriedoutas


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necessarytoensurethattherearenodiscrepanciesoutsideacceptablelimits.

6.11. Operationsondifferentproductsshouldnotbecarriedoutsimultaneously

orconsecutivelyinthesameroomorarea.

6.12. Ateverystageofprocessing,productsandmaterialsshouldbeprotected

frommicrobialandothercontaminations.

6.13. Whenworkingwithdrymaterialsandproducts,specialprecautionsshould

betakentopreventthegenerationanddisseminationofdust.Provision

shouldbemadeforproperaircontrol(e.g.supplyandextractionofairof

suitablequality).Thisappliesparticularlytothehandlingofhighlyactiveor

sensitizingmaterials.

6.14. Atalltimesduringprocessing,allmaterials,bulkcontainers,majoritemsof

equipment,theroomsandpackaginglinesbeingusedshouldbelabelledor

otherwiseidentifiedwithanindicationoftheproductormaterialbeing

processed,itsstrengthandthebatchnumber.Whereapplicable,this

indicationshouldalsomentionthestageofproduction.Itisimportantto

alsorecordthenameofthepreviousproductthathasbeenprocessed.

6.15. Labelsappliedtocontainers,equipmentorpremisesshouldbeclear,

unambiguousandinthecompany'sagreedformat.Itisoftenhelpfulin

additiontothewordingonthelabelstousecolourstoindicatestatus(for

example,quarantined,accepted,rejected,cleanetc.).

6.16. Checksshouldbecarriedouttoensurethatpipelinesandotherpiecesof

equipmentusedforthetransportationofproductsfromoneareatoanother

areconnectedinacorrectmanner.

6.17. Accesstoproductionpremisesshouldberestrictedtoauthorizedpersonnel.

6.18. Theproductionoftoxicnon-pharmaceuticalproductsshouldnotbecarried

outinplantsmeantfortheproductionofpharmaceuticalproducts.

6.19. In-processcontrolsshouldbeperformedwithintheproductionarea.The

performanceofsuchin-processcontrolsshouldnothaveanynegativeeffect

onthequalityoftheproductoranotherproduct(e.g.cross-contaminationor

mixup).

Preventionofcross-contaminationinproduction

6.20. Contaminationofastartingmaterialorofaproductbyanothermaterialor

productmustbeavoided.Thisriskofaccidentalcross-contaminationarises

fromtheuncontrolledreleaseofdust,gases,particles,vapours,spraysor

organismsfrommaterialsandproductsinprocess,fromresidueson


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equipment,fromintrudinginsects,andfromoperators'clothing,skin,etc.The

significanceofthisriskvarieswiththetypeofcontaminantandofthe

productbeingcontaminated.Amongthemosthazardouscontaminantsare

highlysensitizingmaterials,biologicalpreparationssuchaslivingorganisms,

certainhormones,cytotoxicsubstances,andotherhighlyactivematerials.

Theseshouldbemanufacturedindedicatedfacilities.Productsinwhich

contaminationislikelytobemostsignificantarethoseadministeredby

injectionorappliedtoopenwoundsandthosegiveninlargedosesand/or

overalongtime.

6.21. Atoxicologicalevaluationshouldbethebasisfortheestablishmentof

thresholdvaluesinrelationtotheproductsmanufactured.Wherethe

toxicologicalevaluationsupportsathresholdvalue,thisshouldbeusedasan

inputparameterinriskassessment.Aqualityriskmanagementapproach

shouldbeusedbasedonthistoxicologicalevaluationandthepotentialcross

contaminationriskspresentedbytheproductsmanufactured.Factors

includingfacility/equipmentdesign,personnelflow,physicochemical

characteristicsoftheactivesubstance,processcharacteristics,cleaning

processesandanalyticalcapabilitiesrelativetothethresholdvaluesfor

productsshouldalsobetakenintoaccount.Theoutcomeofthequalityrisk

managementprocessshouldbethebasisfordeterminingthenecessityfor

andextenttowhichequipmentandfacilitiesshouldbededicatedtoa

particularproductorproductfamily.Thismayrangefromdedicating

specificproductcontactpartstodedicationoftheentiremanufacturing

facility.Itmaybeacceptabletoconfinemanufacturingactivitiestoa

segregated,self-containedproductionareawithinamultiproductfacility,

wherejustified.

6.22. Technicalandorganizationalmeasurestomitigaterisksofcross-

contaminationcouldinclude,butarenotlimitedto,thefollowing:

TechnicalMeasures

a. Dedicatedmanufacturingfacilities;productionindedicatedfacilities

isrequiredforproductssuchasβ-lactams,livevaccines,livebacteria

preparationsandsomeotherbiologics

b. Self-contained production areas having separate processing

equipmentandseparateHVACsystems. Itmayalsobedesirableto

isolatecertainutilitiesfromthoseusedinotherareas.

c. Designofmanufacturingprocess,facilityandequipmenttominimize

opportunities for cross contamination during processing,

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d. Useof“closedsystems”forprocessingandmaterial/producttransfer

betweenequipment,

e. Useofphysicalbarriersystems,includingisolators,ascontainment

measures

f. Controlled removal of dust close to source of the contaminant e.g.

throughlocalisedextraction

g. Dedicationofprocessing equipment, dedicationofproduct contact

partsordedicationofselectedpartswhicharehardertoclean(e.g.

filters),dedicationofmaintenancetools

h. Useofdisposabletechnologies

i. Useofequipmentdesignedforeaseofcleaning

j. Appropriateuseofairlocksandpressurecascadetoconfinepotential

airbornecontaminantswithinaspecifiedarea

k. Minimizingtheriskofcontaminationcausedbyrecirculationorre-

entryofuntreatedorinsufficientlytreatedair

l. Useofautomaticclean-in-placesystemsofvalidatedeffectiveness,

m. Forcommongeneralwashareas,separationofequipmentwashing,

dryingandstorageareas,

OrganizationalMeasures

a. Dedicating the whole manufacturing facility or a self-contained

productionareaonacampaignbasis(dedicatedbyseparationintime)

followedbyacleaningprocessofvalidatedeffectiveness,

b. Keepingprotective clothing insideareaswhereproductswithhigh

riskofcrosscontaminationareprocessed,

c. Cleaning verification after each product campaign instead of a

cleaning validation should be considered as a detectability tool to

supporteffectivenessofthequalityriskmanagementapproach,

d. Cleaningofworking areas and surfaces followedby executionof a

comprehensivesamplingprotocolforcriticalsurfaces

e. Useofairsamplesandwipe/swabsamplestakeninadjoiningareas

outsidetheworkingareatodemonstratetheefficiencyofmitigation

measuresforairborneandmechanicaltransferofcontaminant,

f. Specificmeasuresforwastehandling,contaminatedrinsingwaterand

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g. Recordingofspills,accidentaleventsordeviationsfromprocedures

h. Design of cleaning processes for manufacturing equipment and

buildingfacilitiessuchthatthecleaningprocessesinthemselvesdo

notpresentacrosscontaminationrisk.

i. Designofdetailedrecordsforcleaningprocessestoassurecompletion

of cleaning in accordance with approved procedures and use of

cleaningstatuslabelsonequipmentandmanufacturingareas,

j. Useofcommongeneralwashareasonacampaignbasis.

k. Monitoringofworkingbehaviourtoensuretrainingeffectivenessand

compliancewiththerelevantproceduralcontrols.

6.23. Productionareaswheresusceptibleproductsareprocessedshouldundergo

periodicenvironmentalmonitoring(e.g. formicrobiologicalmonitoringand

particulatematterwhereappropriate).

6.24. Periodicchecksofeffectivenessofmeasurestopreventcross-contamination

accordingtosetprocedures.

Validation

1. Whenanynewmanufacturingformulaormethodofpreparationisadopted,

stepsshouldbetakentodemonstrateitssuitabilityforroutineprocessing.

Thedefinedprocess,usingthematerialsandequipmentspecified,shouldbe

showntoyieldaproductconsistentlyoftherequiredquality.

2. Significantamendmentstothemanufacturingprocess,includinganychange

inequipmentormaterials,whichmayaffectproductqualityand/orthe

reproducibilityoftheprocess,shouldbevalidated.

3. Processesandproceduresshouldundergoperiodiccriticalre-validationto

ensurethattheyremaincapableofachievingtheintendedresults.

Equipmentidentification

6.25. All compounding and storage containers, processing lines, and major

equipmentusedduringtheproductionofabatchofapharmaceuticalproduct

shouldbeproperlyidentifiedatalltimestoindicatetheproductormaterial

being processed, its strength (where applicable) batch number and, when

necessary,thephaseofprocessingofthebatch.

6.26. Majorequipmentshouldbeidentifiedbyadistinctiveidentificationnumberor

code that should be recorded in the batch production record to show the

specificequipmentusedinthemanufactureofeachbatchofapharmaceutical

product.


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Charge-inofmaterials

6.27. Standard operating production and control procedures that describe the

following, are designed to ensure that the pharmaceutical products

manufacturedhavetheidentity,strength,quality,andpurityspecificationsfor

theintendedusetheypurportorarerepresentedtopossess:

a. Thebatchshouldbeformulatedwiththe intenttoprovidenot less

than 100 per cent of the labelled or established amount of active

ingredient.

b. Materials for pharmaceutical product manufacturing should be

weighed,measured,orsubdividedasappropriate.Whereamaterialis

removed fromtheoriginalcontainer toanother, thenewcontainer

shouldbeidentifiedwiththefollowinginformation:

i. Materialnameoritemcode;

ii. Receivingorcontrolnumber;

iii. Weightormeasureinnewcontainer;

iv. Batchforwhichmaterialwasdispensed,includingitsproduct

name,strength,andlotnumber.

c. Weighing,measuring,orsubdividingoperationsformaterialsshould

be adequately supervised.Each containerofmaterial dispensed to

manufacturingshouldbeexaminedbyasecondpersontoensurethat:

i. Thematerialwasreleasedbythequalitycontrolunit;

ii. The weight or measure is correct as stated in the batch

productionrecords;

iii. Thecontainersareproperlyidentified.

d. Eachmaterialshouldbeaddedtothebatchbyonepersonandverified

byasecondperson.

e. Theidentificationofpersonnelperformingeachstepoftheprocess

andofthepersonwhocheckedeachofthesestepsshouldbeclearly

stated.

Calculationofyield

6.28. Actualyieldsandpercentagesoftheoreticalyieldshouldbedeterminedatthe

conclusionofeachappropriatephaseofmanufacturing,processing,packaging,

or holding of the pharmaceutical product. Such calculations should be

performed by one person and independently verified by a second person.

DeviationfromvalidatedyieldrangeshouldbetreatedasdescribedinChange


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Control6.39to6.41.

Samplingandtestingofin-processmaterialsandpharmaceuticalproducts

6.29. Toensurebatchuniformityandintegrityofpharmaceuticalproducts,standard

operating procedures that describe the in-process controls and tests, or

examinationstobeconductedonappropriatesamplesofin-processmaterials

of eachbatch shouldbeestablishedand followed.Suchcontrolprocedures

shouldbeestablishedtomonitortheoutputandtovalidatetheperformanceof

thosemanufacturingprocessesthatmayberesponsibleforcausingvariability

inthecharacteristicsofin-processmaterialandthepharmaceuticalproduct.

6.30. Valid in-process specifications should be consistent with pharmaceutical

productfinalspecificationsandshouldbederivedfrompreviousacceptable

process average and process variability estimates where possible and

determined by the application of suitable statistical procedures where

appropriate. Examination and testing of samples should ensure that the

pharmaceuticalproductandin-processmaterialconformtospecifications.

6.31. In-processmaterialsshouldbetestedforidentity,strength,quality,andpurity

asappropriate,andapprovedorrejectedbythequalitycontrolunit,duringthe

production process, for example, at commencement or completion of

significantphasesorafterstorageforlongperiods.

6.32. Rejected in-process materials should be identified and controlled under a

quarantine system designed to prevent their use in manufacturing or

processingoperationsforwhichtheyareunsuitable.

Timelimitationsonproduction

6.33. Whenappropriate,timelimitsforthecompletionofeachphaseof

productionshouldbeestablishedtoensurethequalityofthepharmaceutical

product.

6.34. Deviationsfromestablishedtimelimitsmaybeacceptablewheresuch

deviationsdonotcompromisethequalityofthepharmaceuticalproduct.

Suchdeviationsshouldbejustifiedanddocumented.

Controlofmicrobiologicalcontamination

6.35. Standardoperatingproceduresdesignedtopreventobjectionablemicro-

organismsinpharmaceuticalproductsnotrequiredtobesterile,shouldbe

establishedandfollowed.

6.36. Standardoperatingproceduresdesignedtopreventmicrobiological

contaminationofpharmaceuticalproductspurportingtobesterile,should


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beestablishedandfollowed.Suchproceduresshouldincludevalidationofany

sterilizationprocess.

Reprocessing

6.37. Standardoperatingproceduresprescribingasystemforreprocessing

batchesthatdonotconformtostandardsorspecificationsandthestepsto

betakentoensurethatthereprocessedbatcheswillconformtoall

establishedstandards,specifications,andcharacteristicsshouldbe

establishedandfollowed.

6.38. Reprocessingshouldnotbeperformedwithoutthereviewandapprovalof

thequalityunit.

Changecontrol

6.39. Aformalchangecontrolsystemshouldbeestablishedtoevaluateallchanges

thatmayaffecttheproductionandcontrolofthepharmaceuticalproduct,

intermediateorAPI

6.40. Writtenproceduresshouldprovidefortheidentification,documentation,

appropriatereview,andapprovalofchangesinrawmaterials,specifications,

analyticalmethods,facilities,supportsystems,equipment(including

computerhardware),processingsteps,labellingandpackagingmaterials,

computersoftware.

6.41. AnyproposalsforGMP-relevantchangesshouldbedrafted,reviewed,and

approvedbytheappropriateorganizationalunitandreviewedandapproved

bythequalityunit.

Packagingandlabellingcontrol

Materialexaminationandusagecriteria

6.42. Standard operating procedures describing in sufficient detail the receipt,

identification, storage, handling, sampling, examination, and/or testing of

labellingandpackagingmaterialsshouldbeestablishedandfollowed.

6.43. Labellingandpackagingmaterialsshouldberepresentativelysampled,and

examinedortesteduponreceiptandbeforeuseinpackagingorlabellingofa

pharmaceuticalproduct.

6.44. Any labelling or packaging material meeting appropriate written

specifications may be approved and released for use. Any labelling or

packagingmaterialthatdoesnotmeetsuchspecificationsshouldberejectedto

preventtheiruseinoperationsforwhichtheyareunsuitable.

6.45. Recordsofeachdifferentlabellingandpackagingmaterialindicatingreceipt,


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examinationortesting,andwhetheracceptedorrejectedshouldbemaintainedforeach

shipmentreceived.

PackagingMaterials

6.46. Containersshouldprovideadequateprotectionagainstdeteriorationor

contaminationoftheintermediate,APIorfinishedpharmaceuticalproduct

thatmayoccurduringtransportationandrecommendedstorage.

6.47. Containersshouldbecleanand,whereindicatedbythenatureofthe

intermediate,APIorfinishedpharmaceuticalproduct,sanitizedtoensure

thattheyaresuitablefortheirintendeduse.

6.48. Thesecontainersshouldnotbereactive,additive,adsorptiveorabsorptive

soastoalterthequalityoftheintermediate,APIorfinishedpharmaceutical

productbeyondthespecifiedlimits.

LabelIssuanceandControl

6.49. Labelsandotherlabellingmaterialsforeachdifferentpharmaceuticalproduct,

strength,dosageform,orquantityofcontentsshouldbestoredseparatelyand

securelywithsuitableidentification.

6.50. Obsoleteandout-datedlabels,labelling,andotherpackagingmaterialsshould

bedestroyed.

6.51. Use of gang printing of labelling for different pharmaceutical products or

different strengths or net contents of the same pharmaceutical product, is

prohibited..

6.52. Wherecutlabellingisused,packagingandlabellingoperationsshouldinclude

oneofthefollowingspecialcontrolprocedures:

a. Dedicationoflabellingandpackaginglinestoeachdifferentstrength

ofeachdifferentpharmaceuticalproduct.

b. Use of appropriate electronic or electromechanical equipment to

conducta100percentexamination forcorrect labellingduringor

aftercompletionoffinishingoperations;or

c. Useofvisual inspectiontoconducta100percentexamination for

correctlabellingduringoraftercompletionoffinishingoperationsfor

hand-appliedlabelling.Suchexaminationshouldbeperformedbyone

personfornotmorethan30minutesateachsittingandindependently

verifiedbyasecondperson.

6.53. Printing devices on/or associated with manufacturing lines used to

imprint/overprint labelling upon the pharmaceutical product unit label or

caseshouldbemonitoredtoensurethatallimprinting/overprintingconform


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6totheprintspecifiedinthebatchproductionrecord.

6.54. Proceduresshouldbeusedtoreconcilethequantitiesoflabelsissued,used,

and returned and to evaluate discrepancies found between the number of

containerslabelledandthenumberoflabelsissued.Suchdiscrepanciesshould

beinvestigated,documentedandapprovedbythequalityunit.

6.55. Allexcesslabellingbearinglotorcontrolnumbersshouldbedestroyed.

6.56. Returnedlabellingshouldbemaintainedandstoredinamannertoprevent

mix-upsandprovideproperidentification.

Packagingandlabellingoperations

6.57. Standard operating procedures designed to ensure that correct labels,

labelling, and packaging materials are used for pharmaceutical products

shouldbeestablishedandfollowed.Theseproceduresshouldincorporatethe

followingfeatures:

a. Designstopreventmix-upsandcross-contaminationbyphysicalor

spatial separation from operations involving other pharmaceutical

products.

b. Identification and handling of filled pharmaceutical product

containers that are set aside andheld in unlabelled conditions for

future labelling operations to preclude mislabelling of individual

containers,batches,orportionsofbatches.Identificationneednotbe

applied to each individual container but should be sufficient to

determinename,strength,quantityofcontents,andbatchorcontrol

numberofeachcontainer.

c. Identification of the pharmaceutical product with a lot or control

numberthatpermitsdeterminationofthehistoryofthemanufacture

andcontrolofthebatch.

d. Examinationofpackagingandlabellingmaterialsforsuitabilityand

correctnessbeforepackagingoperations,anddocumentationofsuch

examinationinthebatchproductionrecord.

e. Inspectionofthepackagingandlabellingfacilitiesimmediatelybefore

use toensure thatallpharmaceuticalproductshavebeenremoved

frompreviousoperations.Inspectionshouldalsobemadetoensure

that packaging and labellingmaterials not suitable for subsequent

operations have been removed. Results of inspection should be

documentedinthebatchproductionrecords.

6.58. Marketingauthorisationholdersforpharmaceuticalproductsshouldobtain

approvalfromtheAgencyforchangesinpackagingandlabelling.


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6 Tamper-resistantpackaging

6.59. A pharmaceutical product that has tamper- resistant packaging should be

designed to remain intact when handled in a reasonable manner during

manufacture,distributionandretail.

6.60. Thereshouldbeastatementthatisprominentlyplacedsothatconsumersare

alertedtothespecifictamper-resistantfeatureofthepackage

6.61. Thetamper-resistantlabellingshouldbesoplacedthatitwillbeunaffected

wherethetamper-resistantfeatureofthepackageisbreachedormissing.

6.62. Toreducethelikelihoodofsuccessfultamperingandtoincreasethelikelihood

that consumers will discover where a product has been tampered with,

tamper-resistant packaging should not be easily duplicated by the use of

commonly available materials or through use of commonly available

processes.

Expirationdating

6.63. To ensure that a pharmaceutical product meets applicable standards of

identity, strength, quality, and purity at the time of use, it should bear an

expirationdatedeterminedbyappropriatestabilitytesting.

6.64. Expirationdates shouldbe related to any storage conditions statedon the

labelling,asdeterminedbystabilitystudies.

6.65. Where the pharmaceutical product is to be reconstituted at the time of

dispensing, its labelling should bear expiration information for both the

reconstitutedandun-reconstitutedpharmaceuticalproducts.

6.66. ExpirationdatesshouldappearonlabellinginaccordancewiththeNAFDAC

DrugLabellingRegulations.

Pharmaceuticalproductinspection

6.67. Packaged and labelled products should be examined during finishing

operations toprovideassurance that containersandpackages in thebatch

havethecorrectlabel.

6.68. A representative sample of units should be collected at the completion of

operationsandshouldbevisuallyexaminedforcorrectlabelling.

6.69. Resultsoftheseexaminationsshouldberecordedinthebatchproductionor

controlrecords.

Productionrecordreview

6.70. Allpharmaceuticalproductmanufactureandcontrolrecords,includingthose

forpackagingandlabelling,shouldbereviewedandapprovedbythequality


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CHAPTER

MATERIALSMANAGEMENT7

Principle

7.1. Themainobjectiveofapharmaceuticalplantistoproducefinishedproducts

forpatients'usefromacombinationofmaterials(startingandpackaging).

Materialsincludestartingmaterials,intermediateandbulk,packaging

materials,gases,solvents,processaids,reagents,labellingmaterialsand

finishedproducts.

General

7.2. Nomaterialsusedforoperationssuchascleaning,lubricationofequipment

andpestcontrolshouldcomeintodirectcontactwiththeproduct.Where

possible,suchmaterialsshouldbeofasuitablegrade(e.g.foodgrade)to

minimizehealthrisks.

7.3. Allincomingmaterialsandfinishedproductsshouldbequarantined

immediatelyafterreceiptorprocessing,untiltheyhavebeensampled,

examinedortested,asappropriateandarereleasedforuseordistribution.

7.4. Allmaterialsandproductsshouldbestoredundertheappropriate

conditionsestablishedbythemanufacturer,andinanorderlyfashion,to

permitbatchsegregationandstockrotationbyafirst-expire,first-outrule

(FEFO).

7.5. Waterusedinthemanufactureofpharmaceuticalproductsshouldbe

suitableforitsintendeduse.

7.6. Thereshouldbewrittenproceduresdescribinginsufficientdetailthe

receipt,identification/internallabelling,storage,handling,sampling,testing,

andapprovalorrejectionofstartingmaterialsandpackagingmaterials;such

writtenproceduresshouldbefollowed.

Suppliers'auditsandapproval

7.7. Thepersonresponsibleforqualityassuranceshouldhaveresponsibility

togetherwithotherrelevantdepartmentsforapprovingsupplierswhocan

reliablysupplystartingandpackagingmaterialsthatmeetestablished

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7.8. Beforesuppliersareapprovedandincludedintheapprovedlistofsuppliers

orspecifications,theyshouldbeevaluated.Theapprovalprocessshould

clearlydefineidentity,locationaddressandGMPlevelofthemanufacturerof

thematerial.

7.9. Theprocessshoulddefineminimumacceptableconditionsforapproval.

Agentsandsuppliersinthesupplychainshouldbeidentifiableandtheir

activitiesshouldbeadequatelycontrolled,soasnottojeopardizethe

identity,performanceorqualityofthematerial.

7.10. Theevaluationshouldtakeintoaccountasupplier'shistoryandthenature

ofthematerialstobesupplied.Ifanauditisrequired,itshoulddetermine

thesupplier'sabilitytoconformwithGMPstandards.

Startingmaterials

7.11. Thepurchaseofstartingmaterialsisanimportantoperationthatshould

involvestaffwhohaveparticularandthoroughknowledgeoftheproducts

andsuppliers.

7.12. Startingmaterialsshouldbepurchasedonlyfromapprovedsuppliersand,

wherepossible,directlyfromtheproduceragainstanagreedspecification.It

isalsorecommendedthatthespecificationsestablishedbythemanufacturer

forthestartingmaterialsbediscussedwiththesuppliers.Itisbeneficialfor

allcriticalaspectsoftheproductionandcontrolofthestartingmaterialin

question,includinghandling,labellingandpackagingrequirementsaswell

ascomplaintsandrejectionprocedures,tobecontractuallyagreedbetween

themanufacturerandthesupplier.

7.13. Wherethesupplierofacriticalmaterialisnotthemanufacturerofthat

material,thenameandaddressofthelattershouldbeknownbythefinished

productmanufacturer.

7.14. Changesinmaterialsorthesourceofsupplyofrawmaterialsshouldbe

handledthroughtheformalchangecontrolsystemofthemanufacturerto

evaluatetheeffectofthechangeontheproductquality.

7.15. Thereshouldbewrittenproceduresandrecordsforthereceiptofeach

deliveryofeachstartingmaterial.

7.16. Foreachconsignment,ataminimum,thecontainersshouldbecheckedat

leastforintegrityofpackageandsealandforcorrespondencebetweenthe

order,thedeliverynote,andthesupplier'slabels.

7.17. Allincomingmaterialsshouldbecheckedtoensurethattheconsignment


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7correspondstotheorder.Containersshouldbecleanedwherenecessaryand

labelled,ifrequired,withtheprescribedinformation.Whereadditional

labelsareattachedtocontainers,theoriginalinformationshouldnotbelost.

7.18. Damagetocontainersandanyotherproblemthatmightadverselyaffectthe

qualityofamaterialshouldberecordedandreportedtothequalityunitand

investigated.

7.19. Ifonedeliveryofmaterialismadeupofdifferentbatches,eachbatchmust

beconsideredasseparateforsampling,testingandrelease.

7.20. Baggedorboxedmaterialsshouldnotbestoredonthefloorandshouldbe

suitablyspacedtopermitcleaningandinspection.

7.21. Startingmaterialsinthestorageareashouldbeappropriatelylabelled.

7.22. Labelsshouldbearatleastthefollowinginformation:

a. Thedesignatednameoftheproductandtheinternalcodereference

whereapplicable;

b. Thebatchnumbergivenbythesupplierand,onreceipt,thecontrol

orbatchnumbergivenbythemanufacturer,ifany,documentedso

astoensuretraceability;

c. Thestatusofthecontents(e.g.inquarantine,ontest,released,

rejected,returned,recalled);

d. Anexpirydateandaretestdate(withintheshelflifeofthematerial)

whereapplicable.Whenfullyvalidatedcomputerizedstorage

systemsareused,notalloftheaboveinformationneedbeina

legibleformonthelabel.

7.23. Thereshouldbewrittenproceduresforsampling,whichincludethe

person(s)authorisedtotakesamples,themethodsandequipmenttobe

used,theamountstobetakenandanyprecautionstobeobservedtoavoid

contaminationofthematerialoranydeteriorationinitsquality.

7.24. Representativesamplesofeachshipmentofeachbatchshouldbecollected

fortesting.

7.25. Samplingmethodsshouldspecifythenumberofcontainerstobesampled,

whichpartofthecontainertosample,andtheamountofmaterialtobe

takenfromeachcontainer.Thesamplingmethodshouldbebasedon

appropriatecriteriasuchas:

a. Statisticalcriteria(variability,confidencelevels,degreeofprecision

desired)

b. Criticalityofthematerial,


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7 c. Pastqualityhistoryofthesupplier,

d. QuantityneededforanalysisandretentionasdescribedinSampling

8.15to8.29.

7.26. Samplesshouldbecollectedinaccordancewiththefollowingprocedures:

a. The containers of materials selected should be cleaned where

necessary,byappropriatemeans.

b. Thecontainersshouldbeopened,sampled,andresealedinamanner

designed to prevent contamination of their contents and

contaminationofothermaterials.

c. Sterileequipmentandaseptic sampling techniquesshouldbeused

whennecessary.

d. Whereitisnecessarytosampleamaterialfromthetop,middle,and

bottom of its container, such sample subdivisions should not be

compositedfortesting.

e. Sample containers should be identified so that the following

informationcanbedetermined:

i. Nameofthematerialsampled

ii. Thebatchnumber

iii. Thecontainerfromwhichthesamplewastaken

iv. Thedateonwhichthesamplewastaken

v. The name and signature of the person who collected the

sample.

f. Samplingshouldbeconductedatdefinedlocationsandbyprocedures

designed to prevent contamination of the material sampled and

contaminationofothermaterials.

g. Containers from which samples are withdrawn should be opened

carefully and subsequently re-closed. They should be marked to

indicatethatasamplehasbeentakenfromthem.

7.27. Samplesshouldbeexaminedandtestedasfollows:

a. Tests should be conducted to verify the identity of eachmaterial.

Specificidentitytests,wheretheyexist,shouldbeused.

b. Eachmaterial shouldbe tested forconformitywithallappropriate

writtenspecificationsforpurity,strengthandquality.Inlieuofsuch


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7testingby themanufacturer,a reportofanalysismaybeaccepted fromthe

supplierofamaterial,providedthatatleastonespecificidentitytest

isconductedonsuchmaterialbythemanufacturerandprovidedthat

themanufacturerestablishesthereliabilityofthesupplier'sanalyses

through appropriate validation of the supplier's test results at

appropriateintervals.

c. Containers and closures should be tested for conformance with

appropriatestandardoperatingprocedures.Inlieuofsuchtestingby

themanufacturer,acertificateof testingmaybeaccepted fromthe

supplier,providedthatatleastavisualidentificationisconductedon

suchcontainers/closuresbythemanufacturerandprovidedthatthe

manufacturerestablishesthereliabilityofthesupplier'stestresults

through appropriate validation of the supplier's test results at

appropriateintervals.

d. Whenappropriate,materialsshouldbemicroscopicallyexamined.

e. Eachbatchofmaterialthatisliabletocontaminationwithfilth,insect

infestation, or other extraneous adulterant should be examined

againstestablishedspecificationsforsuchcontamination.

f. Eachbatchofmaterialthatisliabletomicrobiologicalcontamination

thatisobjectionableinviewofitsintendeduseshouldbesubjectedto

microbiologicaltestsbeforeuse.

g. Any batch of material that meets the appropriate written

specifications of identity, strength, quality, purity and related tests

may be approved and released for use in accordancewithwritten

procedures. Any batch of such material that does not meet such

specificationsshouldberejectedasspecifiedinwrittenprocedures.

7.28. Onlystartingmaterialsreleasedbythequalityunitandwithintheirshelf-life

shouldbeused.

7.29. Materialsapprovedforuseshouldberotatedsothattheoldestapproved

stockisusedfirst.Deviationfromthisrequirementisonlypermittedwhere

suchdeviationistemporaryandappropriate.

7.30. Materialsshouldberetestedorre-examined,asappropriatewithintheshelf-

lifeofthematerial,foridentity,strength,quality,andpurityandapprovedor

rejectedbyqualitycontrolasnecessary,forexample,afterstorageforlong

periodsorafterexposuretoair,heatorotherconditionsthatmight

adverselyaffectthematerial.

7.31. Startingmaterialsshouldbedispensedonlybydesignatedperson(s),


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7 followingawrittenprocedure,toensurethatthecorrectmaterialsareaccurately

weighedormeasuredintocleanandproperlylabelledcontainers.

7.32. Eachdispensedmaterialanditsweightorvolumeshouldbeindependently

checkedandthecheckrecorded.

7.33. Materialsdispensedforeachbatchofthefinalproductshouldbekept

togetherandconspicuouslylabelledassuch.

7.34. Thereshouldbewrittenproceduresfortestingmaterialsandproductsat

differentstagesofmanufacture,describingthemethodsandequipmenttobe

used.Thetestsperformedshouldberecorded.

7.35. Allhandlingofmaterialsandproducts,suchasreceipt,quarantine,sampling,

storage,labellingetc.shouldbedoneinaccordancewithwrittenprocedures

orinstructionsandrecorded.

7.36. Atalltimesduringprocessing,allmaterialsandbulkcontainers,shouldbe

labelledwiththeidentityoftheproductormaterialbeingprocessed,its

strength(whereapplicable)andbatchnumber.

7.37. Labelsappliedtocontainers,equipmentorpremisesshouldbeclear,

unambiguousandinthecompany'sagreedformat.Itisoftenhelpfulin

additiontothewordingonthelabelstousecolourstoindicatestatus(for

example,quarantined,approved,rejected,cleanetc.).

Packagingmaterials

7.38. Thepurchase,handlingandcontrolofprimaryandprintedpackaging

materialsshouldbeasforstartingmaterials.

7.39. Particularattentionshouldbepaidtoprintedpackagingmaterials.They

shouldbestoredinsecureconditionssoastoexcludethepossibilityof

unauthorizedaccess.Rollfeedlabelsshouldbeusedwhereverpossible.Cut

labelsandotherlooseprintedmaterialsshouldbestoredandtransportedin

separateclosedcontainerssoastoavoidmixups.Packagingmaterials

shouldbeissuedforuseonlybydesignatedpersonnelfollowinganapproved

anddocumentedprocedure.

7.40. Eachdeliveryorbatchofprintedorprimarypackagingmaterialshouldbe

givenaspecificreferencenumberoridentificationmark.

7.41. Out-datedorobsoleteprimarypackagingmaterialorprintedpackaging

materialshouldbedestroyedinlinewiththeAgency'srequirementsandits

disposalrecorded.


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77.42. Allpackagingmaterialstobeusedshouldbecheckedondeliverytothe

packagingdepartmentforquantity,identityandconformitywiththe

packaginginstructions.

7.43. Packagingmaterialsshouldprovideadequateprotectionagainstforeseeable

externalfactorsinstorageandusethatcancausedeteriorationor

contaminationoftheintermediate,APIorfinishedpharmaceuticalproduct

orthatmayoccurduringtransportation.

7.44. Thesecontainersshouldnotbereactive,additive,adsorptiveorabsorptive

soastoalterthequalityoftheintermediate,APIorfinishedpharmaceutical

productbeyondthespecifiedlimits.

7.45. Containersshouldbecleanand,whereindicatedbythenatureofthe

Intermediate,APIorfinishedpharmaceuticalproduct,sanitized,sterilized

andprocessedtoremovepyrogenicpropertiesandensurethattheyare

suitablefortheirintendeduse.

7.46. Standardsorspecifications,methodsoftesting,and,whereindicated,

methodsofcleaning,sterilizing,andprocessingtoremovepyrogenic

propertiesshouldbewrittenandfollowedforpharmaceuticalproduct

containersandclosures.

7.47. Wherecontainersarere-usedduringproductionprocess,theyshouldbe

cleanedinaccordancewithdocumentedproceduresandallpreviouslabels

shouldberemovedordefaced.

7.48. Allhandlingofpackagingmaterialsshouldbedoneinaccordancewith

writtenproceduresorinstructionsandrecorded.

Intermediateandbulkproducts

7.49. Intermediateandbulkproductsshouldbekeptunderappropriate

conditions.

7.50. Intermediateandbulkproductspurchasedassuchshouldbehandledon

receiptasthoughtheywerestartingmaterials.

Finishedproducts

7.51. Finishedproductsshouldbeheldinquarantineuntiltheirfinalrelease,after

whichtheyshouldbestoredasusablestockunderconditionsestablishedby

themanufacturer.

7.52. Theevaluationoffinishedproductsandthedocumentationnecessaryfor

releaseofaproductforsalearedescribedinChapter8“QualityControl”.


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7 7.53. Writtenreleaseandrejectionproceduresshouldbeavailableforproducts,

andinparticularforthereleaseforsaleofthefinishedproductbythe

Qualityunit.

7.54. StandardOperatingProceduresforthedistributionofpharmaceutical

productsshouldbeestablished,andfollowed.Theyshouldinclude:

a. Aprocedurewherebytheoldestapprovedstockofapharmaceutical

productisdistributedfirst.Deviationfromthisrequirementisonly

permittedwheresuchdeviationistemporary,appropriateand

documented.

b. Asystembywhichthedistributionofeachlotofpharmaceutical

productcanbetraceabletofacilitateitsrecallwherenecessary

Rejected,recovered,reprocessedandreworkedmaterials

7.55. Rejectedmaterialsshouldbeidentifiedandcontrolledunderaquarantine

systemdesignedtopreventtheiruseinmanufacturingorprocessing

operationsforwhichtheyareunsuitable.

7.56. Wheretherearerejectedmaterials,themanufacturershouldnotifythe

Agencybeforethematerialsareeitherreturnedtothesuppliersor

destroyedinatimelymannerandinlinewiththeguidelinesoftheAgency.

Whateveractionistakenshouldbeapprovedandrecordedbyauthorised

personnel.

7.57. Disposalofrejectedmaterialsshouldbeconductedinaccordancewith

standardoperatingproceduresandenvironmentalregulations.

7.58. Thereworkingoffinishedpharmaceuticalproductsisnotpermittedbythe

Agency

7.59. A pharmaceutical product may be reprocessed provided the subsequent

productmeetsappropriatestandards,specifications,andcharacteristics.

7.60. Therecoveryofallorpartofearlierbatches,whichconformtotherequired

qualitybyincorporationintoabatchofthesameproductatadefinedstage

ofmanufactureshouldbeauthorisedbeforehand.Thisrecoveryshouldbe

carriedoutinaccordancewithadefinedprocedureafterevaluationofthe

risksinvolved,includinganypossibleeffectonshelflife.Therecoveryshould

berecorded.

7.61. Theneedforadditionaltestingofanyfinishedproductthathasbeen

reprocessedshouldbeconsideredbythequalityunit.

Recalledproducts


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77.62. Recalledproductsshouldbeidentifiedandstoredseparatelyinasecurearea

untiladecisionistakenontheirfate.Thisdecisionshouldbemadeassoon

aspossible.

Returnedgoods7.63. Pharmaceuticalproductsreturnedfromthemarketshouldbedestroyed

unlessitiscertainthattheirqualityissatisfactory;insuchcasestheymaybeconsideredforresaleorre-labelling,oralternativeactiontakenonlyaftertheyhavebeencriticallyassessedbyQCinaccordancewithawrittenprocedure.Thenatureofthepharmaceuticalproduct,anyspecialstorageconditionsitrequires,itsconditionandhistory,andthetimeelapsedsinceitwasissuedshouldallbetakenintoaccountinthisassessment.

7.64. Whereanydoubtarisesoverthequalityoftheproduct,itshouldnotbeconsideredsuitableforreissueorreuse.

7.65. Recordsofreturnedpharmaceuticalproductsshouldbemaintainedand

shouldincludethenameandlabelledpotencyofthepharmaceuticalproduct

dosageform,batchnumberorcontrolnumber,reasonforthereturn,

quantityreturned,dateofdisposition,andultimatedispositionofthe

returnedpharmaceuticalproduct.

7.66. Wherethereasonforapharmaceuticalproductbeingreturnedimplicates

associatedbatches,anappropriateinvestigationshouldbeconducted.

Pharmaceuticalproductsalvaging

7.67. Pharmaceutical products that have been subjected to improper storage

conditions including extremes in temperature, humidity, smoke, fumes,

pressure,age,expiry,orradiationduetonaturaldisasters,fires,accidents,or

equipmentfailuresshouldnotbesalvagedandreturnedtothemarketplace.

7.68. Whenever there is doubt whether pharmaceutical products have been

subjected to such conditions, salvaging operationsmay be conducted only

wherethereis:

a. Evidencefromlaboratorytestsandassays(includinganimalfeeding

studieswhereapplicable)thatthepharmaceuticalproductsmeetall

applicablestandardsofidentity,strength,quality,andpurityand;

b. Evidence from inspection of the premises that the pharmaceutical

products and their associated packaging were not subjected to

improperstorageconditionsasaresultofthedisasteroraccident.

7.69. Organolepticexaminationsmaybeacceptableonlyassupplementalevidence

that the pharmaceutical products meet appropriate standards of identity,

strength,quality,andpurity.


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7 7.70. Recordsincludingname,batchnumber,anddispositionshouldbe

maintainedforsalvagedpharmaceuticalproducts

Reagentsandculturemedia

7.71. Thereshouldberecordsforthereceiptandpreparationofreagentsand

culturemedia.Instructionsforuseandstorageshouldbefollowed.Incertain

casesitmaybenecessarytocarryoutanidentificationtestand/orother

testingofreagentmaterialsuponreceiptorbeforeuse.

7.72. Reagentsmadeupinthelaboratoryshouldbepreparedaccordingtowritten

proceduresandappropriatelylabelled.Thelabelshouldindicatethe

concentration,standardizationfactor,thedateofpreparation,thedatewhen

re-standardizationisdue,shelf-life,andthestorageconditions.Thelabel

shouldbesignedanddatedbythepersonpreparingthereagent.

7.73. Bothpositiveandnegativecontrolsshouldbeappliedtoverifythesuitability

ofculturemediaeachtimetheyarepreparedandused.Thesizeofthe

inoculumusedinpositivecontrolsshouldbeappropriatetothesensitivity

required.

Referencestandards

7.74. Wheneverofficialreferencestandardsexist,theseshouldpreferablybeused.

7.75. Officialreferencestandardsshouldbeusedonlyforthepurposedescribedin

theappropriatemonograph.

7.76. Referencestandardsdevelopedbythemanufacturershouldbetestedor

validated,releasedandstoredinthesamewayasofficialstandards.They

shouldbekeptundertheresponsibilityofadesignatedpersoninasecure

area.

7.77. Secondaryorworkingstandardsmaybeestablishedbytheapplicationof

appropriatetestsandchecksatregularintervalstoensurestandardization.

Theirtraceabilitytoprimarystandardsshouldbedemonstratedand

documented.

7.78. Referencestandardsshouldbeproperlylabelledwithatleastthefollowing

information:

a. Nameofthematerial;

b. Batchorlotnumberandcontrolnumber;

c. Dateofpreparation;

d. Shelf-life;


CHAPTER

QUALITYCONTROL8

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8

Principle

8.1. QualityControlisconcernedwithsampling,specificationsandtestingaswell

astheorganization,documentationandreleaseprocedureswhichensure

thatthenecessaryandrelevanttestsarecarriedout,andthatmaterialsare

notreleasedforuse,norproductsreleasedforsaleorsupply,untiltheir

qualityhasbeenjudgedsatisfactory.Qualitycontrolisnotconfinedto

laboratoryoperations,butmustbeinvolvedinalldecisionswhichmay

concernthequalityoftheproduct.

8.2. TheindependenceofQCfromproductionisconsideredfundamentaltothe

satisfactoryoperationofQC

General

8.3. Eachmanufacturerofpharmaceuticalproductsshouldhaveaqualitycontrol

department.Thisdepartmentshouldbeindependentfromother

departments,andundertheauthorityofapersonwithappropriate

qualificationsandexperience,whohasoneorseveralcontrollaboratoriesat

hisdisposal.AdequateresourcesavailablemustmeetminimumNAFDACGLP

requirementstoensurethatallthequalitycontrolarrangementsare

effectivelyandreliablycarriedout.

8.4. ThebasicrequirementsforQC:

a. Adequatefacilities,trainedpersonnelandapprovedprocedures

mustbeavailableforsampling,inspectingandtestingstarting

materials,packagingmaterialsandintermediate,bulkandfinished

productsandformonitoringenvironmentalconditionsforGMP

purposes.

b. Accesstoproductionareasforsamplingandinvestigationas

appropriate.

8.5. TheresponsibilitiesofQCareasfollows:

a. Samplingofstartingmaterials,packagingmaterials,intermediate

products,bulkproductsandfinishedproductsbymethodsand

personnelapprovedbytheQC.


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8 b. Qualificationofequipmentandvalidationoftestmethods.

c. Maintainingrecords(manuallyand/orbyrecordinginstruments)to

demonstratethatalltherequiredsampling,inspectingandtesting

procedureshaveactuallybeencarriedoutandthatanydeviations

havebeenfullyrecordedandinvestigated

d. Ensuringthatfinishedproductscontainingredientsthatcomply

withthequalitativeandquantitativecompositionoftheproductas

describedinthemarketingauthorization.Theyalsoensurethatthe

ingredientsareoftherequiredpurity,intheirpropercontainerand

correctlylabelled

e. Maintainsrecordsofresultsofinspectionandtestingofmaterials,

intermediate,bulkandfinishedproductsagainstspecifications.

f. Ensuresthatsufficientsamplesofstartingmaterialsandproducts

areretainedtopermitfutureexaminationoftheproductif

necessary;theretainedproductmustbekeptinitsfinalpackunless

thepackisexceptionallylarge.

g. Assessmentoffinishedproductsincludingthereviewand

evaluationoftherelevantproductiondocumentationandan

assessmentofdeviationsfromspecifiedprocedures.Product

assessmentincludesallrelevantfactorssuchasproduction

conditions,resultsofin-processtesting,areviewofmanufacturing

(includingpackaging)documentation,compliancewithFinished

ProductSpecificationandexaminationofthefinalfinishedpack.

h. Establish,validateandimplementallQCprocedures

i. Evaluate,maintain,andstorethereferencestandardsforsubstances

j. Ensurethecorrectlabellingofcontainersofmaterialsandproducts

k. Ensurethatthestabilityoftheactivepharmaceuticalingredients

(APIs)andproductsismonitored

l. Participateintheinvestigationofcomplaintsrelatedtothequality

oftheproduct

m. Participateinenvironmentalmonitoring.

8.6. Alltheseoperationsshouldbecarriedoutinaccordancewithwritten

proceduresandrecorded.

Goodpracticesforpharmaceuticalqualitycontrol

8.7. Spaceallocatedforqualitycontrollaboratoryandequipmentshouldmeet

thegeneralandspecificrequirementsforqualitycontrolareasasspecifiedin


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8NAFDACGLPguidelineswhichshowsthelistofessentialequipmentthatmustbe

provided.

8.8. Thepersonnel,premises,andequipmentinthelaboratoriesshouldbe

appropriatetothetasksimposedbythenatureandthescaleofthe

manufacturingoperations.Theuseofoutsidelaboratories,inconformity

withtheprinciplesdetailedinChapter9“ContractManufactureand

Analysis”,canbeacceptedforparticularreasons,butthisshouldbestatedin

thequalitycontrolrecords.

8.9. Theestablishmentofanyspecifications,standards,samplingplans,test

procedures,orotherlaboratorycontrolmechanismsincludinganychangein

suchspecifications,standards,samplingplans,testprocedures,orother

laboratorycontrolmechanisms,shouldbedraftedbythequalitycontrol

departmentandreviewedandapprovedbytheauthorizedperson.

8.10. Anydeviationfromthewrittenspecifications,standards,samplingplans,test

procedures,orotherlaboratorycontrolmechanismsshouldberecordedand

justified.

8.11. Calibrationofinstruments,apparatus,gauges,andrecordingdevicesshould

bedoneatsuitableintervalsinaccordancewithanestablishedwritten

programcontainingspecificdirections,schedules,limitsforaccuracyand

precision,andprovisionsforremedialactionintheeventaccuracyand/or

precisionlimitsarenotmet.

8.12. Instruments,apparatus,gauges,andrecordingdevicesnotmeeting

establishedspecificationsshouldnotbeused.

Documentation

8.13. LaboratorydocumentationshouldfollowtheprinciplesgiveninChapter5

“Documentation”.ThefollowingdetailsshouldbereadilyavailabletoQC:

a. Specifications;

b. Samplingprocedures;

c. Testingproceduresandrecords(includinganalyticalworksheets

and/orlaboratorynotebooks);

d. Analyticalreportsand/orcertificates;

e. Datafromenvironmentalmonitoring,whererequired;

f. Validationrecordsoftestmethods,whereapplicable;

g. Proceduresforandrecordsofthecalibrationofinstrumentsand

maintenanceofequipment


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8 h. Instrumentandequipmentinstallationqualification,operational

qualificationandperformancequalificationcertificates.

i. Inventoryofalllaboratoryequipmentandreagents.

j. Auditcertificatesofsuppliersoflaboratoryreagents.

8.14. AnyQCdocumentationrelatingtoabatchrecordshouldberetainedforone

yearaftertheexpirydateofthebatch.Forsomekindsofdata(e.g.analytical

testsresults,yields,environmentalcontrols,etc.)itisrecommendedthat

recordsinamannerpermittingtrendevaluationbekept.Inadditiontothe

informationwhichispartofthebatchrecord,otheroriginaldatasuchas

laboratorynotebooksand/orrecordsshouldberetainedandreadily

available.

Sampling

8.15. Sampletakingshouldbedoneinaccordancewithapprovedwritten

proceduresthatdescribe:

a. Themethodofsampling;

b. Theequipmenttobeused;

c. Theamountofthesampletobetaken

d. Instructionsforanyrequiredsub-divisionofthesample;

e. Thetypeandconditionofthesamplecontainertobeused;

f. Theidentificationofcontainerssampled;

g. Anyspecialprecautionstobeobserved,especiallywithregardtothe

samplingofsterileornoxiousmaterials;

h. Thestorageconditions;

i. Instructionsforthecleaningandstorageofsamplingequipment

8.16. Eachsamplecontainershouldbearalabelindicating:

a. Thenameofthesampledmaterial;

b. Thebatchorlotnumber;

c. Thenumberofthecontainerfromwhichthesamplehasbeentaken;

d. Thenumberofthesample;

e. Thesignatureofthepersonwhohastakenthesample;

f. Thedateofsampling

8.17. Retentionsamplesshouldberepresentativeofthebatchofmaterialsor


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8productsfromwhichtheyaretaken.Othersamplesmayalsobetakentomonitorthe

moststressedpartofaprocess(e.g.beginningorendofaprocess)

8.18. Retentionsamplesfromeachbatchoffinishedproductsshouldberetained

tilloneyearaftertheexpirydate.

8.19. Finishedproductsshouldbekeptintheirfinalpackagingandstoredunder

therecommendedconditions.Ifexceptionallylargepackagesareproduced,

smallersamplesmightbestoredinappropriatecontainers.

8.20. Samplesofactivestartingmaterialsshouldberetainedforatleastoneyear

beyondtheexpirydateofthecorrespondingfinishedproduct.

8.21. Foranactiveingredientinaradioactivepharmaceuticalproduct,exceptfor

non-radioactivereagentkits,theretentionsampleshouldberetainedfor:

a. Three months after the expiration date of the last lot of the

pharmaceuticalproductcontaining theactive ingredientwhere the

expirationdatingperiodofthepharmaceuticalproductis30daysor

less;or

b. Six months after the expiration date of the last lot of the

pharmaceuticalproductcontaining theactive ingredientwhere the

expirationdatingperiodofthepharmaceuticalproductismorethan

30days.

8.22. Foraradioactivepharmaceuticalproduct,exceptfornon-radioactivereagent

kits,theretentionsampleshouldberetainedfor:

a. Threemonthsaftertheexpirationdateofthepharmaceuticalproduct

wheretheexpirationdatingperiodofthepharmaceuticalproductis

30daysorless;or

b. Sixmonthsaftertheexpirationdateofthepharmaceuticalproduct

wheretheexpirationdatingperiodofthepharmaceuticalproductis

morethan30days.

8.23. Retentionsamplesfromrepresentativesamplelotsorbatchesselectedby

acceptablestatisticalproceduresshouldbeexaminedvisuallyatleastoncea

yearforevidenceofdeteriorationunlessvisualexaminationwouldaffectthe

integrityoftheretentionsample.

8.24. Anyevidenceofpharmaceuticalproductdeteriorationshouldbe

investigated.Theresultsofexaminationshouldberecordedandmaintained

withotherstabilitydataonthepharmaceuticalproduct.

8.25. Retentionsamplesofcompressedmedicalgasesneednotbekept.


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8 8.26. Otherstartingmaterials(exceptsolvents,gasesandwater)shouldbe

retainedforatleasttwoyearsafterthereleaseoftheproductiftheir

stabilityallows.Thisperiodmaybeshortenediftheirstability,asmentioned

intherelevantspecification,isshorter.

8.27. Retentionsamplesofmaterialsandproductsshouldbeofasizesufficientto

permitatleasttwofullre-examinations.

8.28. Out-of-specification(OOS)/out-of-trend(OOT)resultsobtainedduring

testingofmaterialsorproductsshouldbeinvestigatedinaccordancewithan

approvedprocedure.Recordsshouldbemaintained.

8.29. Recordsofquantityandtraceabilityreferenceofreagentmediaand

glasswareusedmustbekept.

Testrequirements

8.30. Theaccuracy,sensitivity,specificity,andreproducibilityoftestmethods

employedshouldbeestablished,validatedanddocumented.Suchvalidation

anddocumentationmaybeaccomplishedasdescribedinChapter4

“QualificationandValidation”.

8.31. Alltestingoperationsdescribedinthemarketingauthorizationshouldbe

carriedoutaccordingtotheapprovedmethods.

8.32. For each batch of pharmaceutical product purporting to be sterile and/or

pyrogen-free, there should be appropriate laboratory testing to determine

conformancetosuchrequirements. Thetestproceduresshouldbeinwriting

andshouldbefollowed.

8.33. Foreachbatchofophthalmicointment,thereshouldbeappropriatetestingto

determine conformance to specifications regarding the presence of foreign

particlesandharshorabrasivesubstances.Thetestproceduresshouldbein

writingandshouldbefollowed.

8.34. Foreachbatchofcontrolled-releasedosageform,thereshouldbeappropriate

laboratorytestingtodetermineconformancetothespecificationsfortherate

ofreleaseofeachactiveingredient.Thetestproceduresshouldbeinwriting

andshouldbefollowed.

Startingandpackagingmaterials

8.35. Beforereleasingastartingorpackagingmaterialforuse,theauthorized

personshouldensurethatthematerialshavebeentestedforconformity

withspecificationsforidentity,strength,purityandotherquality

parameters.

8.36. Anidentitytestshouldbeconductedonasamplefromeachcontainerof


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8startingmaterial.

8.37. Eachbatch(lot)ofprintedpackagingmaterialsmustbeexaminedfollowing

receipt.

8.38. Inlieuoffulltestingbythemanufacturer,acertificateofanalysismaybe

acceptedfromthesupplier,providedthatthemanufacturerestablishesthe

reliabilityofthesupplier'sanalysisthroughappropriateperiodicvalidation

ofthesupplier'stestresultsandthroughon-siteauditsofthesupplier's

capabilities.

8.39. Certificatesofanalysismustbeoriginals(notphotocopies)orotherwise

havetheirauthenticityassured.Certificatesmustcontainatleastthe

followinginformation:

a. Identification(nameandaddress)oftheissuingsupplier;

b. Signatureofthecompetentofficial,andstatementofhisorher

qualifications;

c. Thenameofthematerialtested;

d. Thebatchnumberofthematerialtested;

e. Thespecificationsandmethodsused;

f. Thetestresultsobtained;

g. Thedateoftesting

In-processcontrol

8.40. In-processcontrolrecordsshouldbemaintainedandformapartofthebatch

records.

Finishedproducts

8.41. Foreachbatchofpharmaceuticalproduct,thereshouldbeanappropriate

laboratorydeterminationofsatisfactoryconformitytoitsfinishedproduct

specification,priortorelease.

8.42. Theresultsobtainedshouldberecordedandcheckedtomakesurethatthey

areconsistentwitheachother.Anycalculationsshouldbecritically

examined.

8.43. Wheresterilityand/orpyrogentestingareconductedonspecificbatchesof

short-livedradiopharmaceuticals,suchbatchesmaybereleasedpriorto

completionofsterilityand/orpyrogentesting,providedsuchtestingis

completedassoonaspossible.

8.44. Thereshouldbeappropriatelaboratorytesting,asnecessary,ofeachbatch


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8 ofpharmaceuticalproductrequiredtobefreeofobjectionablemicroorganisms.

8.45. Productsfailingtomeettheestablishedspecificationsoranyotherrelevant

qualitycriteriashouldberejected.

8.46. Thetestsperformedshouldberecordedandtherecordsshouldincludeat

leastthefollowingdata:

a. Nameofthematerialorproductand,whereapplicable,dosageform;

b. Batchnumberand,whereappropriate,nameofthemanufacturer

and/orsupplier;

c. Referencestotherelevantspecificationsandtestingprocedures;

d. Testresults,includingobservationsandcalculations,andreference

toanycertificatesofanalysis;

e. Datesoftesting;

f. Initialsofthepersonswhoperformedthetesting

g. Initialsofthepersonswhoverifiedthetestingandthecalculations,

whereappropriate;

h. Aclearstatementofreleaseorrejection(orotherstatusdecision)

andthedatedsignatureofthedesignatedresponsibleperson

8.47. Allthein-processcontrols,includingthosemadeintheproductionareaby

productionpersonnel,shouldbeperformedaccordingtomethodsapproved

byqualitycontrolandtheresultsrecorded.

8.48. Specialattentionshouldbegiventothequalityoflaboratoryreagents,

volumetricglasswareandsolutions,referencestandardsandculturemedia.

Theyshouldbepreparedinaccordancewithwrittenprocedures.

8.49. Laboratoryreagentsintendedforprolongeduseshouldbemarkedwiththe

preparationdateandthesignatureofthepersonwhopreparedthem.The

expirydateofunstablereagentsandculturemediashouldbeindicatedon

thelabel,togetherwithspecificstorageconditions.Inaddition,for

volumetricsolutions,thelastdateofstandardizationandthelastcurrent

factorshouldbeindicated.

8.50. Wherenecessary,thedateofreceiptofanysubstanceusedfortesting

operations(e.g.reagentsandreferencestandards)shouldbeindicatedonthe

container.Instructionsforuseandstorageshouldbefollowed.Incertain

casesitmaybenecessarytocarryoutanidentificationtestand/orother

testingofreagentmaterialsuponreceiptorbeforeuse.


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88.51. Animalsusedfortestingmaterialsorproducts,shouldbequarantinedbefore

use.Theyshouldbemaintainedandcontrolledinamannerthatassures

theirsuitabilityfortheintendeduse.Theyshouldbeidentified,and

adequaterecordsshouldbemaintained,showingthehistoryoftheiruse.

8.52. Whereareasonablepossibilityexiststhatanon-beta-lactampharmaceutical

producthasbeenexposedtocross-contaminationwithbeta-lactam,thenon-

beta-lactampharmaceuticalproductshouldbetestedforthepresenceof

beta-lactam.Suchpharmaceuticalproductshouldnotbemarketedwhere

detectablelevelsarefoundwhentestedbyappropriatemethods.

Batchrecordreview

8.53. QCrecordsshouldbereviewedaspartoftheapprovalprocessofbatch

releasebeforetransfertotheauthorizedperson.Anydivergenceorfailureof

abatchtomeetitsspecificationsshouldbethoroughlyinvestigated.The

investigationshould,ifnecessary,extendtootherbatchesofthesame

productandotherproductsthatmayhavebeenassociatedwiththespecific

failureordiscrepancy.Awrittenrecordoftheinvestigationshouldbemade

andshouldincludetheconclusionandfollow-upaction.

8.54. Retentionsamplesfromeachbatchoffinishedproductshouldbekeptforat

leastoneyearaftertheexpirydate.

Stabilitystudies

8.55. Aftermarketing,thestabilityofthepharmaceuticalproductshouldbe

monitoredaccordingtoacontinuousappropriateprogrammethatwill

permitthedetectionofanystabilityissue(e.g.changesinlevelsof

impurities,ordissolutionprofile)associatedwiththeformulationinthe

marketedpackage.

8.56. Thepurposeoftheon-goingstabilityprogrammeistomonitortheproduct

overitsshelf-lifeandtodeterminethattheproductremains,andcanbe

expectedtoremain,withinspecificationsunderthelabelledstorage

conditions.

8.57. Thismainlyappliestothepharmaceuticalproductinthepackageinwhichit

issold,butconsiderationshouldalsobegiventotheinclusioninthe

programmeofbulkproduct.Forexample,whenthebulkproductisstored

foralongperiodbeforebeingpackagedand/orshippedfroma

manufacturingsitetoapackagingsite,theimpactonthestabilityofthe

packagedproductshouldbeevaluatedandstudiedunderambient

conditions.Inaddition,considerationshouldbegiventointermediatesthat

arestoredandusedoverprolongedperiods.Stabilitystudieson

reconstitutedproductareperformedduringproductdevelopmentandneed


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8 notbemonitoredonanon-goingbasis.However,whenrelevant,thestabilityof

reconstitutedproductcanalsobemonitored

8.58. QCshouldevaluatethequalityandstabilityoffinishedpharmaceutical

productsand,whennecessary,ofstartingmaterialsandintermediate

products.

8.59. QCshouldestablishexpirydatesandshelf-lifespecificationsonthebasisof

stabilitytestsrelatedtostorageconditions.

8.60. Awrittenprogrammeforon-goingstabilitydeterminationshouldbe

developedandimplementedtoincludeelementssuchas:

a. Acompletedescriptionofthepharmaceuticalproductinvolvedin

thestudy;

b. Thecompletesetoftestingparametersandmethods,describingall

testsforpotency,purity,andphysicalcharacteristicsand

documentedevidencethatthesetestsindicatestability;

c. Provisionfortheinclusionofasufficientnumberofbatches;

d. Testingofthepharmaceuticalproductinthesamecontainer-closure

systemasthatinwhichtheproductismarketed

e. Thetestingscheduleforeachpharmaceuticalproduct;

f. Provisionforspecialstorageconditions;

g. Provisionforadequatesampleretention;

h. Asummaryofallthedatagenerated,includingtheevaluationand

theconclusionsofthestudy.

8.61. Stabilityshouldbedeterminedpriortomarketingandfollowingany

significantchanges,forexample,inprocesses,equipmentorpackaging

materials.

8.62. Acceleratedstudies,combinedwithbasicstabilityinformationonthe

materials,pharmaceuticalproducts,andcontainer-closuresystem,maybe

usedtosupporttentativeexpirationdatesprovidedfullshelflifestudiesare

notavailableandarebeingconducted.

8.63. Wheredatafromacceleratedstudiesareusedtoprojectatentative

expirationdatethatisbeyondadatesupportedbyactualshelflifestudies,

theremustbestabilitystudiesconducted,includingpharmaceuticalproduct

testingatappropriateintervals,untilthetentativeexpirationdateisverified

ortheappropriateexpirationdatedetermined.

8.64. Forhomeopathicpharmaceuticalproducts,thereshouldbeawritten


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8assessmentofstabilitybasedatleastontestingorexaminationofthepharmaceutical

productforcompatibilityoftheingredients,andbasedonmarketing

experiencewiththepharmaceuticalproducttoindicatethatthereisno

degradationoftheproductforthenormalorexpectedperiodofuse.

8.65. Evaluationofstabilityshouldbebasedonthesamecontainer-closuresystem

inwhichthepharmaceuticalproductisbeingmarketed.

8.66. Theon-goingstabilityprogrammeshouldbedescribedinawrittenprotocol

andresultsformalisedasareport.Theequipmentusedfortheon-going

stabilityprogramme(stabilitychambersamongothers)shouldbequalified

andmaintained.

8.67. Theprotocolforanon-goingstabilityprogrammeshouldextendtotheend

oftheshelflifeperiodandshouldinclude,butnotbelimitedto,thefollowing

parameters:

a. Numberofbatch(es)perstrengthanddifferentbatchsizes,if

applicable

b. Relevantphysical,chemical,microbiologicalandbiologicaltest

methods

c. Acceptancecriteria

d. Referencetotestmethods

e. Descriptionofthecontainer-closuresystem(s)

f. Testingintervals(timepoints)

g. Descriptionoftheconditionsofstorage

h. Otherapplicableparametersspecifictothepharmaceuticalproduct.

8.68. Theprotocolfortheon-goingstabilityprogrammecanbedifferentfromthat

oftheinitiallong-termstabilitystudyassubmittedinthemarketing

authorisationdossierprovidedthatthisisjustifiedanddocumentedinthe

protocol.

8.69. Thenumberofbatchesandfrequencyoftestingshouldprovideasufficient

amountofdatatoallowfortrendanalysis.Unlessotherwisejustified,atleast

onebatchperyearofproductmanufacturedineverystrengthandevery

primarypackagingtype,ifrelevant,shouldbeincludedinthestability

programme(unlessnoneareproducedduringthatyear).Forproducts

whereon-goingstabilitymonitoringwouldnormallyrequiretestingusing

animalsandnoappropriatealternativevalidatedtechniquesareavailable,


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9

Principle

9.1. Contractmanufacture,analysis,andanyotheractivitycoveredbyGMPmust

becorrectlydefined,agreedandcontrolledinordertoavoid

misunderstandingswhichcouldresultinaproductorworkoranalysisof

unsatisfactoryquality.

General

9.2. Thereshouldbeawrittenagreementcoveringthemanufactureand/or

analysisarrangedunderthecontractandanytechnicalarrangementsmade

inconnectionwithit.

9.3. Allarrangementsforcontractmanufactureandanalysisincluding

technologytransferandanyproposedchangesintechnicalorother

arrangementsshouldbeinaccordancewiththemarketingauthorisationfor

theproductconcerned.

9.4. Thecontractshouldpermitthecontractgivertoauditthefacilitiesand

activitiesofthecontractacceptorormutuallyagreedsubcontractors.

9.5. Inthecaseofcontractanalysis,thefinalapprovalforreleasemustbegiven

bytheauthorizedpersoninaccordancewithGMPandthemarketing

authorizationasspecifiedinthecontract.

TheResponsibilitiesoftheContract

Giver


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9anyhazardsassociatedwiththeproduct,workortestswhichmightposeahazardto

hispremises,equipment,personnel,othermaterialsorotherproducts.

9.9. Thecontractgivershouldreviewandassesstherecordsandresultsrelated

totheoutsourcedactivities.Thecontractgivershouldensurethatall

productsandmaterialsdeliveredbythecontractacceptorhavebeen

processedinaccordancewithGMPandthemarketingauthorization;comply

withtheirspecificationsandthattheproducthasbeenreleasedbythe

authorizedpersoninaccordancewithGMPandthemarketingauthorization.

9.10. Thecontractgivershouldmonitorandreviewtheperformanceofthe

contractacceptorincludingtheimplementationofanyneeded

improvementsandtheireffectiveness.

9.11. Thecontractgiverisresponsibleforensuringthatthecontractacceptor

understandsthathisorheractivitiesmaybesubjecttoinspectionbythe

Agency.

TheResponsibilitiesoftheContractAcceptor

9.12. Thecontractacceptorshouldhaveadequatepremisesandequipment,

knowledgeandexperience,andcompetentpersonneltocarryout

satisfactorily,theworkorderedbythecontractgiver.Contractmanufacture

maybeundertakenonlybyamanufacturerwhoisauthorisedbytheAgency.

9.13. Thecontractacceptorshouldensurethatallproductsormaterialsdelivered

tohimaresuitablefortheirintendedpurpose.

9.14. Thecontractacceptormustnotpasstoathirdpartyanyofthework

entrustedtohimunderthecontractwithoutthecontractgiver'sprior

evaluationandapprovalofthearrangements.Arrangementsmadebetween

thecontractacceptorandanythirdpartyshouldensurethatinformation

andknowledgeincludingthatfromassessmentofthesuitabilityofthethird

party,aremadeavailableinthesamewayasbetweentheoriginalcontract

giverandcontractacceptor.

9.15. Thecontractacceptorshouldrefrainfromanyactivity(including

unauthorizedchangesoutsidethetermsofthecontract)whichmay

adverselyaffectthequalityoftheproductmanufacturedand/oranalysedfor

thecontractgiver.

TheContract

9.16. Theremustbeawrittencontractbetweenthecontractgiverandthecontract

acceptorwhichclearlyestablishestheresponsibilitiesofeachparty,covering

theoutsourcedactivities,theproductsoroperationstowhichtheyare


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9 related,communicationprocessesrelatingtotheoutsourcedactivitiesandany

technicalarrangementsmadeinconnectionwithit.

9.17. Technicalaspectsofthecontractshouldbedrawnupbycompetentpersons

suitablyknowledgeableinpharmaceuticaltechnology,analysisandgood

manufacturingpractice.

9.18. Allarrangementsformanufactureandanalysismustbeinaccordancewith

themarketingauthorisationandagreedbybothparties.

9.19. Thecontractshouldclearlydescribewhoisresponsibleforcontracted

activities,e.g.knowledgemanagement,technologytransfer,supplychain,

subcontracting,testingandreleasingmaterialsandundertakingproduction

andQC,includingin-processcontrols,andwhohasresponsibilityfor

samplingandanalysis.Inthecaseofcontractanalysis,thecontractshould

statewhetherornotthecontractacceptorshouldtakesamplesatthe

premisesofthemanufacturer.

9.20. Manufacturing,analyticalanddistributionrecords,andretentionsamples

shouldbekeptby,orbeavailableto,thecontractgiver.Anyrecordsrelevant

toassessingthequalityofaproductintheeventofcomplaintsora

suspecteddefectmustbeaccessibleandspecifiedinthedefect/recall

proceduresofthecontractgiver.

9.21. ThecontractagreementmuststatethatthecontractgiverandtheAgency

havetherighttovisitthefacilitiesofthecontractacceptor.

9.22. Incaseofcontractanalysis,thecontractacceptorshouldunderstandthathe

issubjecttoinspectionbytheAgency.

9.23. Thecontractshoulddescribethehandlingofstartingmaterials,intermediate

andbulkproductsandfinishedproductsiftheyarerejected.Itshouldalso

describetheproceduretobefollowedifthecontractanalysisshowsthatthe

testedproductsmustberejected.


CHAPTER

COMPLAINTSAND PRODUCT RECALL10

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10

Principle

10.1. Allcomplaintsandotherinformationconcerningpotentiallydefective

productsshouldbecarefullyreviewedaccordingtowrittenproceduresand

thecorrectiveactionshouldbetaken.Inordertoprovideforall

contingencies,asystemshouldbedesignedtorecall,ifnecessary,promptly

andeffectivelyproductsknownorsuspectedtobedefectivefromthemarket.Complaints

10.2. Apersonresponsibleforhandlingthecomplaintsanddecidingthe

measurestobetakenshouldbedesignated,togetherwithsufficient

supportingpersonneltoassisthimorher.Ifthispersonisdifferent

fromtheauthorizedperson,thelattershouldbemadeawareofany

complaint,investigationorrecall.

10.3. Thereshouldbewrittenproceduresdescribingtheaction(s)tobetaken,

includingtheneedtoconsiderarecall,inthecaseofacomplaintconcerninga

possibleproductdefect.

10.4. Specialattentionshouldbegiventoestablishingthattheproductthatgave

risetoacomplaintwasdefectiveorcausedbycounterfeiting.

10.5. Anycomplaintconcerningaproductdefectshouldberecordedwithallthe

originaldetailsandthoroughlyinvestigated.

10.6. Thepersonresponsibleforqualitycontrolshouldnormallybeinvolvedinthe

investigationofsuchproblems.Theuseofinterdisciplinaryteamsshouldbe

consideredincludingappropriatelytrainedqualitymanagementpersonnel.

10.7. Ifaproductdefectisdiscoveredorsuspectedinabatch,considerationshould

begiventowhetherotherbatchesshouldbecheckedinordertodetermine

whethertheyarealsoaffected.Inparticular,otherbatchesthatmaycontain

reprocessedproductfromthedefectivebatchshouldbeinvestigated.

10.8. Wherenecessary,appropriatefollow-upaction,possiblyincludingproduct

recall,shouldbetakenafterinvestigationandevaluationofthecomplaint.

10.9. Allthedecisionsmadeandmeasurestakenasaresultofacomplaintshould

berecordedandreferencedtothecorrespondingbatchrecords.


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10 10.10. Complaints'recordsshouldbereviewedregularlyforanyindicationof

specificorrecurringproblemsrequiringattentionandpossiblytherecallof

marketedproducts.

10.11. TheAgencyshouldbeinformedifamanufacturerisconsideringaction

followingpossiblefaultymanufacture,productdeterioration,detectionof

counterfeitingoranyotherseriousqualityproblemswithaproduct.

10.12. Writtenrecordsinvolvingapharmaceuticalproductshouldbemaintained

untilatleast1yearaftertheexpirationdateofthepharmaceuticalproduct,

or1yearafterthedatethatthecomplaintwasreceived,whicheverislonger.Recalls

10.13. Thereshouldbeasystemtorecallfromthemarket,promptlyand

effectively,productsknownorsuspectedtobedefective.

10.14. Apersonshouldbedesignatedasresponsibleforexecutionandco-

ordinationofrecallsandshouldbesupportedbysufficientstaffto

handlealltheaspectsoftherecallswiththeappropriatedegreeof

urgency.Thisresponsiblepersonshouldnormallybeindependentof

thesalesandmarketingorganisation.Ifthispersonisnotthe

authorisedperson,thelattershouldbemadeawareofanyrecall

operation.

10.15. Thereshouldbeestablishedwrittenprocedures,regularlychecked

andupdatedwhennecessary,inordertoorganiseanyrecallactivity.

10.16. Recalloperationsshouldbecapableofbeinginitiatedpromptlyandat

anytimedowntotherequiredlevelinthedistributionchain.

10.17. TheAgencyshouldbeinformedpromptlyifproductsareintendedto

berecalledbecausetheyare,oraresuspectedofbeingdefective.

10.18. Thedistributionrecordsshouldbereadilyavailabletotheperson(s)

responsibleforrecalls,andshouldcontainsufficientinformationon

wholesalersanddirectlysuppliedcustomers(withlocationande-

mailaddresses,phonenumbersinsideandoutsideworkinghours,

batchesandamountsdelivered),includingthoseforexported

products,samplesforclinicaltrialsandmedicalsamplestopermitan

effectiverecall.

10.19. Recalledproductsshouldbeidentifiedandstoredseparatelyina

secureareawhileawaitingadecisionontheirfate.

10.20. Theprogressoftherecallprocessshouldbemonitoredandrecorded.

Recordsshouldincludethedispositionoftheproduct.Afinalreport

shouldbeissued,includingreconciliationbetweenthedeliveredand


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10recoveredquantitiesoftheproducts.

10.21. Theeffectivenessofthearrangementsforrecallsshouldbeevaluated

regularly(mockrecall).


CHAPTER

SELF-INSPECTION11

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11

Principle

11.1. Thepurposeofself-inspectionistoevaluatethemanufacturer's

compliancewithGMPinallaspectsofproductionandQC.Theself-

inspectionprogrammeshouldbedesignedtodetectany

shortcomingsintheimplementationofGMPandtorecommendthe

necessarycorrectiveactions.

11.2. Self-inspectionsshouldbeperformedroutinely,andinaddition,may

beperformedonspecialoccasions,e.g.inthecaseofproductrecalls

orrepeatedrejections,orwhenaninspectionbytheAgencyis

announced.

11.3. Self-inspectionsshouldbeconductedinanindependentanddetailed

waybydesignated,competentpersonsfromthecompany.

Independentauditsbyexternalexpertsmayalsobeuseful.

11.4. Theteamresponsibleforself-inspectionshouldconsistofpersonnel

whocanevaluatetheimplementationofGMPobjectively.

11.5. Allrecommendationsforcorrectiveaction(s)shouldbeimplemented.

11.6. Theprocedureforself-inspectionshouldbedocumented,andthere

shouldbeaneffectivefollow-upprogramme.

Itemsforself-inspection

11.7. Writteninstructionsforself-inspectionshouldbeestablishedto

provideaminimumanduniformstandardofrequirements.These

mayincludequestionnairesonGMPrequirementscoveringatleast

thefollowingitems:a. Personnel;b. Premisesincludingpersonnelfacilities;c. Maintenanceofbuildingsandequipment;d. Storageofstartingmaterialsandfinishedproducts;e. Equipment;f. Productionandin-processcontrols;g. QC;h. Documentation;


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11i. Sanitationandhygiene;

j. Validationandrevalidationprogrammes;k. Calibrationofinstrumentsormeasurementsystems;l. Recallprocedures;m. Complaintsmanagement;n. Labelscontrol;o. Resultsofpreviousself-inspectionsandanycorrectivesteps

taken.p. Distributionofthepharmaceuticalproducts

Self-inspectionteam

11.8. Managementshouldappointaself-inspectionteamconsistingof

expertsintheirrespectivefieldsandarefamiliarwithGMP.The

membersoftheteammaybeappointedfrominsideoroutsidethe

company.

Frequencyofself-inspection

11.9. Thefrequencyatwhichself-inspectionsareconductedmaydepend

oncompanyrequirementsbutshouldpreferablybeatleastoncea

year.Thefrequencyshouldbestatedintheprocedure.

Self-inspectionreport

11.10. Areportshouldbemadeatthecompletionofaself-inspection.

11.11. Thereportshouldinclude:a. Self-inspectionresults;b. Evaluationandconclusions;andc. Recommendedcorrectiveactions.

Follow-upaction

11.12. Thereshouldbeaneffectivefollow-upprogramme.Thecompany

managementshouldevaluateboththeself-inspectionreportandthe

correctiveactionsasnecessary.

Qualityaudit

11.13. Itmaybeusefultosupplementself-inspectionswithaqualityaudit.A

qualityauditconsistsofanexaminationandassessmentofallorpart

ofaqualitysystemwiththespecificpurposeofimprovingit.Aquality

auditisusuallyconductedbyoutsideorindependentspecialistsora

teamdesignatedbythemanagementforthispurpose.Suchaudits

shouldalsobeextendedtosuppliersandcontractors(seeChapter9

“ContractManufactureandAnalysis”).


REFERENCES

FURTHER READING

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1. Goodmanufacturingpracticesforpharmaceuticalproducts.In:WHOExpert

CommitteeonSpecificationsforPharmaceuticalPreparations.WHOTechnical

ReportSeries,No.961,2011

2. EudraLex—Volume4GoodManufacturingPractice(GMP)Guidelines.

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

3. PharmaceuticalInspectionConvention,PharmaceuticalInspection

CooperationScheme(PIC/S).In:Guidetogoodmanufacturingpracticefor

medicinalplants,Geneva,PIC/SSecretariat,PIC/SMarch2014

4. GoodManufacturingPractices(GMP)Guidelines–2009Edition,Version2

(GUI-0001)/March4,2011.HealthCanada/HealthProductsandFoodBranch

Inspectorate.http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-

conform/gmp-bpf/docs/gui-0001-eng.pdf

�� ĆŇŇİ Ŀ ÏŃÕĲÏ ĬÔÕÒĹŃĴ ÑÒÏ ĬÔĹĬĮÓĲŇÒÑĶÏÒĿ Ï ĬĮÕÔĹĬÏŁÑÒŇİ ÕĬÔÓNČŃZĜ ĈÉÆŎÑĮÒÔǺŇĿĿĹÔÔĮĮ ŇŃĒÑĮĬĹĲĹĬÏÔĹŇŃÓ

forPharmaceuticalPreparations.WHOTechnicalReportSeries,No.961,2011

2. ÆÕİ ÒÏĎĮŎ—Volume4GoodManufacturingPractice(GMP)Guidelines.


3. ÊĶÏrmaceuticalInspectionConvention,PharmaceuticalInspectionCooperationScheme(PIC/S).In:Guide

togoodmanufacturingpracticeformedicinalplants,Geneva,PIC/SSecretariat,PIC/SMarch2014

4. ĆŇŇİ ĐÏŃÕĲÏ ĬÔÕÒĹŃĴ ÊÒÏ ĬÔĹĬĮÓHĆĐÊIĆÕĹİ ĮŁĹŃĮÓ–2009Edition,Version2(GUI-0001)/March4,2011.

HealthCanada/HealthProductsandFoodBranchInspectorate.http://www.hc-sc.gc.ca/dhp-

mps/alt_formats/pdf/compli-conform/gmp-bpf/docs/gui-0001-eng.pdf



http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/docs/gui-0001-eng.pdf

http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/compli-conform/gmp-bpf/docs/gui-0001-eng.pdf

GLOSSARY

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Act The NAFDAC Act, Cap N1, LFN 2004

Active

pharmaceutical

ingredients

(API)

Any substance or mixture of substances intended to be used in the

manufacture of a pharmaceutical product and which when used in the

production of a pharmaceutical product, becomes an active ingredient of

the product. Such substances are intended to furnish pharmacological

activity or other direct effect in the diagnosis, cure, mitigation, treatment,

or prevention of disease or to affect the structure and function of the body.

Agency National Agency for Food and Drug Administration and Control

Airlock An enclosed space with two or more doors which is interposed between

two or more rooms, e.g. of differing class of cleanliness, for the purpose of

controlling the air-flow between those rooms when either people, goods or

equipment

need to enter or

leave them.

Authorized

person

The person recognised by the Agency as having the necessary basic

scientific and technical background and experience; and who is

responsible

for ensuring that each batch of finished product has been

manufactured, tested and approved for release

in compliance with

regulatory requirements.

Batch (or lot) A defined quantity of starting material, packaging material, or product

processed in a single process or series of processes so that it is expected

to be homogeneous. It may sometimes be necessary to divide a batch into

a number of sub-batches, which are later brought together to form a final

homogeneous batch. In the case of terminal sterilization, the batch size is

determined by the capacity of the autoclave. In continuous manufacture,

the batch must correspond to a defined fraction of the production,

characterized by its intended homogeneity. The batch size can be defined

either as a fixed quantity or as the amount produced in a fixed time

interval.

Batch (or lot)

number

Any distinctive combination of letters, numbers, or symbols, or any

combination of them, from which the complete history of the manufacture,

processing, packaging, holding, and distribution of a batch or lot of

pharmaceutical product or other material can be determined.

Bulk product Any product which has completed all processing stages up to, but not

including, final packaging.

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Calibration The set of operations that establish, under specified conditions, the

relationship between values indicated by an instrument or system for

measuring (especially weighing), recording, and controlling, or the values

represented by a material measure, and the corresponding known values

of a reference standard. Limits for acceptance of the results of measuring

should be established.

Clean area

An area with defined environmental control of particulate and microbial

contamination

constructed and used in such a way as to reduce the

introduction, generation, and retention of contaminants within the area.

Commissioning

The setting up,

adjustment and testing of equipment or a system to ensure

that it meets all the requirements as specified in the user requirement

specification and capacities as specified by the designer or developer. It is

carried out before qualification and validation.

Computerised

system

A system including the input of data, electronic processing and the output

of information to be used either for reporting or automatic control.

Consignment (or

delivery) The quantity of a pharmaceutical or pharmaceuticals, made by one

manufacturer and supplied at one time in response to a particular request

or order. A consignment may comprise one or more packages or

containers and may include material belonging to more than one batch.

Contamination The undesired introduction of impurities of a chemical or microbiological

nature, or of foreign matter, into or on to a starting material or

intermediate during production, sampling, packaging or repackaging,

storage or transport.

Contract

A written agreement between two or more parties

which is enforceable by

law.

Cross

contamination

Contamination of a starting material, intermediate product or finished

product with another starting material or product during production.

Finished product

A finished dosage form that has undergone all stages of manufacture,

including packaging in its final container and labelling.

In-process

control

Checks performed during production in order to monitor and, if necessary,

to adjust the process to ensure that the product conforms to its

specifications. The control of the environment or equipment may also be

regarded as a part of in-process control.

In-process Any material fabricated, compounded, blended, or derived by chemical

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material reaction that is produced for, and used in, the preparation of the

pharmaceutical product.

Intermediate

product

Partly processed material which must undergo further manufacturing steps

before it becomes a bulk product.

Manufacture

All operations of purchase of materials and products, production, quality

control, release,

storage and distribution of pharmaceutical products, and

the related controls.

Manufacturer

A company that carries out operations such as production, packaging,

repackaging, labelling and re-labelling of pharmaceuticals.

Marketing

authorization

A legal

document issued by a

competent drug regulatory authority that

establishes the detailed composition and formulation of the product and

the pharmacopoeial or other recognized specifications of its ingredients

and of the final product itself, and includes details of packaging, labelling

and shelf-life.

This is also called product licence or registration

certificate

Master formula

A document or set of documents specifying the starting materials with

their quantities and the packaging materials, together with a description of

the procedures and precautions required to produce a specified quantity of

a finished product as well as the processing instructions, including the in-

process.

Materials A general term used to denote components, raw materials (starting

materials, reagents, solvents), process aids, intermediates, APIs, product

containers, closures, packaging and labelling materials and in-process

materials.

Pharmaceutical

product

Any substance or combination of substances which may be administered

to human beings or animals with a view to preventing diseases, making a

medical diagnosis or restoring, correcting or modifying physiological

functions in human

beings or in animals. Pharmaceutical products may

also be referred to as medicinal products

or drugs as defined under the

NAFDAC Act.

Packaging

All operations, including filling and labelling, which a bulk product has to

undergo in order to become a finished product.

Note: Filling of a sterile product under aseptic conditions or a product

intended to be terminally sterilized, would not normally be regarded as

part of packaging

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Packaging

material

Any material employed in the packaging of a pharmaceutical product,

excluding any outer packaging used for transportation or shipment.

Packaging materials are referred to as primary or secondary according to

whether or not they are intended to be in direct contact with the product.

Production

All operations involved in the preparation of a pharmaceutical product,

from receipt of materials, through processing and packaging, to its

completion as a finished product.

Qualification

Action of proving that any premises, systems and items of equipment work

correctly and actually leads to the expected results.

The word validation is sometimes widened to incorporate the concept of

qualification.

Quality

assurance (QA)

The sum total of the organised arrangements made with the object of

ensuring that all pharmaceutical products are of the quality required for

their use and that quality systems are maintained.

Quality control

(QC)

Quality control is the part of GMP that is concerned with sampling,

specifications, testing, documentation, and release procedures which

ensures that materials are not released for use, and that pharmaceutical

products are not released for sale or supply, until their quality has been

deemed satisfactory. Quality unit

An organizational unit independent of production which fulfils both quality

assurance and quality control responsibilities. This can be in the form of

separate QA and QC units or a

single individual or group, depending upon

the size and structure of the organization.

Quarantine

The status of starting or packaging materials, intermediate, bulk or

finished products isolated physically or by other effective means whilst

awaiting a decision on their release or refusal.

Regulatory

action

Includes but not limited to product hold, recall, forfeiture, or destruction,

sealing of manufacturing line or facility, withdrawal of GMP certificate or

product license/registration certificate, prosecution

Representative

sample

A sample that consists of a number of units that are drawn based on

rational criteria such as random sampling and intended to ensure that the

sample accurately portrays the material being sampled.

Reconciliation A comparison between the theoretical quantity and the actual quantity.

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Recovery The introduction of all or part of previous batches (or of redistilled solvents

and similar products) of the required quality into another batch at a

defined stage of manufacture. It includes the removal of impurities from

waste to obtain a pure substance or the recovery of used materials for a

separate use.

Reprocessing

Subjecting all or part of a batch or lot of an in-process product, bulk

process intermediate (final biological bulk intermediate) or bulk product of

a single batch or lot to a previous step in the validated manufacturing

process due to failure to meet predetermined specifications. Reprocessing

procedures are foreseen as occasionally necessary for biological products

and, in such cases, are validated and pre-approved as part of the

marketing authorization.

Radiopharmaceu

tical

Any pharmaceutical product which when ready for use contains one or

more radionuclides (radioactive isotopes) included for medicinal purpose.

Retention

sample

Retained sample of each batch of starting materials and finished

pharmaceutical product and that is representative of the batch.

Signed

(signature) The record of the individual who performed a particular action or review.

This record can be initials, full handwritten signature, personal seal, or

authenticated and secure electronic signature. Specifications

A list of detailed requirements with which the products or materials used

or obtained during manufacture have to conform. They serve as a basis for

quality evaluation.

Standard

operating

procedures

(SOP)

An authorized written procedure giving instructions for performing

operations not necessarily specific to a given product or material (example

equipment operation, maintenance and cleaning; validation; cleaning of

premises and environmental control; sampling and inspection). Certain

SOPs may be used to supplement product-specific master and batch

production documentation.

Starting material

Any substance of a defined quality used in the production of a

pharmaceutical product, but excluding packaging materials.

Strength The concentration of the drug substance (for example, weight/weight,

weight/volume, or unit dose/volume basis), and/or

The potency, that is, the therapeutic activity of the pharmaceutical

product as indicated by appropriate laboratory tests or by adequately

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developed and controlled clinical data (expressed, for example, in terms of

units by reference to a standard).

SystemA regulated pattern of interacting activities and techniques which are united to form an organised whole.

Theoretical yield

The quantity that would be produced at any appropriate phase of manufacture, processing, or packaging of a particular pharmaceutical product, based upon the quantity of materials to

be used, in the absence of any loss or error in actual production.

Validation

A documented program that provides a high degree of assurance that a

specific process, method, or system will consistently produce a result

meeting pre-determined criteria.

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