GuidanceforIndustry:

ProductQualityReview

Version1.0

DrugOffice
DepartmentofHealth

Contents

1.

Introduction..............................................................................................................................3

2.

Purposeofthisdocument.........................................................................................................3

3.

Scope........................................................................................................................................3

4.

Schedulingproductqualityreviews.........................................................................................3

5.

GroupingProducts....................................................................................................................4

6.

Preparingproductqualityreviews...........................................................................................4

7.

ConductinganddocumentingaPQR........................................................................................5

8.

EvaluatingPQRresults.............................................................................................................7

9.

PQRresponsibilitieswithcontractmanufacturing...................................................................8

GuidanceforIndustry:ProductQualityReviewsPage2

1.

Introduction
ThisguidelineisintendedtoprovidegeneralguidanceontheinterpretationofthePIC/SGuideto
Good Manufacturing Practice for Medicinal Products (PIC/S Guide to GMP) with respect to
implementingProductQualityReview(PQR).
There may beother acceptable approaches thatprovide an equivalent level of quality assurance.
This guideline is not intended to create additional requirements and is not intended to form the
basisforGMPinspections.

2.

Purposeofthisdocument
ToprovideguidancetoindustryonhowtoimplementProductQualityReviews(PQRs).

3.

Scope
PQRsarearequirementinPIC/SGuideforGMP,Clause1.4.
Regular periodic or rolling quality reviews of all registered pharmaceutical products, including
exportonly products, should be conducted to highlight any overall trends (not necessarily visible
with other quality systems) and to identify product/process improvements by verifying and
identifying:

4.

theconsistencyoftheexistingprocess(es);
trendsinproductdata;
the appropriateness of current specifications for starting materials, intermediates and
finishedproducts;
to verify compliance of the registered particulars of pharmaceutical products (Marketing
Authorisation);
deficienciesnotdetectedbyroutinetesting,monitoringorperformancemetrics;and
identifyopportunitiesforproductandprocessimprovements.

Schedulingproductqualityreviews
PQRsshouldtypicallybe:

carriedoutforeachproductmanufacturedinthepreviousyear;
takeintoaccountreviewsfrompreviousyears;and
useariskbasedapproach,refertoPIC/SGuidetoGMPAnnex20:QualityRiskManagement.

A PQR schedule is documented (typically annually) for each product/group of products within a
PQRregister(orequivalentmanagementtool).

Manufacturing
circumstances
Lowbatchnumbers

PQR scheduling requirements

Ifveryfewbatches(forexample,lessthanthree)aremanufacturedwithin12
months,aPQRcouldbeconductedeverytwoyears.
In this case the justification should also consider the risk associated with the
typeofmedicineandshouldbedocumented.1

Prioritisingspecific
PQRs

Considerthefollowingtoassistwiththeprioritisationofproductsforreview:

recurringdeviationsoncriticalparameters;

recalls,complaintsandreturns;and

processchanges.

http://www.tga.gov.au/industry/manufmedicinescgmpqa.htm#ch1Question20.

GuidanceforIndustry:ProductQualityReviews Page3

5.

GroupingProducts
PQRmaybecompletedbygroupingproductsbyaparticularcharacteristic/type.
Product groupings must be scientifically justified. For example, products selected within a group
must be similar enough so that the parameters being reviewed in the PQR are representative of
thegroup.Manufacturersshouldrevieweverybatchwithinthegrouping.
The justification for the groupings selected must be documented in the PQR report, or
alternatively, within the PQR procedure if groupings/approach will remain the same across
successivePQRs.
Important:Groupingsshouldnotbejustifiedbasedoncommercialfactors.
The grouped products should be of the same pharmaceutical form containing the same or very
similaractiveingredientsandexcipients,andmanufacturedusingthesametypeofequipment.

Example of appropriate groupings:

Example of inappropriate groupings:

Groupingsrelevanttothefacilitysfinished
productscouldinclude:

Thefollowinggroupingsareunlikelytobe
appropriatebecauseoffactorssuchas
significantlydifferentexcipients,chemical/physical
interactions,differenttypeofequipmentusedto
manufactureetc.:

finalpresentationsarethesamebutdifferent
packsizeordifferentbrandname;

ingredientsandprimarypackagingisthe
same,butdifferentstrengths;and

finalpresentationsarethesamebutdifferent
marketedregionsand/orproduct
registrations.

productswiththesameAPIbutverydifferent
excipients;and

liquidvs.solidpreparationsofthesameAPI
(e.g.creamvs.topicalointment,tabletvs.
gelcapvs.capsule).

The number and name of all finished products manufacturedwillvary from yearto year and as
newlicensedproductscomeontothemarket.Therefore,thenumberandnameofeachproduct
manufactured during the period of review for the PQR must be included within the PQR report
andwithinthePQRregister.

6.

Preparingproductqualityreviews
A PQR report should be preparedfor every scheduled review using a controlled reporttemplate
toensureastandardiseddocumentationapproach.Thereportshouldincludethefollowing:

productname(s);

batchsize(s)andpresentation(s);

reviewdate;

referencestosourcedata;

comparisonofthereviewfrompreviousPQRs;

datethatthenextreviewisrequired;

groupingsandscientificjustification;

identificationofissuesortrends;

summaryoffindings,conclusionsandrecommendations;

proposedactions;and

names and signatures (with date) of the persons responsible for preparing, reviewing and
approvingthereport.

GuidanceforIndustry:ProductQualityReviews Page4

7.

ConductinganddocumentingaPQR
PIC/SGuidetoGMP(Clause1.4)requiresthefollowingparameters(atminimum)tobeassessed
whenconductingPQR.

Parameter

Examples of information to be reviewed

Startingmaterials:

Areviewofstartingmaterials
includingpackagingmaterialsused
intheproduct,especiallythose
fromnewsources.

Identifyallstartingandpackagingmaterialsreceivedinthe
yearandusedinproductmanufacture

Nameofthesuppliers/manufacturersofthematerials

SuppliersCertificateofAnalysis(CoA)orCertificatesof
Compliance(CoC)oranalyticalresults

Significantdeviationsortrends

Inspectionrejectionrate

Changestoproductionprocessorspecificationsby
suppliers

Resultsofanalyticaltests

Inprocesscontrolsandquality
controltesting:
Areviewofcriticalinprocess
controlsandfinishedproduct
results.

TrendinprocesstestresultsandQCtestresultsinthe
manufacturingandpackagingprocessfrombothchemistryand
microbiologyaspects:
Trendingmaytakeintoconsideration:

Physicalvariationse.g.weight/dimension,friability,
hardness,disintegrationtime,fillvolume/overage,
uniformityofcontent

Chemicalvariationse.g.assay,related
substances/manufacturingrelatedimpurities,pH,residual
solvents

Rejectedunitse.g.breakages,particulates,etc.

Yieldreconciliationfromstagesofthemanufacturingprocess
usingdatafromtheassociatedbatchrecords.
Manufacturedbatches
(intermediates,bulk,finished
productsandcampaign
batches):
Areviewofallbatchesthatfailedto
meetestablishedspecification(s)
andtheirinvestigation.

Listdeviationsandnonconformancesassociatedwiththe
productunderreview

Identifydeviation/CAPAreportsandtheassociatedbatches

Identifycurrentstatusofinvestigationsprovidinga
summaryofthe:
- reasonforthefailure
- completedinvestigations
- correctiveactionstaken
- effectivenessoftheaction

DeviationsandCAPA:

Areviewofallsignificantdeviations
ornonconformances,theirrelated
investigations,andtheeffectiveness
ofresultantcorrectiveand
preventiveactionstaken.

Listthefollowingrelatingtosignificantdeviationsandnon
conformances:
- reasonforthefailure
- completedinvestigations
- correctiveactionstaken

Assesscorrectiveactionsforsignificantdeviationsandnon
conformancesfrompreviousPQRs,indicatingthestatusof
eachofthecorrectiveactions,andtheireffectiveness

GuidanceforIndustry:ProductQualityReviewsPage5

Parameter

Examples of information to be reviewed

Processortestingchanges:

Changesassessedshouldconsiderboththoseclosedduring
thereviewperiodandapprovedtocommencebutnotyet
implemented.Thechangestatusshouldbeidentifiede.g.
approvedtocommence,closedandassociateddates

Categorisethechangetypee.g.component,labelling
packagingmaterials,manufacturingprocess,analytical
methodsetc.andassessfortrendsandoverallimpacton
quality

Identifythebatchesaffected

Provideajustificationforthechange

Reviewtheeffectiveness/impactofthechangeonthe
batchunderreview

Areviewofallchangescarriedout
totheprocesses,oranalytical
methods.

Marketingauthorisations:
AreviewofMarketingAuthorisation
variationssubmitted/granted/
refused,includingthoseforthird
country(exportonly)dossiers.

ListandreviewtheMarketingAuthorisationvariations(include
thirdcountry/exportonlydossiers):

numberofproductssubmittedandgranted/refused

numberofproductsregisterslocallyandoverseas

anychangesmadetotheproductthatrequiresubmission
ofavariationtotheMarketingAuthorisation

fortheabove,variationsthathavebeensubmitted.Ifnot
submitted,thereasonsthereforeshouldbeinvestigated
andaconclusiondocumented

forvariationssubmitted,whetherornottheyhavebeen
grantedorrefused.Ifrefused,theimpactshouldbe
assessedanddocumented

Stabilityprogramme:

Areviewoftheresultsofthe
stabilitymonitoringprogrammeand
anyadversetrends.

Listthenumberofbatchesofproductinreviewincludedin
stabilitystudiesduringthereviewperiod

Reviewtheresultsofanylongtermandongoingstability
ofthebulkandmarketedproduct

Includeproductinformationsuchasmanufacturingdate,
referencetotheassociatedmethod,shelflife,etc.

Reviewanyoutofspecificationresults

Returnedproduct:

Batchnumber(s)

Areviewofallqualityrelated
returnsandtheinvestigations
performedatthetime.

Reasonforreturnandclassificationofreasonfortrending

Associatedinvestigationreportnumber

Actionstakenandbatchesaffected

Complaintsand/oradverse
events:

Batchnumber(s)

Reasonforcomplaintandclassificationfortrending

Previousinstancesoveradesignatedtimeperiod

Associatedinvestigationreportnumber

Actionstakenandbatchesaffected

Currentstatus

Recalls:

Batches/productrecalled

Areviewofallqualityrelatedrecalls
andtheinvestigationsperformedat
thetime.

Reasonforrecallandclassificationfortrending

Regulator(s)notifiedandrequiredregionalresponses

Associatedinvestigationreportnumber

Actionstakenandbatchesaffected

Currentstatus

Areviewofallqualityrelated
complaintsandtheinvestigations
performedatthetime.

GuidanceforIndustry:ProductQualityReviewsPage6

Parameter

Examples of information to be reviewed

ReviewofpastPQRresponses:

ThefocusofthisrequirementisonpreviousPQRsandthe
statusandeffectivenessofassociatedactions:

Areviewofadequacyofanyother
previousproductprocessor
equipmentcorrectiveactions.

reviewandreportonpreviousPQRCAPAsandchange
implementationstatus

assesseffectivenessofactionstakingintoaccountthe
currentPQRfindings

Postmarketingcommitments:

Countryofcommitment

FornewMarketingAuthorisations
andvariationstoMarketing
Authorisations,areviewofpost
marketingcommitments(ifany).

Productnameandpresentation

Descriptionofthecommitment

Statusofthecommitment

Equipmentqualification:

Listandreviewthefollowingforcriticalequipment/instruments
andutilitiesinproductionandlaboratorydepartments
associatedwiththeproductinreview:

Thequalificationstatusofrelevant
equipmentandutilities,e.g.HVAC,
water,compressedgases,etc.

Contractualagreements:
Areviewofanycontractual
arrangementstoensurethatthey
areuptodate.

Qualification/requalificationstatusandthenext
qualificationduedateofequipmentusedintheproduction
processesandQClaboratory

Referencetorelevantqualificationreports

Reviewchangesmadetoequipmentandutilitieswhich
resultedinrequalificationandassessforsubsequent
impacttoproductquality

Reviewcontractsforservicesassociatedwiththeproductin
reviewandreport:

nameandaddressofthecontractacceptor

availabilityanddetailsofthewrittencontract

typeofserviceprovidede.g.testingormaintenanceand
calibrationservices

confirmationthattheservicesprovidedarealignedwiththe
marketingauthorisation

RefertoPIC/SGuidetoGMP,Chapter7foradditional
informationoncontractmanufactureandcontract
requirements.

8.

EvaluatingPQRresults
The manufacturer must evaluate the results of the PQR to determine whether actions are
required,including:

correctiveorpreventativeactions;
validationorrevalidation;and

othersiteorprocesschanges.

Processesshouldbedemonstratedtobeincontrolbydeterminingupper/lowerlimitsandtrends.
Preventative actions mustbe implementedfor anyprocesses shown tobe notin control before
deviationsoroutofspecificationsoccur.
8.1Identifyingtrends
Appropriate statistical analysis technique should be used to review the data collected as part of
thePQR.

GuidanceforIndustry:ProductQualityReviewsPage7

Technique

Example

Charting

Runchart
Controlchart(e.gIandMRcharts)

Processcapability
studies

Processcapabilitystudyisastatisticalmethodwhichcanbeusedby
manufacturerstoestablishifspecificationlimitsaresetappropriately(eg.
UCLandLCL).Itcomparesprocessinformationtotheupperandlower
specificationlimits
ItisrecommendedthatCp/Cpkvaluesaretargetedat1.33orabove

8.2Interpretingresults
Analysis must be interpreted and documented as this will assist manufacturers to identify
correctiveandpreventativeactionsifrequired.
Proposed actionsandconclusions,includingjustification fornotimplementingactionswhen the
PQR has revealed an adverse trend on product quality must also be documented in the PQR
report.

9.

PQRresponsibilitieswithcontractmanufacturing
When manufacturingprocesses are partlyor whollycontractedout,technical agreements should
beinplacebetweenthevariouspartiesthatdefinestheirrespectiveresponsibilitiesinconducting
thePQR.
Refer toPIC/S Guide to GMP,Chapter 7 for additional information on contractmanufacture and
contractrequirements.

GuidanceforIndustry:ProductQualityReviewsPage8

DocumentInformation

Version

Date

DescriptionofChange

1.0

27Dec2013

Firstversion

References

DocumentTitle
PIC/SGuidetoGoodManufacturingPracticeforMedicinalProductsPE00910:PartIandII
PIC/SGuidetoGMPAnnex20:QualityRiskManagement
HealthSciencesAuthorityRegulatoryGuidance:GuidanceNotesonProductQualityReview

DOCUMENTEND

GuidanceforIndustry:ProductQualityReviewsPage9