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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
O RI UT
GAN
NAFDAC
NAFDAC G
OO
D M
AN
UFACTURIN
G P
RACTIC
E G
UID
ELIN
ES F
OR P
HARM
ACEUTIC
AL P
RO
DUCTS 2
016
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
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
LE O
F C
ON
TEN
TS
ACRONYMNS
AC
RO
NY
MN
S
4
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
AC
KN
OW
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ENT
5
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
NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016
INTRODUCTION
INTR
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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
NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016
INTR
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organisationaswellastheirsuppliers.
Thisdocumentistobeusedinconjunctionwithotherexistingrelevantpharmaceuticalproductstatutesinthecountry.Thegoodpracticesoutlinedbelowaretobeconsideredgeneralguides,andtheymaybeadaptedtomeetindividualneedsaslongastheindustryachievescompliancewithregulatoryobjectives.Asnewtechnologybecomesavailable,operationalproceduresandequipmentstandardsintheindustrymayvaryfromthosedescribedinthisdocument.Materialsand/ormethodsotherthanthosespecifiedintheguidelinesmaybeusedbymanufacturers,iftheycanprovidesoundandscientificevidencethatclearlydemonstratescompliancewiththeregulatoryobjectives.
AllstakeholdersareencouragedtosendtheircommentstotheAgencyduringtheuseoftheseguidelinesinordertoimprovefutureeditions.
NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016
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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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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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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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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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
beattachedasAppendix2.
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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
(architecturalorengineeringdrawingsarenotrequired);
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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
limits
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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
b. Arrangementsforthehandlingofrejectedmaterialsandproducts
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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,
maintenanceandcleaning
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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
soiledgowning,
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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
specifications.
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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;
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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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CHAPTER
CONTRACT MANUFACTUREAND ANALYSIS9
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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.
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CHAPTER
COMPLAINTSAND PRODUCT RECALL10
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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).
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SELF-INSPECTION11
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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”).
NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016
REFERENCES
FURTHER READING
102
REF
EREN
CES
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.
http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm
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
NAFDAC GOOD MANUFACTURING PRACTICE GUIDELINES FOR PHARMACEUTICAL PRODUCTS 2016
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.