a model quality assurance system for procurement agencies

This publication is intended to assist procurement agencies to procure safe, effective pharmaceuticals of suitable quality. The model described here focuses on four key agency activities: prequalification, purchase, storage and distribution of pharmaceutical products. The long-term goal of the recommendations made is the design and implementation of a uniform and harmonized system that will ensure procurement of pharmaceutical products of defined quality for supply to patients. The system should be based on a mutually recognized process of prequalification of products and manufacturers.

The publication is divided into six modules, with the first addressing the general requirements for the quality assurance system that should be in place at all procurement agencies. Module II sets out recommendations for agencies when they are evaluating their product needs, assessing the products offered, and the manufacturing and supply arrangements provided by the manufacturers. The next module describes principles of purchasing pharmaceutical products, and is followed by recommendations on how to receive and store them. Good distribution practices are covered in Module V, while the final module describes monitoring and reassessment of products and contracted-out activities. In addition to a useful glossary, the publication includes a number of appendices with sample forms and questionnaires to use when implementing the model, as well as the text of relevant WHO guidelines.

This is an interagency document published by the WHO Department of Medicines Policy and Standards on behalf of the organizations listed. The text was previously included as Annex 6 of the 40th Report of the WHO Expert Comittee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series No. 937, Geneva, World Health Organization, 2006).

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Recommendations for quality assurance systems focusing on prequalification of products and manufacturers,

purchasing, storage and distribution of pharmaceutical products

World HealtH organization

United nations CHildren’s FUnd

United nations development programme

United nations popUlation FUnd

World Bank

WHO/PSM/PAR/2007.3

Acknowledgements This document was previously published as Annex 6 of the 40th Report of the WHO Expert Comittee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series No. 937, Geneva, World Health Organization, 2006). WHO is grateful to the Committee members and to all of those acknowledged in that Technical Report.

© World Health Organization 2007

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]).

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization.

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Contents

Introduction.............................................................................................................5

Glossary. .................................................................................................................9

Module.I..General.requirements.for.procurement.agencies.....................................15

Introduction...........................................................................................................15

I.1 Physicalresources................................................................................................15

I.1.1 Premises..................................................................................................15

I.1.2 Equipment..............................................................................................16

I.1.3 Materialsandconsumables......................................................................17

I.1.4 Financialsystems.....................................................................................17

I.1.5 Humanresources.....................................................................................18

I.2 Documentationofpoliciesandstandards............................................................19

I.2.1 Qualitymanual.......................................................................................20

I.2.2 Standardoperatingprocedures................................................................20

I.2.3 Changecontrolpolicy.............................................................................22

I.2.4 Codeofconduct......................................................................................22

I.2.5 Guidelinesonconflictofinterest.............................................................23

I.2.6 Listofprequalifiedproductsandmanufacturers......................................23

I.2.7 Maintenanceofrecords...........................................................................24

Module.II..Prequalification................................................................................... 25

Introduction. ...................................................................................................... 25

II.1 Principlesforprequalification.............................................................................25

II.1.1 WHOModelListofEssentialMedicines................................................26

II.2 Standardsforprequalification.............................................................................26

II.3 Keypersonsandresponsibilities..........................................................................26

II.3.1 Staffresponsibleforprequalification........................................................26

II.3.2 Staffresponsibleforevaluationofproductinformation...........................27

II.3.3 Staffresponsibleforinspectionofmanufacturingsites.............................27

II.4 Keystepsinprequalification...............................................................................28

II.4.1 Step1:solicitandreceiveexpressionsofinterest......................................28

II.4.2 Step2:receiveproductinformation.........................................................32

Contents

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A model quality assurance system for procurement agencies

II.4.3 Step3:screenproductinformation..........................................................33

II.4.4 Step4:evaluateproductinformation.......................................................33

II.4.5 Step5:plan,prepareandperforminspections.........................................35

II.4.6 Step6:finalizeassessmentprocessandupdateprequalificationlist..........38

II.5 Requalificationandmonitoring..........................................................................40

II.6 Monitoringofcomplaints...................................................................................40

II.7 Costrecovery......................................................................................................40

Module.III..Purchasing.......................................................................................... 41

Introduction. ...................................................................................................... 41

III.1Strategiesforhealthsystems................................................................................41

III.2Procurementmethods.........................................................................................42

III.2.1Restrictedtender.....................................................................................43

III.2.2Competitivenegotiation..........................................................................43

III.2.3Directprocurement.................................................................................43

III.2.4Opentender............................................................................................43

III.3Qualityassuranceinpurchasing..........................................................................43

III.4Keyactivitiesinpurchasing.................................................................................44

III.4.1Productselectionandspecification..........................................................44

III.4.2Productquantification.............................................................................44

III.4.3Selectionofsuppliers...............................................................................45

III.4.4Adjudicationoftenders...........................................................................45

III.5Organizationandresponsibilities........................................................................46

III.5.1Procurementagencystructure..................................................................46

III.5.2Responsibilities........................................................................................47

III.6Monitoringofperformanceofprequalifiedmanufacturers..................................48

III.7Patents .........................................................................................................48

III.8Donations.........................................................................................................49

Module.IV..Receipt.and.storage.of.purchased.products......................................... 50

Introduction. ...................................................................................................... 50

IV.1 Pre-shipmentqualitycontrol...............................................................................50

IV.2 Receiptofstock..................................................................................................50

IV.3 Post-procurementqualitycontrol........................................................................51

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IV.3.1Sampling.................................................................................................51

IV.3.2Rejectedmaterials....................................................................................51

IV.4 Storageofmaterialsandproducts........................................................................52

IV.4.1Staff.........................................................................................................52

IV.4.2Storageareas............................................................................................52

IV.4.3Storageconditions...................................................................................52

IV.4.4Labellingandcontainers..........................................................................53

IV.4.5Miscellaneousandhazardousmaterials....................................................54

IV.4.6Stockcontrol...........................................................................................54

IV.4.7Documentation:writteninstructionsandrecords....................................55

Module.V..Distribution.......................................................................................... 56

Introduction. ...................................................................................................... 56

V.1 Transportconditions...........................................................................................56

V.2 Coldchain.........................................................................................................56

V.3 Temperaturemonitoringandrecords..................................................................56

V.4 Deliveryorder.....................................................................................................56

V.5 Dispatchproceduresandpolicies........................................................................57

V.6 Dispatchcontainers............................................................................................57

V.7 Dispatchrecords.................................................................................................57

V.8 Traceability.........................................................................................................57

V.9 Portofentry.......................................................................................................57

V.10Packagingofproductsandmaterials...................................................................57

Module.VI..Reassessment....................................................................................... 58

Introduction. ...................................................................................................... 58

VI.1Re-evaluationofmanufacturers...........................................................................58

VI.2Re-evaluationofproducts...................................................................................58

VI.3Monitoringofcontracted-outservices.................................................................59

VI.3.1Storageanddistribution..........................................................................59

VI.3.2Qualitycontrollaboratories.....................................................................60

VI.3.3Contractresearchorganizations...............................................................60

Conclusion.. ...................................................................................................... 60

References. . ...................................................................................................... 62

Contents

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Appendix1– Exampleofacodeofconduct.............................................................65

Appendix2– Exampleofaguidelineonconfidentiality...........................................71

Appendix3– Exampleofaguidelineonconflictofinterest.....................................72

Appendix4– Exampleofastandardoperatingprocedure(SOP) forwritinganSOP.............................................................................78

Appendix5– Exampleofaninvitationforexpressionofinterest..............................83

Appendix6– Pharmaceuticalproductquestionnaire................................................88

Appendix7– Exampleofastandardoperatingprocedureforscreening andassessingproductinformation......................................................93

Appendix8– Technicalquestionnaireforpharmaceuticalmanufacturers...............106

Appendix9– Exampleofastandardoperatingprocedureforplanning ofinspections...................................................................................114

Appendix10–Exampleofastandardoperatingprocedureforpreparing foraninspection..............................................................................120

Appendix11–Exampleofastandardoperatingprocedure forperforminganinspection............................................................125

Appendix12–Exampleofachecklistforgoodmanufacturingpractices..................131

Appendix13–Guidanceongoodmanufacturingpractices:inspectionreport.........133

Appendix14–Goodstoragepractice.......................................................................134

Appendix15–Goodtradeanddistributionpractices...............................................135

Appendix16–Qualitysystemrecommendationsforpharmaceutical inspectorates.....................................................................................136

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IntroductionThe World Health Organization (WHO), the United Nations Children’s Fund(UNICEF) and many other organizations are involved in the procurement ofpharmaceuticalproducts.Inparticular,thesupplyofpharmaceuticalproductsusedin the treatment of human immunodeficiency virus/acquired immunodeficiencysyndrome(HIV/AIDS),malariaandtuberculosishasbecomeamajorconcernatboththeinternationalandcountrylevels.CommitmentsbytheEuropeanCommissionand G8 countries, among others, offer the potential for significant increases infunding for efforts to combat communicable diseases. Low-cost pharmaceuticalproductsofassuredqualityhavethegreatestpotentialformaximizingtheimpactoftheseefforts.

The need for a model quality assurance system

Efforts to accelerate access to pharmaceutical products used in the treatment ofHIV/AIDS through negotiation and generic competition have highlighted theimportanceofqualityassuranceforprocurementofpharmaceuticalproductsanddiagnostics.Considerablesumsofmoneyareinvestedinprocuringpharmaceuticalproductsfromvariousmanufacturersindifferentcountries.However,evaluationofproduct-specificdataandinformationonqualityisoftenlacking,andinspectionsat manufacturing sites are not routinely performed to a consistent standard. Atpresent,someorganizationsinvolvedinprocurementofpharmaceuticalproductsdohavequalitysystemsforthedifferentactivitiesinplace.However,thesesystemsvarygreatlybetweenorganizations.Someprocurementagenciesrequestmanufacturerstosubmitachecklistorquestionnairecontainingproductinformationforassessment.In some cases, these checklists fail to address important aspects that should beevaluatedaspartofprequalification.Othersusedetailedquestionnairesorrequestproduct dossiers for evaluation. Some procurement agencies contract inspectorstoperforminspectionsattheplaceofmanufacture,buttheextentandqualityoftheseinspectionsmayvaryaccordingtotheresourcesavailable.Moreover,mutualrecognitionandcoordinationof such inspections isanexceptionrather thantherule.

Without a quality assurance system, organizations risk sourcing substandard,counterfeitorcontaminatedpharmaceuticalproducts,leadingtocomplaintsaboutproductsandproductrecalls,wastageofmoneyandserioushealthriskstopatients.Suchproblemsaffectthecredibilityofprocurementagencies,causefinanciallossesandputpatients’safetyindanger.

Background

Apreparatory studycarriedoutbya teamof experts emphasized the substantialdifferencesbetweenprequalificationofvaccinesandpharmaceuticals.Apilotprojecttostudythefeasibilityofprequalifyingmanufacturersofessentialpharmaceuticalproductsfortreatingprioritydiseaseswasrecommended.TheaccumulatedexperienceofexpertsfromUNICEF,theUnitedNationsPopulationFund(UNFPA),WHOand theWorldBankhas identified thenecessary elements to ensure appropriateproceduresforprocurement.

Introduction

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WHOthereforeundertook aprojectwith the above-mentionedUnitedNationspartners, which was supported in principle by the World Bank. The projectfocusedontheprequalificationofproductsandmanufacturersofHIVandAIDS-relatedproducts,andthedraftingofamodelqualityassurancesystem(hereafterreferredtoastheModel).ThisModelisintendedtoassistorganizationspurchasingpharmaceutical products, vaccines, or other health sector goods or which areotherwise involved in the prequalification, purchasing, storage and distributionof such products, hereafter referred to as procurement agencies, to procure safe,effectivepharmaceuticalsofsuitablequality.

Goal and objectives

Thelong-termgoaloftheserecommendationsisthedesignandimplementationofauniformandharmonizedsystemthatwillensureprocurementofpharmaceuticalproductsofdefinedqualityforsupplytopatients,basedonamutuallyrecognizedprocess of prequalification of products and manufacturers by means of productdossier evaluation and inspection of manufacturing sites. Such a process, asdefinedintheGlossaryanddescribedinModuleII,willhereafterbereferredtoasprequalification.

Establishing, harmonizing and implementing a quality assurance system forprequalification,purchasing,storageanddistributionofpharmaceuticalsisataskofconsiderablemagnitude,whichshouldbeundertakeninstages.Thefollowingobjectiveswereidentified:

• creation of a model quality assurance system (MQAS) to be adopted andimplementedbyprocurementagencies;

• creationofguidelinestoharmonizetheevaluationofdataandinformationonproductsaspartoftheprequalificationprocedure;and

• creationofunifiedstandardsforinspectionofmanufacturersandsupplierstoassesscompliancewithgoodmanufacturingpractices(GMP).

Quality assurance in procurement

Qualityassuranceisawide-rangingconceptwhichcoversallmattersthatindividuallyorcollectivelyinfluencethequalityofaproduct.Itisthetotalityofthearrangementsmadetoensurethatpharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.Qualityassurancethereforeincorporatesseveralfactorsandit isanintegralpartofallkeyactivitiesinprocurement.

The implementation of a quality assurance system in procurement, includingsystems forprequalification, storageanddistribution,mayaffectcosts.However,thebenefitsofensuringqualityoutweighthecostinvestmentbecausetheyreducethepossiblelossescausedbythepurchaseandsupplyofsubstandardproducts.

Prequalificationofproductsandmanufacturers,purchasing,storageanddistributionarecomplexprocessesthatmayinvolvemanyoffices,procurementagencies,sections

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ordepartmentsandseveralstagesofadministration,financeandtechnicaldecisions.Pharmaceuticalproductsarenotordinarycommoditiesoftradeandrequirespecialattention.Supportfromtheofficesresponsibleforqualityassuranceiscrucial.Theefficiencyoftheproceduresdependsingreatpartontheuseofaprovenmethodinaconsistentmanner.Theuseofastandardapproachwillensureconsistencyinallactivitiesinvolvedinprocurementofpharmaceuticalproductsofdefinedacceptablequality.

ThisModelfocusesonthefollowingfourkeyactivitiesofprocurementagencies:

• prequalificationofpharmaceuticalproductsandmanufacturers;

• purchaseofpharmaceuticalproducts;

• storageofpharmaceuticalproducts;and

• distributionofpharmaceuticalproducts.

Procurementagenciesareultimately responsible for theoutcomesofall fourkeyactivities. In some cases, one or more of the activities may be contracted out.Wherethisoccurs,awrittencontractwhichdescribestheresponsibilitiesofbothpartiesshouldbeagreeduponbetweenthetwoparties.Thecontract-giverremainsresponsibleforensuringthatthecontract-acceptormeetsthenormsandstandardsreflectedinthisModel.

Recommendations

ItisrecommendedthatprocurementagenciesinvolvedinanyofthekeyactivitiesofprocurementdevelopandimplementtheirowninternalqualityassurancesystemsonthebasisoftheModel,includingtheelementsdescribedandtechnicaldetailsspecified.Itisimportanttoensurethatthesystemisadaptedtoreflecttheactivitiesof each specific procurement agency. The system should cover all aspects of theagency’sactivitiesandshouldbecomprehensiveenoughtoensurethatinterrelatedactivitieswhichimpactonthequalityofpharmaceuticalproductsarelinked.

ThisdocumentprovidesguidelinesforUnitedNationsprocurementagencies,buttheymayalsobeusedbyotherprocurementagenciestoestablishqualityassurancesystemsfortheirownactivities.

Theseguidelinesaredesignedforprocurementofpharmaceuticalproducts.Theymayalsobeapplicabletotheprocurementofdiagnostickitsormedicaldevices.

Overview

This document is divided into six modules. Module I addresses the generalrequirements for the quality assurance system that should be in place at allprocurement agencies, irrespective of the number of key activities performed.ModuleIIsetsoutrecommendationsthatprocurementagenciesshouldimplementwhen evaluating their product needs, assessing the products offered and themanufacturingandsupplyarrangementsprovidedbythemanufacturers.Module

Introduction

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IIIdescribesprinciplesofpurchasingpharmaceuticalproducts.ModuleIVcontainsrecommendationsonhowtoreceiveandstorepurchasedproducts.InModuleV,gooddistributionpracticesaredescribedandModuleVIdealswithmonitoringandreassessmentofproductsandcontracted-outactivities.Thisdocumentalsoincludesdocumentation examples of elements of this Model as well as relevant existingWHOguidelines.

Throughout this document, reference will be made to existing WHO norms,standards, guidelines and texts. An effort has been made to avoid duplicationwhereverpossible.Whererelevant,referenceismadetorelateddocuments.

ThestandardtextManaging drug supply (1)providesacompleteanddetailedoverviewoftechnicalaspectsofpharmaceuticalsmanagement,includingallthekeyactivitiesofprocurement.

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GlossaryaccountabilityTheobligationtoaccountforone’sconductandactions,usuallytoanindividualorgroup,butultimatelytothepublic.Bothindividualsandorganizationsmaybeaccountable.There is someoverlapbetweenaccountabilityandtransparency (seebelow).

active pharmaceutical ingredient (API)Asubstanceorcompoundintendedtobeusedinthemanufactureofapharmaceuticalproductasatherapeuticallyactivecompound(ingredient).

affordabilityTheextenttowhichpharmaceuticalproductsareavailabletothepeoplewhoneedthematapricetheycanpay.

authorized personAperson(amongkeypersonnelofamanufacturingestablishment)responsibleforthereleaseofbatchesoffinishedproducts for sale. Insomegoodmanufacturingpractice(GMP)guidesandlegaltexts,thetermqualifiedpersonisusedtodescribeanalogousfunctions.

bioequivalenceTwo pharmaceutical products are bioequivalent if they are pharmaceuticallyequivalentorpharmaceuticalalternativesandtheirbioavailabilities,intermsofpeak(CmaxandTmax)andtotalexposure(areaunderthecurve(AUC)),afteradministrationinthesamemolardoseunderthesameconditions,aresimilartosuchadegreethattheireffectscanbeexpectedtobeessentiallythesame.

bioavailabilityTherateandextentatwhichtheactivepharmaceuticalingredientoractivemoietyisabsorbedfromapharmaceuticaldosageformandbecomesavailableatthesite(s)ofaction.

competitive tenderA procedure for procuring pharmaceutical products which puts a number ofsuppliersintocompetition.Purchasingisdoneonthebasisofquotationssubmittedbythesuppliersinresponsetoapublicnotice.

drugAnysubstanceorpharmaceuticalproductforhumanorveterinaryusethatisintendedtomodifyorexplorephysiologicalsystemsorpathologicalstatesforthebenefitoftherecipient.Inthisdocument,thetermsdrug, medicineandpharmaceutical product(seebelow)areusedinterchangeably.

drug legislationThe legal conditionsunderwhichpharmaceutical activities shouldbeorganized.(Seealsolegislationbelow.)

Glossary

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drug regulatory authorityAnationalbody that administers the full spectrumofdrug regulatory activities,includingatleastallofthefollowingfunctionsinconformitywithnationaldruglegislation:

•marketingauthorizationofnewproductsandvariationsofexistingproducts;

•qualitycontrollaboratorytesting;

•monitoringofadversedrugreactions;

•provisionofdruginformationandpromotionofrationaldruguse;

•good manufacturing practice(GMP)inspectionsandlicensingof manufacturers,wholesalersanddistributionchannels;

•enforcementoperations;

•monitoringofdrugutilization.

effectivenessAnexpressionofthedegreetowhichactivitieshaveproducedtheeffectsplanned.

efficiencyThe relationship between the results of activities and the corresponding effortexpendedintermsofmoney,resourcesandtime.

essential pharmaceutical productsThosepharmaceuticalproductsthatsatisfythehealthcareneedsofthemajorityofthepopulation.WHO’sExpertCommitteeontheSelectionandUseofEssentialMedicinesupdatestheWHO Model List of Essential Medicinesattwo-yearintervals.Eachcountrymayusethismodeltogenerateitsownlistofessentialpharmaceuticalproducts.

generic productsThetermgeneric producthassomewhatdifferentmeaningsindifferentjurisdictions.Theuseofthistermisthereforeavoidedasfaraspossible,andthetermmultisource pharmaceutical product(seebelow)isusedinstead.Genericproductsmaybemarketedeither under the approved nonproprietary name or under a brand (proprietary)name. They may be marketed in dosage forms and/or strengths different fromthoseoftheinnovator products(seebelow).Wherethetermgeneric productisused,itmeans a pharmaceutical product, usually intended tobe interchangeablewiththeinnovatorproduct,whichisusuallymanufacturedwithoutalicencefromtheinnovator company and marketed after expiry of the patent or other exclusivityrights.ThetermshouldnotbeconfusedwithgenericnamesforAPIs.

generic substitutionPracticeofsubstitutingaproduct,whethermarketedunderatradenameorgenericname,withanequivalentproduct,usuallyacheaperone,containingthesameactiveingredient(s).

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good manufacturing practice (GMP)Thatpartofqualityassurancewhichensuresthatproductsareconsistentlyproducedand controlled to thequality standards appropriate to their intendeduse andasrequiredbythemarketingauthorization.

indicatorCriterionusedtomeasurechanges,directlyorindirectly,andtoassesstheextenttowhich the targetsorobjectivesof aprogrammeorproject arebeingattained.Indicators shouldmeet thecriteriaofclarity,usefulness,measurability,reliability, validity(seebelow)andacceptancebykeystakeholders.

innovator pharmaceutical productGenerally the pharmaceutical product which was first authorized for marketing(normallyasapatentedproduct)onthebasisofdocumentationofefficacy,safetyandquality according to requirements at the timeof the authorization.Whenasubstancehasbeenavailableformanyyears,itmaynotbepossibletoidentifyaninnovatorpharmaceuticalproduct.

interchangeabilityAninterchangeablepharmaceuticalproductisonethatistherapeuticallyequivalenttoacomparator(reference)product.

International Nonproprietary NameTheshortenedscientificnamebasedontheactiveingredient.WHOisresponsibleforassigningINNstopharmaceuticalsubstances.

legislationThefirststageofthelegislativeprocess,inwhichlawsarepassedbythelegislativebodyofgovernmentwithregardtoasubjectmatter,e.g.controlofpharmaceuticals.Lawsdefinetheroles,rightsandobligationsofallparties involvedinthesubjectmatteringeneralterms(seealsoregulationsbelow).

licensing systemNational legal provisions on who should manufacture, import or supplypharmaceuticalproducts,whatqualificationspeopleinthesupplyingagencyshouldhave,andwhoshoulddispenseandsellpharmaceuticalproducts.

manufacture (manufacturing)Alloranyoperationsofpurchaseofmaterials andproducts,production,qualitycontrol, release, storage and distribution of finished products and the relatedcontrols.

marketing authorizationAlegaldocumentissuedbythecompetentdrugregulatoryauthorityforthepurposeofmarketingorfreedistributionofaproductafterevaluationforsafety,efficacyandquality.Itmustsetout,interalia,thenameoftheproduct,thepharmaceuticaldosageform,thequantitativeformula(includingexcipients)perunitdose(usingINNsornationalgenericnameswheretheyexist),theshelf-lifeandstorageconditions,and

Glossary

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packagingcharacteristics.Itspecifiestheinformationonwhichauthorizationisbased(e.g.“Theproduct(s)mustconformtoallthedetailsprovidedinyourapplicationand as modified in subsequent correspondence.”). It also contains the productinformation approved forhealthprofessionals and thepublic, the sales category,thenameandaddressoftheholderoftheauthorization,andtheperiodofvalidityof theauthorization.Onceaproducthasbeengivenmarketingauthorization, itisincludedonalistofauthorizedproducts–theregister–andisoftensaidtobe“registered”orto“haveregistration”.Marketauthorizationmayoccasionallyalsobereferredtoasa“licence”or“productlicence”.

medicineSeedrug.

multisource (generic) pharmaceutical productPharmaceuticallyequivalentorpharmaceuticallyalternativeproductsthatmayormaynotbetherapeuticallyequivalent.Multisourcepharmaceuticalproducts thataretherapeuticallyequivalentareinterchangeable.

national list of essential pharmaceutical productsThelistofessential pharmaceutical products(seeabove)thathasbeendefined,adoptedandpublishedatcountrylevel.Itisnormallyusedbyallhealthfacilities,includingthemainhospitals.

pharmaceutical productSeedrug.

prequalificationTheactivitiesundertakenindefiningaproductorserviceneed,seekingexpressionsof interest fromenterprises to supply theproductor service, and examining theproduct or service offered against the specification and the facility where theproduct or service is prepared against common standards of good manufacturing practice (GMP).Theexaminationoftheproductorserviceandofthefacilitywhereitismanufacturedisperformedbytrainedandqualifiedinspectorsagainstcommonstandards.Oncetheproductisapproved,andthefacilityisapprovedforthedeliveryof the specified product or service, other procurement agencies are informed ofthedecision.Prequalificationisrequiredforallpharmaceuticalproductsregardlessof theircompositionandplaceofmanufacture/registration,but theamountandtypeofinformationrequestedfromthesupplierforassessmentbytheprocurementagencymaydiffer.

procurementTheprocessofpurchasingorotherwiseacquiringanypharmaceuticalproduct,vaccine,ornutraceuticals forhumanuse.For thepurposeof thisdocument,procurementmeans the pre-selection of products and manufacturers through a procedure ofqualification, including prequalification (see above) and continuous monitoringthereafter,purchaseof theprequalifiedproducts fromprequalifiedmanufacturers(linkedto the specificproduct) throughdefinedpurchasingmechanisms, storageanddistribution.

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procurement agencyAnyorganizationpurchasingorotherwiseacquiringanypharmaceuticalproduct,vaccineornutraceutical forhumanuse.Inthecontextof theseguidelines itwillnormallybeanot-for-profitorganization,anongovernmentalorganization(NGO)or a United Nations organization. A procurement agency in the context of thisdocument is defined as any organization purchasing pharmaceutical products,vaccines,orotherhealthsectorgoodsorotherwiseinvolvedintheirprequalification(seeabove),purchasing,storageanddistribution.

product informationIn the context of this document, product information means information onpharmaceutical products submitted by manufacturers or suppliers in any of theformats specified in the procurement agency’s guidelines (including productdossiers,productquestionnairesorotherformats)toobtainprequalificationfortheproducts.

qualificationAction of proving and documenting that any premises, systems and equipmentare properly installed and/or work correctly and lead to the expected results.Qualification is often apart (the initial stage) of validation, but the individualqualificationstepsalonedonotconstituteprocessvalidation.Inthecontextofthisdocumentitistheworkdonetoprovethatthesupplysystemwilldeliverproductsofthequalityrequiredandspecifiedonaroutinebasis,meetingalltheapplicablequalityrequirements.

quality assuranceQualityassuranceisawide-rangingconceptcoveringallmattersthatindividuallyorcollectivelyinfluencethequalityofaproduct.Itisthetotalityofthearrangementsmadewiththeobjectofensuringthatpharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.

quality controlQualitycontrolisconcernedwithsampling,specificationsandtesting,andwiththeprocurement agency’sdocumentation and acceptance/rejectionprocedureswhichensurethatthenecessaryandrelevanttestsareactuallycarriedoutandthatstartingmaterials, intermediates and finished products are not accepted for use, sale orsupplyuntiltheirqualityhasbeenjudgedtobesatisfactory.

regulationsThesecondstageofthelegislativeprocess(thefirststagebeinglegislation,seeabove).Regulationsarespecificallydesignedtoprovidethelegalmachinerytoachievetheadministrativeandtechnicalgoalsoflegislation.

reliabilityAnexpressionofthedegreetowhichameasurementperformedbydifferentpeopleatdifferenttimesandunderdifferentcircumstancesproducesthesameresults(seealsovalidity).

Glossary

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reliable quantification of drug needsAcarefulevaluationofthequantitiesneededofeachdrug,basedoneitheradjustedpastconsumptionoranticipatedpatternofdiseasesandstandardtreatment,whichcanbeexpectedtomatchactualneedsreasonablywell.

transparencyThetermtransparencymeans:➣ definingpoliciesandproceduresinwritingandpublishingthewritten documentation;and➣ givingreasonsfordecisionstothepublic(seealsoaccountabilityabove).

validationAction of proving and documenting, in accordance with the principles of goodmanufacturing practice, that any procedure, process, or method actually andconsistentlyleadstotheexpectedresults(seealsoqualificationabove).

validityAnexpressionofthedegreetowhichameasurementperformedactuallymeasuresthecharacteristicwhichtheinvestigatorwishestomeasure(seealsoreliability above).

WHO-type certificateAcertificateofpharmaceuticalproductofthetypedefinedintheWHOCertificationScheme on the quality of pharmaceutical products moving in internationalcommerce.1

1 World Health Organization. WHO Certification Scheme on the quality of pharmaceuti-cal products moving in international commerce. Geneva, World Health Organization, 2000.WHO/EDM/QSM/2000.2.

(http://www.who.int/medicines/organization/qsm/activities/drugregul/certification/certifschemes.html).

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Module I

General requirements for procurement agencies

Introduction

Procurementagenciesoftenhavetopurchaseandsupplypharmaceuticalproductsusing scarce resources. In many cases, product quality is compromised whenproducts are obtained from unqualified sources. Procurement agencies will dealwithvarioustypesofsuppliersandcustomers,includingdrugregulatoryauthorities,manufacturers, quality control laboratories, contract manufacturers, contractlaboratories, traders, brokers, distributors and pharmacies. A quality assurancesystemwillassistinensuringthattransactionswiththesepartnersultimatelyresultinprocuringpharmaceuticalproductsofthebestpossiblequality.

Thismoduleaddressesthegeneralrequirementsforsuchasystem,includingphysicalresourcessuchaspremises,equipmentandpersonnel,aswellasthedocumentedpolicies, standards and procedures required to ensure consistency in all the keyactivitiesofprocurement.Thegeneral requirementsdescribed inthismodulearethereforeapplicabletoalltheactivitiescoveredinsubsequentmodules.

I.1 Physical resources

I.1.1 Premises

Offices

Theprocurementagency shouldhave sufficientoffice space toaccommodate thepersonnelrequiredandtheactivitiestobeperformed.

Storage

Theprocurementagencyshouldhavesufficientspaceforstorageandretentionofcommodities,includingproductdocumentation,productsamples,stock,reports,filesandotherrecordsrelatingtoallkeyactivitiesofprocurement.

Samplesandproductsshouldbestoredundersuitableconditionswhicharespecified,e.g.withregardtotemperature,humidityorprotectionfromlight.DetailsofstoragerequirementsaregiveninModuleIV.

There should be sufficient space for storage of equipment, stationery andmaterialsforproperdistribution.DetailsofdistributionrequirementsaregiveninModuleV.

Module 1

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I.1.2 Equipment

Computers

The use of computers can facilitate, but not replace, efficient procedures inpharmaceuticalprocurement.Whenimplementedappropriately,computerizationwillspeedupcomplextasks,increaseaccuracyandautomaterepetitivetasks.Staffmustbetrainedadequatelyintheuseofcomputerizedsystems.

Manyaspectsofprocurementaresuitableforcomputerization,includingplanningofrequirements,budgetmanagement,financialanalysis,preparationofdocumentationandreportsandinventorycontrol.Hardcopies(printouts)shouldbeproducedasrequiredtoprovidedocumentedevidenceoftheactivities.

Wherecomputersystemsarenotused,manualsystemsshouldprovidedocumentedevidenceoftheactivitiesperformed.

Software

Thesoftwareselectedshouldbesuitablefortheintendeduse.Theprogrammesusedshouldbeabletoprovidetherequiredqualityandmanagementinformationreliablyandaccurately.Theyshouldbeuser-friendlyandstaffshouldbetrainedadequatelyintheiruse.Wherepossible,differentprogrammesusedshouldbecompatiblesothatdatacanbetransferredbetweenthemwithouthavingtoberetyped.

Where information is exchanged between the procurement agency and themanufacturer(s)byelectronicmeans,appropriateprogrammesshouldbeinplace.

Suitable security systems should be in place to prevent unauthorized access orchanges to computer records and reports. Back-up systems must be in place topreventlossofdata.Agood-qualityvirusprotectionprogrammeandfirewallmustbeinstalled,configured,usedandupdatedregularlytopreventunauthorizedaccessandlossofdata.

Technicalsupportshouldbeavailabletoensurethatsoftwareandsecuritysystemsarekeptfunctionalanduptodate.

Hardware

Thehardwareselectedwhichshouldbeabletohandletherequiredsoftwareefficiently.Thesystemshouldhavesufficientcapacityandmemoryfortheintendeduse,aswellasadequateinputandoutputdevices,includinggoodqualityprinters.AccesstotheInternetandpossiblytoaninternalnetwork(LAN)shouldbeprovidedtofacilitateexchangeofinformation.

A maintenance and upgrading plan must be in place to ensure that the systemremainsfunctional.

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Telecommunications

There should be access to telephone and facsimile facilities to ensure instantcommunication. If at all possible, electronic mailing (e-mail) systems should beavailable.

Furniture

Suitable office furniture should be provided, including desks, chairs, shelves,cupboards,filingcabinetsandotheritemsasrequired.

Office equipment

Office equipment including copying machines, staplers and punches should beprovided.

I.1.3 Materials and consumables

Stationery and consumables

Theprocurementagencyshouldprovidestationerytoenablestafftoperformtherelevanttasks,includingpaper,letterheads,businesscardsandpre-printedformsasrequired.Computerconsumablestobeprovidedincluderemovablestoragedevices(floppydisks,CDsand/orflashmemorysticks),printercartridges,printingpaper,aswellasanyreplacementpartsnotcoveredbyamaintenancecontract.

Vehicles and transport

Officialtransportorreimbursementoftransportcostsincurredshouldbeprovidedfortripstomeetings,visits,inspectionsandperformanceofotherofficialduties.

Incaseswheretheprocurementagencyisresponsibleforlocaltransportationanddistributionofproducts,appropriatetransportshouldbeprovidedtoensurethatthequalityoftheproductsismaintained.

I.1.4 Financial systems

Theprocurementagencyshouldbeabletoeffectnationalandinternationalfinancialtransactionsasrequired.Fundsmustbeavailabletoensurecontinuedoperations,whetherornotcostrecoverymechanismsforkeyactivities,e.g.prequalification,areinplace.

Adequatebankingfacilitiesmustbeavailable.Signatoriesofbankaccountsshouldbeappointedtoensurecontrolononehand,andcontinuityofoperationsduringtheabsenceofkeypersonnelontheotherhand.

An accounting system should be in place. Regular financial audits should beperformed.

Iftheprocurementagencyispartofalargerorganization,itshouldhavesufficientautonomyand/orsufficientlygoodcommunicationwiththemotherorganization’s

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financialdepartmenttoenableittoconductall itsfinancialtransactionswithoutdelay.

I.1.5 Human resources

Personnel

There should be a sufficient number of appropriately trained, educated andexperiencedpersonnel toperform thekey activities.Thenumberofmembersofstaffrequiredinthedepartmentresponsibleforthekeyactivitieswilldependonthevolumeandvalueofproductssourcedandtobesupplied.Sufficientsupportstaffforsecretarial,organizationalandaccountingdutiesaswellaslegalsupportshouldalsobeavailable.

Key personnel should include those responsible for prequalification, purchasing,storageanddistribution.Thepersonresponsibleforprequalificationcouldalsoberesponsibleforqualityassurance.Nationallegislationshouldbecompliedwith,e.g.requirements foraresponsiblepersonforpurchasing, storageanddistributionofpharmaceuticalproducts.

Thepersonresponsibleforprequalificationandthepersonresponsibleforpurchasingshouldbeindependentofoneanother.Oneshouldnotreporttotheother.

TheresponsibilitiesofthestaffinchargeofthedifferentkeyactivitiesaredescribedinModulesIItoV.

Qualifications and experience

Personnel responsible for prequalification, purchasing, storage and distributionshouldhavesufficientqualifications,knowledgeandexperienceoftheirrespectivefields(seeModulesIItoV).

Code of conduct

Allstaffmembersshouldcomplywithacodeofconductwhichshouldguidealltheir professional activities. More detail on codes of conduct is given in sectionI.2.4.AnexampleofacodeofconductisshowninAppendix1.

Confidentiality

It is essential that all information obtained by any person working for theprocurementagency is treatedasconfidential.Mostof the informationobtainedfromcompaniesandmanufacturersisproduct-specific,maybepatentedandwillbecommerciallysensitive.Theevaluatorsandinspectorsmusttreatallinformationsubmittedandobservedduringtheassessmentofproductdossiersandinspectionsat manufacturing sites, and otherwise in connection with the discharge of theirresponsibilitiesinregardoftheabove-mentionedproject,asstrictlyconfidentialandproprietarytothepartycollaboratingwiththeprocurementagency.

Confidentialityagreementsshouldbesignedbyassessorsandinspectors.Anexample

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ofsuchanagreement isattachedinAppendix2.Additional informationmaybefoundinAppendix3(exampleofaguidelineonconflictofinterest).

Conflict of interest

Before undertaking any work, assessors and inspectors (including contractedpersonnel) should signadeclarationof interest. If,basedon theirdeclarationofinterest, it isdeemedappropriateforthemtoundertaketheworkspecified,theyagreetocarryouttheirfunctionsexclusivelyfortheagency.Theyshouldconfirmthattheinformationdisclosedbytheminthedeclarationofinterestiscorrect,thatnosituationofreal,potentialorapparentconflictofinterestisknowntothemandthat theyhavenofinancialorother interest in, and/or relationshipwithapartywhich:

• mayhavevestedcommercialinterestinobtainingaccesstoanyconfidentialinformation disclosed to them in the course of the evaluation activitiesdescribedinthedeclaration;and/or

• mayhaveavestedinterestintheoutcomeoftheevaluationactivitiesincluding,but not limited to, parties such as the manufacturers whose products aresubjecttoevaluationormanufacturersofcompetingproducts.

Personnel should undertake to advise the procurement agency promptly of anychangeintheabovecircumstances,forinstanceifanissuearisesleadingtoaconflictofinterestduringthecourseoftheirworkfortheprocurementagency.

Job descriptions

Thereshouldbewrittenjobdescriptions,withdefinitionsofresponsibilities,forallpersonnel.

Organizational structure

Theprocurementagencyshouldhaveanorganizationchartindicatingthepositions,namesofresponsiblepersonsandreportinglines.

The organization chart should reflect the responsibilities and reporting lines inaccordancewiththejobdescriptions.

I.2 Documentation of policies and standards

Documentation isacriticalpartofaqualityassurance system.Theprocurementagencyshouldhaveacomprehensivedocumentationinfrastructure,whichshouldinclude policies, guidelines, norms, standards, manuals, procedures, records andrelateddocuments.

Allactivitiesofeachsectionordepartmentshouldbeperformedanddocumentedinastandardizedmanner,followingapprovedwrittenprocedures.

The main elements of the documentation system of this Model are describedbelow.

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I.2.1 Quality manual

The procurement agency should have a quality manual. The purpose of such amanualistodocumentthequalitypolicyasdefinedbymanagementinrelationtothevariousactivitiesundertakenbytheprocurementagency.Thereshouldbepolicystatementsandaqualitypolicy in termsof theagency’sactivitiesandobjectives,as well as documents describing the policy of each section or department withregardtoallactivitiesinprequalificationandsubsequentpurchasing,storageanddistribution.

Oncethisqualitypolicyisdefined,itshouldbeimplemented,maintained,reviewedandamendedasnecessaryatregularintervalsbytheprocurementagency.

I.2.2 Standard operating procedures

Theprocurementagencyshouldhavewritten,clearanddetailedstandardoperatingprocedures(SOPs)foralltheactivitiestobeperformedintheprocurementagency.ThecontentofeachSOP,particularlythestep-by-stepdescriptionsofactivitiesandapprovedrecordingorreportingformatsattachedasaddenda(seebelow),shouldreflecttheoperationsoftheparticularprocurementagency.

SOPsshouldbedraftedbythepersonresponsiblefortheprocedure.AnSOPforwriting anSOP shouldbe followed to ensure consistencyofdesign, format andlayout.AnSOPonhowtowriteanSOPisattachedasAppendix4.

Style and layout

SOPs should be written in the procurement agency’s approved format, and beformallyapproved(signedanddated)bytheauthorizedperson(s).

SOPsshouldbewritteninclear,unambiguouslanguage.

Thenameand/orlogooftheprocurementagencyshouldbeincludedonthefrontpageofeachSOP.

Elements of standard operating procedures

TheSOPshouldcontainatleastthefollowingelements.

Title and number

EachSOPshouldhaveatitle.Thetitleshouldgiveaclearindicationoftheactivitywhichitdescribes.Anumberingsystemisuseful to identifytowhichactivityordepartmenttheSOPrefers.

Objective

Thissectionshoulddescribewhatistobeaccomplishedand/orachievedwiththeSOP.

Scope

This section should describe to what level or depth, or how widely, the SOP isapplicable.

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Policy

Thissectionshouldreflecttheprocurementagency’spolicyregardingthisparticularactivity.

Responsibility

Thissectionshouldlisttheperson(s)responsibleforperformingtheactivitieslistedintheprocedure.Itmaybeusefultorefertothepositionratherthanthenameoftheperson.

Action

Thissectionshoulddescribethesequenceofactionstepstobefollowed,fromthebeginningtotheendoftheprocess,toperformtheactivity.Theactionstepsshouldbewrittenintheimperativeandshouldbenumbered.Itisadvisabletoindicatewhoisresponsibleforeachstep.Thiscouldbedonebyputtingtheposition(jobtitle)oftheresponsiblepersoninbracketsnexttoeachstep,orbyindicatingthenumbersoftherelevantstepsnexttothepositionslistedundertheheading“Responsibility”.Whereastepleadstoanotherproceduretobefollowed,theapplicableSOPshouldbereferredtointhatparticularstep.

Distribution and retrieval

Documentationshouldbedistributedwithcare.NosupersededorobsoleteSOPsshouldbeavailableatuserpoints.Thesectionsand/orresponsiblepersons(positions)towhomtheSOPwasdistributedshouldbelisted.EachtimetheSOPisreviewedand amended, superseded versions of the SOPs shouldbe removed fromall theuserpoints listed and replacedwith theupdatedversion; the retrieval shouldbedocumented.

Revisions

Inasectionwhichcouldbeheaded“History”,thedateofeachchangetotheSOP,thepersonresponsibleforthereview,thechangeitselfandthereasonforthechangeshould be recorded. This section will provide the procurement agency with thehistoryoftheamendmentstotheSOP.

Addenda

Anyrecords tobecompletedormaintainedaspartof theactivityshouldhaveastandardizedformat. It isuseful todefineandapprovethese formats inadvance.TheapprovedstandardformatshouldbepartoftheSOPandcanbeattachedasanaddendumtotheSOP.

Activities to be covered by standard operating procedures

ThefollowinglistgivesexamplesofactivitieswhichcouldbecoveredbySOPs:➣ howtowriteastandardoperatingprocedure(seeAppendix4);➣ draftingacontractoragreement;➣ amendmentstocontractoragreement;➣ identifyingandreportingcounterfeitproducts;➣ reportingofdeviations;➣ appointingevaluatorsofproductinformation;

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➣ appointingcontractinspectors;➣ maintainingamasterdocumentationlist;➣ receivingandscreeningofanofferreceived;➣ evaluatingoffersreceived;➣ orderingproduct(s)fromsupplierormanufacturer;➣ publishingspecificationsofproductsforprocurement;➣ sendingout,receivingandevaluatingsupplierquestionnaires;➣ handlingrecalls;➣ policyforregularre-inspection;➣ routinefollow-upofinspections;➣ inspectionfaultcorrection;and➣ standardformatsforinspectionreporting.

I.2.3 Change control policy

Theprocurementagencyshouldhaveapolicyforchangecontrol.Thispolicyshouldbedesignedtomanagechangesintheagency’sownproceduresanddocumentation,aswellaschangesindataandinformationonthepharmaceuticalstobeprequalified.

AprocedureforcontrollingchangesthataffectAPIs,formulation,manufacturingprocesses,analyticaltestingmethodsorpackagingofprequalifiedproductsisessential.Theprocedureshouldensurethatthesechangesarereportedtotheprocurementagency before new batches are manufactured or before they are delivered andreleasedfordistribution.DetailsofmanagingchangesinproductinformationaregiveninModuleVI.

I.2.4 Code of conduct

Theprocurementagencyshoulddesign,authorizeandimplementawrittencodeofconduct.

The code of conduct should describe the policy of the procurement agencyregardingtheconductofstaffinrespecttotheiractivities.Itshouldbefollowedbyallpersonnel.

Thecodeofconductshouldgiveguidancetostaffmembersonappropriateconductinvarioussituations.Thefollowingtopicscouldbecoveredinthecode:➣ introductionandobjectives;➣ keyresponsibilities;➣ personalresponsibilities;➣ safety;➣ professionalcompetence;➣ qualificationsandexperience;➣ conduct;➣ integrityandattitude;➣ attire,healthandhygiene;➣ managementrelationship;➣ SOPs;

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➣ travelandaccommodation;➣ confidentialityandconflictofinterest;➣ documentationandrecords;➣ contractsandtermsofreference(TOR);➣ productfiles,evaluationandinspection;➣ samples;➣ evaluationandinspectionreports;and➣ provisionofinformationandadvice.

I.2.5 Guidelines on conflict of interest

The procurement agency should have a policy on conflict of interest which allpersonnelshouldobserve.AnexampleofaguidelineonconflictofinterestisshowninAppendix3.

Thedocumentshouldaddressatleastthefollowingpoints:➣ introductionandobjectives;➣ definitionsandprinciples;➣ responsibilities;➣ confidentiality;and➣ impartiality.

I.2.6 List of prequalified products and manufacturers

Theprocurementagencyshouldhaveaprocedurefordraftingandmaintainingalistofprequalifiedproductsandmanufacturers,basedontheoutcomeoftheevaluationofproductdataandinformationandmanufacturingsiteinspections.Thelistshouldbeproduct- andmanufacturing site-specific, i.e. sites areprequalified foroneormorespecifiedproducts,andproductsareprequalifiedasmanufacturedatspecifiedsites.

Thekeypersonresponsibleforprequalificationshouldberesponsibleforadditiontoand/ordeletionsfromthelist.

Once the evaluation of a product dossier is complete, and the inspection hasbeen performed to assess compliance with good manufacturing practices, goodstoragepracticesandgooddistributionpracticesasappropriate,theprocurementagencyshouldpreparealistreflectingthestatusoftheprequalifiedproductsandmanufacturers.

Thelistshouldcontainatleastthefollowinginformation:➣ nameoftheprocurementagency;➣ authorizationsignatures;➣ referencenumberandversionofthelist;➣ dateofpreparationofthelist;➣ nameandphysicaladdressofmanufacturer,includingtheapprovedsite(s)of

manufacturelinkedtoeachproduct;➣ contactdetails, includingpostaladdress,telephone,faxnumberande-mail

addressofthemanufacturerandsupplier;

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➣ productdetails,includingthebrandname,INN,dosageform,strengthperdoseandpacksize;

➣ dateoforiginalprequalification;➣ dateofexpiryoftheprequalification;and➣ dateuntilwhichthelistisvalid.

I.2.7 Maintenance of records

Recordsofalloperations shouldbemaintainedandkept ina suitablyorganizedmanner.

Sufficient areas for the storage of records, including product information,manufacturers’informationandinspectionreports,shouldbeavailable.

Access to these areas should be restricted to authorized personnel only, asconfidential informationmaybefiled (including recordsofmanufacture, testingand/orstorage).

Records should be maintained for a defined period of time, in accordance withnationallegislation.Generallytheyshouldberetainedforatleastoneyearbeyondtheexpirydateofthefinishedproduct.

Module II. Further guidance on record-keeping in quality assurance systems isprovidedintheWHOpublicationQuality assurance of pharmaceuticals (2, 3).

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Module II

Prequalification

Introduction

Prequalification is one of the key elements in ensuring purchase and supply ofpharmaceuticalproductsofacceptablequality.Theprequalificationprocesscanbesubdividedintotwomajorparts,i.e.product-relatedassessmentandmanufacturer-relatedassessment.

• Product-related assessmentshouldensurethatthecorrectproductisspecifiedbytheprocurementagency.Theprocurementagencyshouldthenassesswhetherthemanufacturerisofferingaproductthatmeetsthepredeterminednormsandstandardsintermsofsafety,qualityandefficacy.

• Manufacturer-related assessmentshouldensurethatthemanufacturerisabletomanufacturetheproductasspecifiedintheproductinformationpackageandinaccordancewithgoodmanufacturingpractices(GMP)asrecommendedbyWHO.Themanufacturermustbecapableofroutinelycarryingouttheactivities to the specifiedstandards toensurebatch-to-batchconsistencyoftheproduct.

Assessment of contracted-out services, e.g. by storage and distribution agents,contract research organizations (CROs) and quality control laboratories forcompliancewithGMP,goodclinicalpractices(GCP)andgoodlaboratorypractices(GLP),arefurtherelementsthatmaysupplementtheprequalificationprocess.

TheprocurementagencyisresponsibleforensuringthatallstepsintheprequalificationprocessarecarriedoutinaccordancewiththisModel.Thisshouldensurethatthemanufacturerswillbeprovidingproductsasspecifiedthatmeetallpredeterminednormsandstandards.Itwillassistprocurementagenciesinmaximizingtheuseofresourcesandwillavoidduplicationofprequalificationbydifferentprocurementagencies.Itshouldalsominimizetheriskofprocurementagenciespurchasingandsupplyingsubstandardproducts.

This module sets out recommendations which procurement agencies shouldimplementwhenevaluatingtheirproductneedsandwhenassessingtheproductsandthemanufacturingandsupplyarrangementsofferedbythemanufacturers.

II.1 Principles for prequalification

Prequalificationproceduresshouldbebasedonthefollowingprinciples:• reliance on the information supplied by the national drug regulatory

authority;• evaluation of product data and information submitted by manufacturers,

includingproductformulation,manufactureandtestdataandresults;• ageneralunderstandingof theproductionandqualitycontrolactivitiesof

themanufacturersandsuppliersandoftheircommitmenttotheprinciplesofGMP;

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• assessment of consistency in production and quality control throughcompliancewithGMPasdescribedintheWHOpublicationQuality assurance of pharmaceuticals,Volumes1and2(2,3)andsupplementaryWHOGMPguidelines;

• availabilityofappropriatequalitysystemsandSOPs;• randomsamplingandtestingofpharmaceuticalproductssupplied;• adequatepurchasingmechanisms(seeModuleIII);• goodstoragepractices(seeModuleIV);• gooddistributionpractices(seeModuleV);• monitoringofcomplaintsfromprocurementagenciesandcountries;• adequatehandlingofcomplaintsandrecalls;and• continuousmonitoringandrequalification.

The procurement agency should have a document describing the policy andprocedures forprequalification, including theassessmentofproduct informationandofmanufacturersforcompliancewithstandards.

II.1.1 WHO Model List of Essential Medicines

Procurement agencies may find that many of the products they require are onWHO’sModelList ofEssentialMedicines,which containsmedicinesofprovensafety and efficacy and is updatedperiodically (4).Procurement agencies shouldfocusonprocurementofmedicinesreflectedintheModelList.Theywillfindthislist auseful reference forestablishing specifications for themedicinesneeded fortheirpurposes.

II.2 Standards for prequalification

TheprequalificationprocedureshouldbebasedontheProcedureforassessingtheacceptability,inprinciple,ofpharmaceuticalproductsforpurchasebyUnitedNationsAgencies (5). In principle, products should meet at least the recommendationsmadebyWHOinMarketing authorization of pharmaceutical products with special reference to multisource (generic) products – a manual for drug regulatory authorities(6).ManufacturingsitesshouldcomplywithatleastWHOGMP(3).

II.3 Key persons and responsibilities

II.3.1 Staff responsible for prequalification

Thepersonresponsibleforprequalificationshouldbeindependentfromthepersonresponsibleforpurchasing.

The key responsibilities of the person responsible for prequalification activitiesshouldincludethefollowing:➣ establishingspecificationsforproducts;➣ publicationofinvitationsforexpressionsofinterest(EOI);➣ preparationofaquestionnaire forcollectingproductdataand information

and/orguidelinesforthe—compilationofproductinformation;

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➣ assessmentofproductdataandinformationforcompliancewithnormsandstandards;

➣ assessmentofmanufacturingsites,throughinspection,forcompliancewithWHOGMP;and

➣ preparationofthelistofprequalifiedproductsandmanufacturers.

II.3.2 Staff responsible for evaluation of product information

Thepersonresponsibleforevaluationofproductinformationshouldbeindependentfromthepersonevaluating themanufacturing site.Neither should report to theotherintermsofdecision-making.

Thekeyresponsibilitiesofthepersonresponsibleforevaluatingproductinformationshouldinclude:➣ preparingandimplementingSOPsandguidelinesforevaluationofproduct

information;➣ receiptofproductinformation;➣ screeningofproductinformation;➣ evaluationofproductinformation;➣ informingmanufacturers of the outcomeof the evaluationof theproduct

information;and➣ communicatingwiththepersonresponsibleforinspectionsofmanufacturing

sites.

Thepersonresponsiblefortheevaluationofproductinformationmaybeamemberoftheexistingstafforappointedforthistask.

The people assigned to evaluate product information should have relevantqualifications and experience, including a background in pharmaceuticals,pharmaceutical chemistry and pharmacology. Ideally they should be from aregulatorybackground,orhaveregulatoryexperience.

II.3.3 Staff responsible for inspection of manufacturing sites

Thekeyresponsibilitiesofthepersonresponsibleforinspectionofmanufacturingsitesshouldincludethefollowing:➣ preparationandimplementationofguidelinesandSOPs;➣ coordinationofinspectionstobeperformed;➣ recruiting or appointing inspectors with appropriate qualifications and

experiencewhennecessary;➣ trainingofinspectors;➣ organizationofinspections;➣ finalizinginspectionreports;and➣ informingmanufacturersoftheoutcomeoftheinspection.

Asaminimum,thepersonnelresponsibleforinspectingmanufacturingsitesshouldhave relevant qualifications and experience in pharmaceutical manufacturing,qualityassurance,GMP,performinginspectionsandaudits,chemistryandqualitycontrol.Ideallytheyshouldhaveaninspectionbackgroundfromworkingwitharegulatoryauthority.

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Althoughdecision-makingshouldbeindependent,thereshouldbecommunicationbetween the person responsible for evaluation of product information and thepersonresponsibleforinspectionofmanufacturingsites,assomeinformationontheproductmayhavetobeverifiedduringthesiteinspection.

II.4 Key steps in prequalification

ThekeystepsinprequalificationaresummarizedinFig.1.Detaileddescriptionsofthedifferentstepsaregivenbelow.Thepreparatorystepsofdraftingadocumentationsystem, including confidentiality agreements, declaration of conflict of interest,SOPsandguidelines,aredescribedinModuleI.

II.4.1 Step 1: solicit and receive expressions of interest

Draft product specifications for prequalification

Specificationsfortheproduct(s)tobeprequalifiedshouldbedraftedwithinputfromthepersonresponsibleforpurchasing,sothattheproductmeetstherequirementsfortheintendedpurpose.

Thespecificationsshouldbedetailed,clearandunambiguoustoavoidunnecessarysubmission and processing of documentation not relevant to the product to besourced.

Thespecificationshouldstateatleast:➣ thenameoftheactivepharmaceuticalingredient(s);➣ pharmacopoeia reference (if any), e.g. European Pharmacopoeia,

Japanese Pharmacopoeia, United States Pharmacopeia and InternationalPharmacopoeia;

➣ strengthperdoseanddosageform;➣ dosageform(routeofadministration);➣ packsize;➣ packingmaterial;and➣ labellingrequirements.

ThespecificationcouldbepublishedaspartoftheinvitationforEOIs.

Draft and publish invitation for expressions of interest

Oncethespecificationisfinalized,aninvitationforEOIsshouldbepublishedwidelyto reach any manufacturers that may be interested in supplying the product(s).

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Figure 1Key steps in prequalifi cation

Step 1: solicit and receive expressions of interest (EOIs)

Step 2: receive product information

Step 3: screen product information

Step 5: plan, prepare and perform inspection

Step 6: finalize assessment process and update prequalification list

Draft documentation system, confidentiality agreements, declaration of conflict of interest, SOPs and guidelines

Make administrative arrangements for transport, accomodation, etc.

Draft screening form, guidelines for evaluation, product assessment report format

Draft product specifications and invitation for EOIs

Collate information to plan inspections

Draft documentation, guidelines and SOP for inspections

Plan inspections

Evaluate product information

Step 4: evaluate product information

Write reports

Communicate results to suppliers, requesting additional information if necessary

Perform inspections

Write reports

Communicate contents to manufacturers, requesting additional information if necessary

Review additional information submitted

Inform manufacturers of outcome

Make decision on prequalification

Finalize list of prequalified manufacturers and products

Inform recipients of any changes to the list

Publish revised list periodically

Publish invitation for EOIs

Receive EOIs

Send guidelines for submitting product information to manufacturers

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Theprocessof inviting all interestedmanufacturers to submit theirEOI for thepharmaceutical products listed should be open and transparent. Invitations forEOIsmaybepublishedforgroupsofproducts,andmayberepeatedasnecessary.

TheinvitationforEOIsshouldbedetailedandshouldstateatleast:➣ thepurposeoftheinvitationforEOIs;➣ theobjectiveoftheinvitationforEOIs;➣ thelistofproducts,includingspecificationsforeachproduct;➣ informationonquantitiesrequired(ifavailable);➣ detailsoftheinformationtobesubmitted;➣ guidelinesforsubmission,includinginformationondetailstobesubmitted

aspartoftheEOI,onthefocalpointforthesubmissionandontheformatforthesubmission;

➣ contact details (name, address, telephone number, fax, e-mail and postaladdress)forsubmissionoftheEOI;and

➣ theclosingdateforreceiptoftheEOIbytheprocurementagency.

AnexampleofaninvitationforEOIsisshowninAppendix5.

Manufacturers should submit their EOI with the requested information abouttheproduct(s)andmanufacturer(s),beforethedatespecifiedbytheprocurementagency.

Receive expressions of interest

TheprocurementagencyshouldensurethattherelevantinfrastructureexistsforthereceiptandprocessingoftheEOIsthroughthesubsequentprequalificationsteps.

The procurement agency should have a clear policy regarding the acceptance ofEOIs after the specified closing date. Processing of late submissions should notnormallybeallowed.OnlyinexceptionalinstancesshouldlateEOIsbeconsidered,e.g.whenamanufactureristheonlyonetoexpressaninterestinsupplyingaspecificproduct.

It would be appropriate to express concern at the late arrival of the EOI, andmanufacturersshouldgivereasonsforlatesubmission.

ArecordofalltheEOIsreceivedfromeachmanufacturershouldbemaintained.

Send guidelines for submitting product information to manufacturers

Manufacturers who have submitted an EOI before the closing date specified inthe invitation shouldbegivenguidelines for the compilation and submissionofinformation on products and manufacturers. The guidelines should be publiclyavailableandaccessible. Incaseswhere this isnotdone, reasons for thedecisionshouldbegivenanddocumented.

Theguidelinesshouldbewritteninclear,unambiguouslanguage.Guidelinesshouldcontaininformationincludingatleast:• the content and format of submission, including the type and format of

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information required (e.g. the procedure for submission of informationforaproductregisteredinacountryrecognizedashavinganeffectivedrugregulatoryagency,and instructions forcross-referencinganexistingdossierwiththeprescribedsubmissionformat);and

• theprocessofsubmission,includingtheaddresstowhichthedocumentationshouldbesentandastatementofanyfeespayableforcostrecovery.

Content and format of submission

Foreachproducttobeprequalified,interestedmanufacturersshouldbeaskedtosubmitproductinformation,togetherwithasampleofsufficientquantitytoallowanalysesof theproduct against itsfinishedproduct specification as stated in theproductinformation,acoveringletter(asrecommendedontheEOI)andachecklistfortheproductinformation.

Dependingontheactive ingredients,countryofmanufactureandregistrationofproductstobeprequalified,differentformatsforsubmissionwillberequired.

Detailedinformationshouldbesubmittedforproductsforwhichbioavailabilitymaybealteredbychirality,isomerism,controlledreleaseformulation,polymorphismorotherpropertieswhichmayaffectthetherapeuticoutcome.

In thisdocument, the term“product information”refers toanyof the followingfourformats,inwhichsubmissionsshouldbemade:1. A product dossier, which should be submitted for multisource (generic)

products,forinnovatorproductswhichhavebeenonthemarketforlessthanfiveyears,andforproductscontainingsubstancesthathavespecificpropertiesthatmayhaveexplicitimpactonthesafety,efficacyorqualityoftheproduct.The“Model application form for new marketing authorizations, periodic reviews and variations, with notes to the applicant” (7) may also provide a helpfulexampleofguidelinesforthistypeofsubmission.

2. Astandardproductdossieraspreparedforanationaldrugregulatoryauthoritycanbesubmitted,provideditcontainstheappropriateinformationasrequiredintheseguidelines.Insuchcases,thesuppliershouldprovideacoveringletterwhichindicateswheretherequiredinformationcanbefoundinthestandardproductdossier.

3. For products manufactured and registered in countries where regulatoryrequirementsareinlinewithinternationalregulationsforassessmentofsafety,efficacyandquality,thefollowinginformationshouldbesubmitted:

• aWHO-typecertificateofapharmaceuticalproduct(CPP)(8)issuedbyoneoftheregulatoryauthoritiesofanInternationalConferenceonHarmonisation(ICH)region(EuropeanUnion,JapanortheUSA),togetherwithasummaryofproductcharacteristics(SmPC);

• anassessmentreportissuedbytheregulatoryauthority;• aWHO-typebatchcertificatefromthemanufacturer.

IfthepackagingoftheproductisdifferentfromthatapprovedbyaregulatoryauthorityofanICHregion,stabilitytestingdatashouldbesubmitted.Ifthe

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formulation,strengthorotherspecificationsaredifferentfromtheproductforwhichtheWHO-typeproductcertificate(CPP)wasissued,argumentsand/ordatatosupporttheapplicabilityofthecertificatedespitethedifferencesshouldbesubmitted.

4. Acompletedquestionnairewithlimitedinformationontheproductshouldbesubmittedforproductscontainingonlysubstancesthatdonothavespecificpropertiesthatmayhaveexplicitimpactonthesafety,efficacyorqualityoftheproduct.AnexampleofapharmaceuticalproductquestionnaireisshowninAppendix6.

Informationaboutthesite(s)whereeachproductismanufacturedwillalsoberequiredatalaterstage.Forguidelinesonsubmissionofinformationonmanufacturingsites,see“Planningandpreparationofinspections”.

Thesameprocessasoutlinedaboveshouldbefollowedforsupplierswhoperformonlypartofthesupplyprocess.Thisisparticularlyrelevantwhereaproductfromaprequalifiedmanufactureristobesuppliedthroughanewdistributionchannel.Forexample,aprocurementagencymightwishtoshipanalreadyprequalifiedproductto a new country using new traders, brokers or distributors. The organizationsinvolvedinthenewdistributionchannelwillneedtobeappropriatelyprequalified.Dependinguponthenatureofthesupplyarrangement,therequirementsforproductinformationandtheGMPinspectionprocessmaybemodified.

Process of submission

Suppliersshouldbeallowedatleast60daysforthecompilationandsubmissionofproductinformation.

Suppliersshouldberequestedtosubmitacoveringletter,containingaclearstatementbytheresponsiblepersonthattheinformationsubmittedistrueandcorrect.

Theprocurementagencyshouldreservetherighttoterminatetheprequalificationprocedureofaproductandmanufacturerifthemanufacturerfailstoprovidetherequiredinformationinaspecifiedtimeperiod,oriftheinformationsuppliedisinadequatetocompletetheprequalificationeffectively.

II.4.2 Step 2: receive product information

Theprocurement agency shouldhave thenecessary infrastructure to receive andprocess the product information submitted by manufacturers. It will requirepersonnel for processing the documentation; written procedures for receiving,identification, marking files, containers and samples, and sufficient space forunpackingandstorage.

Containerswithproduct information shouldbe receivedat the specifiedaddressbeforeaspecifieddateasdeterminedbytheprocurementagency.

Containersshouldbeopenedinthepresenceofatleasttwopeople.Arecordshouldbekeptofthenamesofthepeoplewhoopenedthecontainersandthecontentsofthecontainers.

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Eachproductshouldbeallocatedauniquereferencenumbertoensuretraceabilityoftheproductinformation.

II.4.3 Step 3: screen product information

Each product information package submitted by the manufacturer should bescreenedforcompleteness.Thescreeningshouldbedoneinaccordancewithawrittenprocedure.Iftheproductinformationsubmittedfailstomeettherequirements,itshouldbeexcludedfromtheevaluationprocedureandinspectionprocess.

Ascreeningformshouldbeusedtoensureconsistencyofscreening.Thereshouldbeawrittenrecordofthescreeningofeachproductinformationpackage.Informationtoberecordedshouldinclude:➣dateofreceipt;➣nameoftheinterestedmanufacturer(s);➣addressofthemanufacturer;➣nameoftheproduct;➣countryofmanufacture;➣productnumber;and➣outcomeofthescreening.

AnexampleofanSOPforscreeningandassessingproductinformation,includingasamplescreeningform,isshowninAppendix7.Incompleteinformationshouldnotbekept for evaluationpurposes.Themanufacturer shouldbe informed thatanincompleteinformationpackagewasreceived,andberequestedtosupplythemissinginformationwithinaspecifiedperiod.Ifthisrequestisnotcompliedwith,theapplicationshouldberejectedongroundsofincompleteness.

Product information packages which meet the requirements of the screeningprocedureshouldberetainedforfullevaluation.

Asummaryshouldbemadeofeachproductinformationpackagereceived,statingany reference number allocated to the product by the procurement agency, theINN,strength,dosageformandpacksizeoftheproduct,thenameofthesupplier,the name and address of the manufacturing site(s), whether a sample has beensubmitted,andifso,thesamplesize.

II.4.4 Step 4: evaluate product information

Evaluators

Evaluatorswithsuitablequalificationsandexperienceintheevaluationofproductdataandinformationshouldbeavailabletoconducttheassessment.Suitablyqualifiedexternalevaluatorsmaybeappointed.Appointmentofexternalevaluatorsshouldbesubjecttocompliancewiththepolicyoftheprocurementagency,regardingaspectssuch as confidentiality, conflicts of interest and financial resources. Examinationofpotentialconflictsofinterestandconfidentialitymustgobeyondthepotentialevaluatorsigningadeclaration.Checksonreferencesshouldalsobemade.

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A formal agreement for the performance of work and terms of reference forcontractedevaluatorsshouldbeinplacebeforecommencementofwork.

A summary list of names, addresses, dates of appointment, qualifications andexperienceofevaluatorsshouldbemaintained.Copiesofsignedagreementsshouldbekeptinacentralfile.

Evaluation

Timeframesshouldbesetforevaluationofproductinformation.Productinformationshouldbeevaluatedwithin21daysaftertheclosingdateforsubmission.

Awrittenprocedureforevaluationshouldbefollowed.AnexampleofanSOPforscreeningandassessingproductinformationisattachedasAppendix7.

The person responsible for evaluation should monitor the process to ensurethat each product information package is evaluated in compliance with theserequirements.Informationontheproduct’spatentstatusshouldbeconsideredtoavoidinfringementofintellectualpropertyrights(seealsoSectionIII.7).

ContractresearchorganizationsshouldbeinspectedaspartoftheassessmentprocesstoensurethatbioequivalencestudieshavebeendoneinaccordancewithGCPandGLP,andthattabulateddatasubmittedtoprovebioequivalenceaccuratelyreflectthegeneratedrawdata.

Evaluation reports

Eachevaluatorshouldprepareaformalevaluationreportforeachproduct,includinga recommendation for acceptance or rejection. The evaluation report should becommunicatedtothemanufacturerwithin14daysoftheevaluation.

A response should be invited from the manufacturer in cases where data andinformationarefoundtobeincompleteordonotmeettheguidelines.Aperiodofatleast60daysshouldbeallowedforsubmissionofadditionaldataandinformation.

This additional information should be assessed and the final outcome of theevaluationshouldbecommunicatedtothemanufacturer.

Theevaluationreportshouldbefiledwiththeproductevaluationdocumentationforreferencepurposesandfollow-upwhererelevant.

Analysis of samples

Samplessubmittedtogetherwithproductinformationpackagesshouldbeanalysedinaccordancewiththefinishedproductspecification.Certificatesofanalysisoffinalproductsreleasedbythemanufacturershouldbemadeavailabletotheprocurementagencyonrequest.

The procurement agency should have access to a quality control laboratory toperform the analyses. The WHO Guide for a quality systems manual in a control laboratory(9)seekstoestablishapracticalbasisforthequalitysystemsmanualofa

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controllaboratorywhicheachcountrycanadoptandadapttoprepareitsownmoredetailedmanualtomeettherequiredlevelofspecificityandcomplexity.

A laboratory may be contracted to perform the analyses. In that case, theprocurement agency should ensure that the laboratory complies with GMP andgoodpracticesforcontrollaboratories(10).Theuseofanaccreditedlaboratoryisthereforerecommended.Theprocurementagencyshouldverifytheaccreditation.Thereshouldbeawrittencontractoragreementbetweentheprocurementagencyand the contract laboratory.Thewordingof the contract shouldbe clear and itshouldspecifytheresponsibilitiesofthecontract-giverandthecontract-acceptor.

Theprocurementagencyisresponsibleforensuringaccesstorawdata.

Theprocurementagencyshouldhaveaprocedureforinvestigating,handlingandreportingout-of-specificationresultswhentheseareobtainedfromlaboratories.Ifasamplefailstomeetthespecifications,theprocurementagencyshouldinvestigatetheproblemandcommunicatetheoutcometothemanufacturer.

II.4.5 Step 5: plan, prepare and perform inspections

Each batch of every product procured by a procurement agency should bemanufactured in compliance with GMP to ensure batch-to-batch consistency.Theactualsiteofmanufactureoftheproductshouldbeknownandspecified.Insomecases,acontractmanufacturermaymanufacturetheproductonbehalfofthesupplier or agent. Each manufacturing site specified in the product informationshouldbeinspectedtoassesscompliancewithWHOGMP.

Manufacturers of the active pharmaceutical ingredients (APIs) used shouldbe inspected as part of the assessment procedure to ensure that the APIs weremanufacturedinaccordancewithGMP.

Existing certificates

ISO certification is not an assurance of compliance with GMP and is not areplacementorsubstituteforverificationofcompliancewithGMP.

Similarly, a CPP is not a guarantee of compliance with GMP. Participation intheWHOCertificationscheme(8)isavoluntaryprocess,andthereisnoformalassessmentorevaluationofdrugregulatoryauthoritiesenteringthescheme.Insomecases,relianceontheCPPaloneisthereforenotrecommended.Thecertificationscheme is an administrative tool and is reliableonlywhere the relevantnationaldrug regulatory authority has an established system which is known to complywithacceptablestandardsforevaluationandregistration/licensingofproductsandmanufacturers, including products for export markets. Information in additionto theCPP,e.g. a copyof the inspection report andcorrectiveactionplan fromthe manufacturer, may be requested. These documents, in addition to otherdocumentation, may be considered useful in the prequalification process and infollow-upassessmentorevaluationatalaterstage.

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TheprocurementagencyshouldstillverifycompliancewithWHOGMPaspartoftheprequalificationprocedure,andaninspectionofthemanufacturingsitemustbeconsideredineverycase.

Inspectors

Inspectionsshouldbeperformedbyasuitablyqualified,experiencedinspectororteamofinspectorswithrelevantqualifications,trainingandexperienceinperforminginspectionsinforeigncountries.InspectorsshouldhavesoundknowledgeofqualityassuranceandGMPinpharmaceuticalproductproductionandqualitycontrol.Asufficientnumberofinspectorsshouldbeappointedtocarryoutinspectionswithinpredeterminedtimeframes.

Where possible, a representative from the procurement agency (the personresponsibleforprequalificationwithaknowledgeofGMP)shouldbepartoftheinspectionteam.

In exceptional cases, consultants from the private sector may be appointed toperform inspections, provided that there is no conflict of interests and that allconfidentialityundertakings are agreedupon andmaintained.For these reasons,persons working in a manufacturing company may not be considered suitable.Interestedexternalinspectorsshouldsubmittheirlettersofinterestandcurriculumvitae to the procurement agency. The agency should review the documentationbeforedecidingtoappointanyinspectors.Aformalagreementfortheperformanceofworkandtermsofreferenceshouldbeinplacebeforecommencementofworkbycontractedinspectors.

A summary list of names, addresses, dates of appointment, qualifications andexperienceofinspectorsshouldbemaintained.

Planning and preparation of inspections

Inpreparationfortheinspection,theprocurementagencyshouldensurethatthemanufacturerswhohavesubmittedEOIstosupplyproductsarelistedinarecordingsystemforinspectionplanningpurposes.

Tofacilitateplanningandtosavecosts,manufacturersshouldbegroupedtogetherbycountry.Insomecountries,onemanufacturermayhavedifferentmanufacturingsitesinadditiontothesubmittedaddressoftheheadquarters.

Manufacturers should be informed of tentative inspection dates, and should berequestedtosubmitinformationabouteachmanufacturingsitetobeinspected.Thisinformationshouldnormallybeprovidedinasitemasterfile(SMF).AnexampleofatechnicalquestionnaireforpharmaceuticalmanufacturersisattachedasAppendix8. This information will be used during the preparation for the inspection andduringtheinspectionitselftoverifyinformationsuppliedbythemanufacturertotheprocurementagency.

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AnexampleofastandardoperatingprocedureforplanninganinspectionisshowninAppendix9.

As the manufacturer will be inspected as part of the prequalification processfor specific products to the procurement agency, inspectors should prepare forinspectionsbystudyingtheproductinformationsubmittedbythemanufacturer.Appendix10containsanexampleofanSOPforpreparingforaninspection.

AsitevisitbeforedecidingwhetheraGMPinspectionshouldbeperformedmayinsomecasesbeappropriate.Thisvisitisoptionalanddoesnotleadtotherequirementfortheperformanceoftheinspectionbeingwaived.

Performing inspections

Inspections should be performed in accordance with a written procedure. TheinspectionshouldcoverallaspectsofGMP.AnexampleofanSOPforperforminganinspectionisshowninAppendix11.

Information submitted in relation to the supply of the API, formulation of theproduct,manufacturingmethodandstabilitydatashouldalsobeverifiedduringtheinspection.

Theinspectionshouldcovertheevaluationandassessmentofthedocumentation,premises, equipment, utilities and materials. It should also cover verification ofdataanddocumentationsuchasresults,batchrecords,compliancewithSOPandinformation submitted on the manufacturing method, equipment and aspectsincluding(butnotlimitedto)validationofthemanufacturingprocess,validationofutilitiesandsupportsystems,andvalidationofequipment.

If checklists are used, these should be drawn up and agreed upon for use bycollaborating procurement agencies implementing this Model. An example of aGMPchecklistisshowninAppendix12.

Waiving of inspections

Theneedforaninspectionmaybewaivedwhereaninspectionreportisavailablefrominspectorsrepresentingnationaldrugregulatoryauthoritiesforthemanufacturingsiteunderconsideration,coveringactivitiesfortheproduct(s)beingprequalified,providedthatthereportsatisfiestheagencythat:• allaspectsofGMPfortherelativeproduct(s)havebeencovered;• theinspectionreportisnotolderthan24months;• thereisastatementfromthemanufacturerthatnomajorchangeshavebeen

madetopremises,equipmentandkeypersonnelsincetheinspectionbythemedicinesregulatoryauthority;

• the reports of thenationaldrug regulatory authoritydemonstrate that themanufacturerhasahistoryofcompliancewithGMP;and

• theinspectionreporthasafavourableoutcome.

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Inspection report

Each inspector or inspection team (where inspection teams are performinginspections)shouldprepareaformalinspectionreportforeachmanufacturingsiteinspected.

TheinspectororinspectionteamshouldmakearecommendationonthestatusofthemanufacturerinrelationtocompliancewithGMP.Accordingtothefindings,the recommendation following the inspection may for example be one of thefollowing:• The manufacturer is considered to be operating at a reasonable level of

compliancewithWHOGMPandafollow-upinspectionisrecommendedto verify implementation and acceptability of corrective actions prior toparticipationinanytender.

• The manufacturer is considered to be operating at an acceptable level ofcompliancewithWHOGMP.

• ThemanufacturerisconsiderednottobeoperatingatanacceptablelevelofcompliancewithWHOGMP.

The inspector or inspection team(s) will finalize a report according to therecommended format. The WHO Guidance on Good Manufacturing Practices (GMP): inspection report (11)(seeAppendix13)providesinformationonhowtowriteaninspectionreport.

Acopyoftheinspectionreportshouldbefiledinacentralmanufacturer’sfilethatisuniquetothatmanufacturer.

Theinspectionreportshouldbecommunicatedtothemanufacturer.Wherenon-compliancewasobserved, corrective actions and time lines for completing themshouldbesuggested.Aresponsewithsupportivedocumentationshouldbeinvitedfromthemanufacturer.

Ifanyadditional information is required,or ifcorrectiveactionhas tobe taken,afinal recommendationas to the acceptabilityof theproduct andmanufacturershouldbemadeonlyaftersuchinformationhasbeenevaluated,orthecorrectiveactionhasbeenverified.

Intheeventofanydispute,astandardprocedureshouldbefollowedfordiscussingandresolvingtheissue.

The ownership of the report should be with the procurement agency, as it isresponsiblefortheprequalification.

II.4.6 Step 6: finalize assessment process and update prequalification list

Decision-making process for acceptance or rejection of a manufacturer

Theprocurementagencyshouldfollowawrittenproceduretocollatetheoutcomesof theevaluationofproduct information, laboratoryresults for samplesanalysedandinspectionreports.

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TheSOPshouldalsoidentifythepeopleresponsiblefortakingthedecisiontoacceptorrejectaproductand/ormanufacturer,includingthegroundsforthedecision.Itmaybehelpfultorefertothepersonbyposition,ratherthanbyname.

Theprocurementagencyshouldinformthemanufacturerinwritingoftheoutcomeoftheprequalificationofeachproductmanufacturedateachspecifiedsite.

Recording of outcomes

The person responsible for prequalification should record the outcome of theprequalificationprocess ina listofprequalifiedproductsandmanufacturers.ThelistshouldincludeonlythoseproductsevaluatedasindicatedbythemanufacturerandlistedintheEOI.Itshouldbeproduct-andmanufacturingsite-specific.

Thelistshouldbepublishedinthepublicdomainandshouldincludeatleastthefollowinginformation.

General information➣ Normsandstandardsused;➣ referencetothegeneralprocedureforprequalification;➣ a statement to indicate that the list is not comprehensive for any disease

category,but includesonly thoseproducts submittedbypossible suppliersandprequalifiedbytheprocurementagency;

➣ astatementto indicatethatthepurchaserofproducts fromthe list shouldensurethatonlyprequalifiedproducts(i.e.thesameformula,manufacturingmethods,manufacturingsite,etc.asintheproductinformationsubmitted)willbesuppliedbythesupplierthroughcontractualagreementbetweenthebuyerandthesupplier;

➣ astatementthatbeingonthelistdoesnotguaranteecontractsorsalestothesuppliers;

➣ astatementthatthelistshouldnotbeusedbysuppliersasamarketingtooltogeneratebusiness;

➣ dateofpublication;and➣ periodofvalidity.

Product information• Products and theirmanufacturing siteswhereproducts andmanufacturers

meet the standards set for the prequalification, including the followingspecifications:

➣ INNofactiveingredient(s);➣ strength;➣ dosageform;➣ packsize;➣ shelf-life;➣ storageconditions;➣ nameofsupplier;➣ nameofmanufacturerandmanufacturingsite(s).

Theprocurementagencyshouldhaveamechanismforsharing informationwithotherprocurementagencies.

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The procurement agency should have an agreement with the supplier to ensurecompliancewiththeprequalificationprinciplesandthattheproductssuppliedarethesameproductsaswereprequalified(e.g.theyaremanufacturedatthesamesiteandthesameprocessesareadheredto).Thelistshouldbereviewedandupdatedat regular intervals, at least every year.Newlyprequalifiedmanufacturers shouldbeaddedto the listas theybecomequalified,andnon-compliantmanufacturersshouldberemovedfromthelistassoonastheyarerecognizedassuch.

Wherepossible,morethanonesupplierofaproductshouldbe includedonthelisttoensureopenandtransparentprocurementthroughcompetitiveprocurementprocedures(seeModuleIII).

II.5 Requalification and monitoring

Requalification should occur at regular intervals. Routine reinspection ofmanufacturersshouldtakeplaceatleastonceeverythreeyears.Routinere-evaluationofproductinformationorquestionnairesshouldbedoneeverythreeyears.Non-routinere-evaluationand/orinspectionshouldbedonewhennecessary,e.g.whenthemanufacturerimplementsanychangetotheformula,manufacturingmethodormanufacturingsite;ifanyproductsuppliedisconsiderednottobeincompliancewith the agreed specification of the product; or if a serious complaint has beenreceived.FormoredetailsonreassessmentseeModuleVI.

Randomsamplesofbatchesofpharmaceuticalproduct(s)suppliedbyprequalifiedmanufacturersshouldbetakenforindependenttestingforcompliancewithfinalproductspecificationsaspartofthecontinuousmonitoringprogramme.

II.6 Monitoring of complaints

Complaintsshouldbehandledinaccordancewithawrittenprocedure.

Awrittenreportofthecomplaint,investigation,recommendationsforactionwhererelevant,andoutcomeshouldbeavailabletotheprocurementagency.

Anycomplaintconcerningapharmaceuticalproductorbatchofproductssuppliedbythemanufacturershouldbethoroughlyinvestigated.Thenatureofthecomplaintshouldbecommunicatedtothemanufacturer.

II.7 Cost recovery

It is recommended that the costs of prequalification should be covered by theprocurementagency.

Ifcostsaretoberecovered,definedtransparentproceduresshouldbeestablishedandmanufacturersshouldbenotifiedoftheseproceduresinadvance.Costrecoveryshouldbebasedonafee-for-servicesstructure.

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Module III

Purchasing

Introduction

Pharmaceuticalproductsshouldbepurchasedwiththeaimofprocuringeffective,good-qualitymedicinesatthelowestpossiblecost.PrequalificationofproductsandmanufacturersasdescribedinModuleIIcontributestoensuringinadvancethatmanufacturersandsupplierscandeliverqualityproductsonasustainedbasis.

Thismodulegivesanoverviewofthestrategiesandmethodsusedinpharmaceuticalprocurement. The term procurement in this module relates specifically to thepurchaseofhealthsectorgoodsfrommanufacturersorsuppliers.Themodulegoesontodescribethekeyactivitiesinpurchasingpharmaceuticalproducts,aswellastherecommendedorganizationalstructureoftheprocurementagencieswhocarryoutthesekeyactivities.

III.1 Strategies for health systems

Although many health systems are decentralizing, some aspects of the healthsystemareoftenhandledmoreefficientlyatacentral level.Approval fora listofessentialpharmaceuticalproductsandregistrationor licensingofpharmaceuticalproductsarenormallytheresponsibilityofthecompetentauthorityatthenationallevel.Centralizedprocurementofpharmaceuticalproducts increasesthequantityobtainedundereachpurchasecontractandusuallyreducesthecostoftheproducts.Programme officials should therefore consider consolidating quality assuranceproceduresatthenationallevelandpoolingdemandsforpharmaceuticalproductsunderacommoncontract.

Fourstrategicobjectivesforgoodpharmaceuticalprocurementarerelevanttoanypublic sectordrug supply system,whether it ismanagedusingpublicorprivateservicesoracombinationofboth.Theseareasfollows(12):• selectionofreliablesuppliersofqualityproducts;• procurementofthemostcost-effectivepharmaceuticalproductsintheright

quantities;• timelydelivery;and• achievementofthelowestpossibletotalcost.

Theseobjectivesshouldbeachievedthroughefficientandtransparentmanagementreflected in an adequate division of the different activities and responsibilities;appropriate standardization, selection, specification and quantification ofpharmaceutical products; theuse of goodfinancialmanagementprocedures andcompetitiveprocurementmethods;andaqualitysystemthatinvolvestheselectionandmonitoringofqualifiedsuppliersandtheirproducts.

Itisrecommendedthatastandardprocedurebepreparedtoassistinthecalculationofthelowestpossibletotalcost.Thisapproachaimstoensurethatcostsarecalculated

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inaconsistentmanner,withaconsistentweightgiventoeachofthefactorstakenintoaccount.

Tobeeffective,aprocurementofficeshouldensurethatthefollowingprinciplesareapplied.• Prequalifiedproductsarepurchasedfromapprovedmanufacturerswhenever

possible.• Procurementandpurchasingproceduresaretransparent.• Activitiesfollowformalwrittenproceduresthroughouttheprocess,including

explicitcriteriaforawardingcontracts.• Purchasing is based on competitive procurementmethods, except for very

smalloremergencyorders.• Membersof thepurchasinggroupspurchaseall contracted items fromthe

supplierswhoholdthecontract.• Purchasingandtenderdocuments listallpharmaceuticalproductsby their

INNornationalgenericnames.• Suppliersareselectedandmonitoredthroughaprocessthattakesintoaccount

productquality,servicereliability,deliverytimeandfinancialviability.• Intellectualpropertyrightsarerespectedinaccordancewithbestpracticeand

internationallaw.

Considerableefforthasbeenputintothedevelopmentofappropriatepoliciesandproceduresfortheprocurementofhealthsectorgoods(pharmaceuticals,vaccinesand condoms) by the World Bank. The reference documents are the standardbidding documents (13) and the accompanying technical note (14). AlthoughthesedocumentsaredesignedtomeettheWorldBank’sspecificrequirements,theyincludemuchsoundguidanceforusebyallinvolvedintheprocessesofprocuringhealthsectorgoods.

III.2 Procurement methods

Althoughtherearedifferentmethodsofprocurement, theyall involveanumberof common activities that must take place beforehand. These activities are theestablishmentoftechnicalspecifications,quantificationofrequirements,issuingofsome formof tender, and selectionofproduct(s) andmanufacturer(s)preferablybasedonprequalification.

Responsestotendersshouldbeexaminedtoensurethatoffershavebeenreceivedfrominvitedsuppliersandthattheoffersaresubstantiallyresponsivetothetermsandconditionsofthetender.Awardsshouldbemadetothemakerofthelowestacceptablebidthatmeetsthetermsandconditionsofthetender.Disqualificationoflowbiddersshouldbedocumentedandformpartofthetenderrecord.Followinga reviewof the adjudicationby an independentpanel, the companies shouldbeinformedoftheoutcomeofthetender,andacontractshouldbeawardedtothesuccessfulcompany.Thecontractmustsubstantiallyreflectthetermsandconditionsdetailedinthetender.

Abriefdescriptionofdifferentprocurementmethodsisgivenbelow.

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III.2.1 Restricted tender

In a restricted tender, also called a “closed bid” or “selective tender”, interestedsuppliersareapprovedinadvancethroughaprequalificationprocess.Thistypeofprocurement is often referred to as “limited international bidding” (LIB) whichisan“invitationtocompetitivebids”(ICB)conductedbydirect invitationtoallprequalifiedsuppliers.

Procurementagenciesshoulduserestrictedtenderstoinvitebidsfromprequalifiedsuppliersforallhealthsectorgoodsandserviceswheneverpossible.

III.2.2 Competitive negotiation

Thismethodisalsoreferredtoas“international/nationalshopping”.Thebasisofthismethodisthecomparisonofpricequotationsobtainedfromseverallocalorforeignsuppliers.Usually,quotationsaresolicitedfromaminimumofthreesupplierstoensurecompetitiveprices.

Thismethodisappropriateforprocuringsmallamountsofreadilyavailableproducts.However, its use should be explicitly justified, and approval should be obtainedfromseniormanagement.Onlyprequalifiedsuppliersshouldbeused.

III.2.3 Direct procurement

Indirectprocurement,productsareobtaineddirectlyfromasinglesourcewithoutapplyingtherequirementsofatenderprocessorcomparingpricequotations.

Normally direct procurement is not recommended, but it may be used whenthereisonlyoneprequalifiedsourcefortheproducttobeprocured.Ahistoryof“reasonable”pricesfortheproductinquestionshouldbeassessedtonegotiatethepricewiththesupplier.

III.2.4 Open tender

Open tender is the formal procedure by which all manufacturers, national andinternational,areinvitedtobidforthesaleofgeneralgoods.Theterm“internationalcompetitivebidding”(ICB),whichisanopentendertoallmanufacturers,isoftenused.

Opentenderingisnotappropriateforhealthsectorgoods,becauseitmaybedifficulttoestablish,beforeacontractisawarded,whetherunknownbidderswillbeabletosupplyproductsof therequiredquality in therequiredquantitiesona sustainedbasis.

III.3 Quality assurance in purchasing

Theprocurementagencyshouldhaveadocumentedinfrastructureforpurchaseandprocurementofhealthsectorgoodsandservices,whichshouldaimtoensurethatpharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.Quality

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assurancethereforeincorporatesGMPandotherfactors,someofwhichareoutsidethescopeoftheseguidelines,suchasproductdesignanddevelopment.

III.4 Key activities in purchasing

III.4.1 Product selection and specification

The selection of pharmaceutical products based on a national formulary or onthe essential medicines list is recommended.WHO’s Model Formulary (15) andModel Essential Medicines List (4) identify the most cost-effective and affordablepharmaceutical products to treat prevailing health problems. They are updatedregularly and are made freely available for adaptation by countries. The healthsystems of many industrialized and developing countries have used the essentialmedicinesconceptfordecadestouseexistingresourceseffectively.Becausetheuseofanationalformularyreducesthenumberofproductsused,supplymanagementactivitiesandinventorycarryingcostsareminimized.

Mechanismsforprocurementofnon-essentialpharmaceuticalproductsbypublicandprivatehealthsystemsshouldbeavailable.Procurementofsuchproductsshouldbeexplicitlyjustifiedandsubjecttoapprovalbyauthorizedofficials.

Procurementandtenderdocumentsshould listpharmaceuticalproductsbytheirINNornationalgenericnames.

Eachproductselectedshouldbeavailableinadosageformwhichoffersacceptablesafety, efficacyandquality, includingacceptable stability and shelf-lifeunder therecommendedstorageconditions.

If twoormorepharmaceutical products appear tobe similar according to thesecriteria,thechoicebetweenthemshouldbemadeafteracarefulevaluationoftheirrelative efficacy, safety, quality, cost, lead-time and availability from prequalifiedmanufacturing sites. When comparing costs of pharmaceutical products, thecost of the whole course of treatment, not only the unit cost, should be takeninto consideration. The choice may also be influenced by other factors such astransportationcharges,storagerequirementsandshelf-life.

III.4.2 Product quantification

All requests for products should include quantities and required delivery dates.Accurate quantification of needs is essential to avoid shortages or excess stocks.Shortages could lead to patients not being treated or being improperly treated.Excessstockscouldleadtoadditionalstoragecostsandexpiryofproductsbeforetheyareused.

Thepossiblemethodsofproductquantificationincludetheconsumptionmethod,themorbiditymethod,andtheadjustedorextrapolatedconsumptionmethod.

The consumption method uses records of past consumption of individualpharmaceuticalproducts.

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The morbidity method estimates the need for specific pharmaceutical productsaccordingtotheincidenceofcommondiseases,thenumberofpatientsattendinghealthcarefacilitiesandtreatmentpatternsforthediseasestreated.Adherencetostandardtreatmentguidelineswillmaketreatmentpatternsmorepredictable.

The adjusted or extrapolated consumption methodusesdataondiseaseincidenceanddrugconsumptionfromastandardsupplysystemandextrapolatestheutilizationratetothesupplysystemunderconsideration.

The consumption method is the most reliable method provided that theconsumption records are accurate, the supply pipeline has been consistently fullandnomajorchangesareanticipatedinthenearfuture.Otherwise,oneoftheothermethodsshouldbeusedtoenableamoreaccuratequantificationofprocurementrequirementstobemade.

Ifsufficientdataareavailable,themorbiditymethodofquantifyingdrugrequirementscanbeusedtodetectdiscrepanciesinpastconsumptionpatterns,whichcouldbeindicativeofirrationaldruguseortheftofpharmaceuticalproducts.

III.4.3 Selection of suppliers

Prequalificationistheprocedurebywhichtheproducts,manufacturersandsuppliersare assessed before bids are solicited for specific products. The prequalificationprocessforpharmaceuticalproductsdevelopedbyWHOisbasedontheprinciplesstatedinModulesIandII.

Prequalification requires time.However, once a list ofprequalifiedproducts andmanufacturershasbeenprepared,adjudicationandawardingofcontractscanbeexpedited.

Postqualificationistheprocessbywhichproductsandmanufacturersareassessedafterbidshavebeenreceived.Thisprocessmaycausedelaysbecause, if thereareseveraloffersfromunknownsuppliers,itwillbenecessarytovalidatetheabilityofthesesupplierstosupplyproductsoftherequiredqualityintherequiredquantitiesbeforeanycontractsareawarded.Postqualificationisthereforenotrecommendedforpharmaceuticalproductprocurement.

Procurement agencies should restrict tenders to prequalified products andmanufacturers, soliciting bids from those manufacturers and suppliers that havebeen prequalified as described in Module II, or by contracting the services of aprocurement agency which meets the recommended norms and standards forcarryingoutprequalification.

III.4.4 Adjudication of tenders

Theadjudicationoftendersisanimportantstepinprocurement.Theprocedure,including the decision-making process, should be transparent and documented.Decisions taken should ensure both appropriate quality and lowest cost to theprocurementagency.

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Followingabidtheawardshouldbemadetothesuppliermakingthelowestofferrespondingfullytothebid.Whenconsideringinformationsubmittedonaspectsofqualityassurance,theprocurementagencyshouldseekexpertadvicetodetermineiftheofferisfullyresponsive.

When adjudicating tenders, the attention given to the financial stability of themanufacturershouldnotoutweightheconsiderationofmeasurestakentoensurequalityofproducts.

III.5 Organization and responsibilities

The key activities of purchasing pharmaceutical products (product selection andspecification,quantification,prequalificationandadjudicationof tenders) shouldbe performed by different people, sections or departments with the appropriateexpertiseandresourcesforperformingthespecificfunctions.

III.5.1 Procurement agency structure

Thesectionordepartmentresponsibleforpurchasingpharmaceuticalproductsintheprocurementagencyshouldhaveanorganizationalchartindicatingthepositionsandnamesofthepersonnelresponsibleforthekeyactivities,aswellasthereportinglines.

Purchasing office

Thepurchasingofficeshouldbeappropriatelystaffedtoprepareandissuetenders,andtoaward,administerandmonitorcontracts.Inaddition,itshouldbeabletoensurethatinformationconcerningproductselection,specification,quantification,supplierpreselectionandfundingishandledappropriately.Thisofficeshouldfollowtransparent,writtenproceduresthroughouttheprocessofpurchasingandshoulduseexplicitcriteriafordecidingtowhomtoawardcontracts.

All staff in the purchasing group must sign confidentiality agreements anddeclarationsofconflictofinterest.

Product selection office

Acommitteeshouldberesponsibleforidentifyingproductstobepurchasedfromtheessentialmedicineslistorthenationalformulary.Ifsuchacommitteedoesnotexist,anadhoccommitteemaybesetupforthispurpose.

Each selected product should have standard specifications, including the dosageform, pack size, acceptable shelf-life and any other information necessary (e.g.storageconditions).

Quantification office

Thisofficeshouldberesponsibleforensuringthefollowing.• Thequantitiesorderedarebasedonareliableestimateofactualneed.• Procurement takes into consideration long-term contracts to achieve

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economiesofscaleandreduceworkinprequalification.Thisapproachappliestobothcentralizedanddecentralizedsystems.

• Procurementtakesintoaccountthepotentialbenefitsofjoiningwithotherprocurementagenciesandpoolingrequirements.

• Productsaredeliveredaccordingtorequesteddeliverydates.

Finance office

Thereshouldbemechanismsinplacetoensurereliablefinancingforprocurement.Goodfinancialmanagementproceduresshouldbefollowedtoensurethatfinancialresourcesareusedwithmaximumefficiency.

Funds shouldbe allocatedbefore the tender is issued, and shouldbe released inaccordancewiththepurchasecontract.

Quality office

Prequalification procedures should provide assurance that the pharmaceuticalproducts purchased are of acceptable quality and meet applicable internationalstandardsasdescribedinModuleII.

Adequate laboratory services shouldbe available to testpharmaceuticalproductsindependently according to specifications and standards. Random sampling andtestingshouldbecarriedoutbeforeandafterpurchase.

The procurement agency (contract-giver) may decide to contract the services ofan agency (contract-acceptor) with expertise in technical assessment of productdataandinformationand/orinspectionofmanufacturingfacilities.However,thecontract-giverremainsresponsiblefortheimplementationandmonitoringoftheseactivities.

Management oversight

Procurementshouldbeplannedproperly,andprocurementperformanceshouldbemonitoredregularly.

Anindependentcommitteeshouldreviewadjudicatedtenders.Committeemembersshouldhavefinancial,legalandprogrammeplanningexpertiseandexperience.

III.5.2 Responsibilities

Each staff member who undertakes procurement or provides support toprocurement should have a job description which clearly describes his or hertasks and responsibilities. All staff must have signed confidentiality agreementsanddeclarationsof conflictof interestbefore they carryout any tasks related topurchasingofpharmaceuticalproducts.

Theresponsibilityplaceduponanyindividualshouldnotbemorethanthatpersoncanhandle.Thereshouldnotbeanygapsoroverlapsintheareasofresponsibility.

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III.6 Monitoring of performance of prequalified manufacturers

Thereshouldbeaprocedureforcontinuousmonitoringofprequalifiedproductsandmanufacturers,whetherornotthemanufacturerissupplyingproduct(s).

Ifadecisionistakentoremoveaproductormanufacturerfromtheprequalificationlist,themanufacturershouldbenotified.Allrecipientsofthelistshouldbeinformedaccordingly.

Performance of manufacturers and product compliance should be monitored.Monitoringshouldincludeatleastthefollowingaspects:• samplingandtestingofsamplesforqualitycontrol;• verification that the product batches supplied have been manufactured

in compliance with standards and specifications accepted in the productinformation;

• pharmacovigilance;• monitoringofcomplaints;• reinspectionofmanufacturingsites;• reassessmentofproductinformation;• monitoringofdirectandindirectproductcosts;and• monitoringofadherencetodeliveryschedules.

The monitoring process should include continuous commercial monitoring thatincludes tracking of lead-time and monitoring for compliance with all of thecontracttermsandconditions.

Inaddition,thequalityofthepharmaceuticalproductssuppliedshouldbemonitored.Thisincludessamplingandindependenttestingoforderedanddeliveredproducts.Testsshouldincludeatleastvisualexamination;shelf-life;compliancewithlabelling,packagingandshippinginstructions;andlaboratoryanalysiswhenappropriate(e.g.identificationorassay).

Thereshouldbeaninformationsystemthatkeepstrackofthevalueofcontractsawarded,thevalueoftotalpurchasesfromeachsupplierperyearandtheperformanceforeachtender(e.g.speedofdeliveryandcompliancewithspecifications).

Thesectionordepartmentoftheprocurementagencyresponsibleforprequalificationof products and manufacturers should schedule routine requalification atpredeterminedintervalsasdescribedinModuleVI.

III.7 Patents

Inevaluatingproduct informationduringprequalificationandduring tendering,informationregardingthepatentstatusshouldberequested.NoinfringementofpatentsbyanyUnitedNationsorotherprocurementagencyshouldoccur.

Apersonwithintheprocurementagencyshouldbeidentifiedashavingresponsibilityfor checking the patent status of a particular product or formulation and torecommendactions tobe taken regarding theprotectionof intellectualproperty

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rightsfortheproduct.Thispersonwilloftenbeamemberofthelegaldepartmentoftheorganization.

Countriesrequestingproductsfromprocurementagenciesshouldberesponsibleforensuringthattheproductssuppliedcomplywiththedestinationcountry’slegislationonregistration/licensingstatusandpatentregistrationorrestrictions.

III.8 Donations

Any procurement agency receiving donations should handle donated drugs inaccordance with a written procedure to ensure that patients receive products ofknown,appropriatequality.

WHO’s Guidelines for drug donations (16) outline the key issues. The principlesestablishedintheseguidelinesshouldbefollowed.

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Module IVReceipt and storage of purchased products

Introduction

Theprocurementagencyshouldensurethatthepharmaceuticalproductspurchasedarereceivedandstoredcorrectlyandincompliancewithapplicablelegislationandregulations. Products should be received and stored in in such a way that theirqualityandintegrityispreserved,batchtraceabilityismaintainedandstockcanberotated.Thismodulefocusesonqualityassuranceandqualitycontrolduringreceiptandstorageofproducts.

Quality control is concernedwith sampling, specifications and testing aswell aswiththeorganization,documentationandreleaseprocedureswhichensurethatthenecessaryandrelevanttestsarecarriedout,andthatmaterialsorproductsarenotreleasedforuseuntiltheirqualityhasbeenjudgedsatisfactoryfortheirintendedpurpose.

Eachprocurementagencyshouldhaveaccesstoaqualitycontroldepartment,whichshouldmeet thegeneral requirements for facilities,policies andprocedures, staffexpertise,experienceandtrainingasspecifiedinModuleI,aswellastherequirementsoutlinedinModuleIIunder“Analysisofsamples”.Thequalitycontroldepartmentmustbecapableofundertakingthefullrangeoftestsrequired,orofmanaginganysubcontractingofsuchworktothirdpartiescorrectlywhileretainingresponsibilityforthequalityoftheworkdone.

TheprinciplesestablishedintheWHO guidelines for good storage practice (17)(seeAppendix14)shouldbefollowedthroughoutthestepsdescribedinthismodule.

IV.1 Pre-shipment quality control

Eachbatchoffinishedproductshouldbetestedinalaboratorytodeterminethatitconformssatisfactorilytoitsfinishedproductspecification,priortosupply.

Inlieuoftestingbytheprocurementagency,acertificateofanalysismaybeacceptedfromthesupplier,providedthattheagencyestablishesthereliabilityofthesupplier’sanalysis through appropriate periodic validationof the supplier’s test results andthroughon-siteauditsofthesupplier’scapabilities.

Productsfailingtomeettheestablishedspecificationsoranyotherrelevantqualitycriteriashouldberejected.

IV.2 Receipt of stock

Receivinganddispatchbaysshouldprotectmaterialsandproductsfromtheweather.Receivingareasshouldbedesignedandequippedtoallowcontainersofincomingmaterialstobecleanedifnecessarybeforestorage.

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Allincomingmaterialsandfinishedproductsshouldbequarantinedimmediatelyafterreceiptuntiltheyarereleasedforuseordistribution.Importedpharmaceuticalproductsshouldbequarantineduntiltestresultsconfirmthattheproductsmeetall of the requirements, specifications, terms and conditions of the purchaseorder.Areviewofcertificatesofanalysisshouldbemadetoconfirmthatwhathasbeendelivered iswhatwasorderedand is certifiedby themanufacturer tomeetspecifications.

Uponreceipt,eachincomingdeliveryshouldbecheckedforcorrespondencebetweentheorder,thedeliverynoteandthesupplier’s labels.Theconsignmentshouldbeexaminedforintegrityofpackagesandseals,andforuniformityofthecontainers.Should the delivery comprise more than one batch, it should be subdividedaccording to the supplier’s batch number. Containers should be cleaned wherenecessaryandlabelled,ifrequired,withtheprescribeddata,e.g.labeldescription,batch number, type and quantity. Each container should be carefully inspectedforpossiblecontamination,tamperinganddamage,andanysuspectcontainersorthe entire delivery should be quarantined. Damage to containers and any otherproblemthatmightadverselyaffectthequalityofthematerialshouldberecordedandinvestigated.

Thepersonresponsibleforreceivingthegoodsshouldbeindependentofthepersonresponsibleforpurchasingthegoods.

IV.3 Postprocurement quality control

IV.3.1 Sampling

The procedures for receipt of supplies should include random sampling forindependentlaboratoryanalysistoensurethatpharmaceuticalproductsmeettherequired standards. Sampling shouldbeperformed in accordancewith awrittenprocedure.Productsmayalsoberandomlysampledattheendofthedistributionchainandsent for independentanalysis.Representative samples shouldbe takenfromcontainersintheconsignment.Thesamplesshouldbeanalysedforcompliancewiththeproductspecification.

Samplesshouldbetakenonlybyappropriatelytrainedandqualifiedpersonnelandstrictlyinaccordancewithwrittensamplinginstructions.Containersfromwhichsampleshavebeentakenshouldbelabelledaccordingly.

Following sampling goods should be quarantined. Batch segregation shouldbe maintained during quarantine and all subsequent storage. Materials andpharmaceuticalproductsshouldremain inquarantineuntilanauthorizedreleaseorrejectionisobtained.

IV.3.2 Rejected materials

Stringent precautions should be taken to ensure that rejected materials andpharmaceuticalproductscannotbeused.Rejectedgoodsshouldbeclearlymarkedassuchandstoredseparatelyfromothermaterialsandpharmaceuticalproductsina

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lockedcompoundaccessibleonlytoauthorizedandtrainedresponsiblepersonnel,whilethematerialsawaitdestructionorreturntothesupplier.Whateveractionistakenshouldbeapprovedbyauthorizedpersonnelandrecorded.Rejectedmaterialsshouldbehandledinaccordancewithawrittenprocedure.

IV.4 Storage of materials and products

IV.4.1 Staff

Allmembersofstaffshouldbetrainedtoobservehighlevelsofpersonalhygieneandsanitation.Thedutiesandresponsibilitiesofallmembersofstaffshouldbeavailableintheformofawrittenjobdescription.

Personnelemployedinstorageareasshouldwearprotectiveorworkinggarmentsappropriatefortheactivitiestheyperform.

IV.4.2 Storage areas

Storageareasshouldbeofsufficientcapacitytoalloworderlystorageofthevariouscategories of materials and products, including segregation of rejected, expired,recalledorreturnedstock.

Adequateventilationshouldbeinplacetocontroltemperatureandrelativehumidity.Wherespecialstorageconditionsarerequired(e.g.temperatureandhumidity)theseshouldbeprovided,checkedandmonitored.

Precautionsshouldbetakentopreventunauthorizedentryintothestorageareas.

A written procedure for fire control measures should be in place, includingpreventionoffire,firedetectionmeasures andfiredrills.Firedetectionandfire-fightingequipmentshouldbeservicedregularly.Smokingshouldnotbepermittedinthestorageareas.

IV.4.3 Storage conditions

All materials and products should be stored under the appropriate conditionsestablishedbythemanufacturerandinanorderlyfashiontopermitbatchsegregationandstockrotationaccordingtothefirst-in,first-outrule.

Stock shouldbe storedoff thefloor and suitably spaced topermit cleaning andinspection.Palletsshouldbekeptinagoodstateofcleanlinessandrepair.

Storageareasshouldbekeptcleanandfreeofverminandaccumulatedwaste.Awrittensanitationprogrammeshouldbeavailableindicatingthecleaningandpest-controlmethodsused,andtheirfrequencyofuse.Safepest-controlagentsshouldbeusedwhichwillnotcontaminatematerialsandpharmaceuticalproducts.Thereshouldbeappropriateproceduresforthecleaningupofanyspillagetoeliminateanyriskofcontamination.

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Storageconditionsusedforpharmaceuticalproductsandmaterialsshouldcomplywiththeinstructionsonthelabelwhicharebasedontheresultsofstabilitytesting.

Ingeneral,theinstructionsonthelabelhavethemeaningsgiveninTable1.

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Storage areas should be kept clean and free of vermin and accumulated waste. A written sanitation programme should be available indicating the cleaning and pest-control methods used, and their frequency of use. Safe pest-control agents should be used which will not contaminate materials and pharmaceutical products. There should be appropriate procedures for the cleaning up of any spillage to eliminate any risk of contamination.

Storage conditions used for pharmaceutical products and materials should comply with the instructions on the label which are based on the results of stability testing.

In general, the instructions on the label have the meanings given in Table 1.

In certain cases, e.g. with freeze-sensitive vaccines, products that have been stored below the temperature specifi ed on the label should be destroyed. Freeze-sensitive products should be equipped with a “freeze-watch” moni-toring device.

Monitoring of storage conditions

The equipment used for monitoring should be calibrated at suitable predeter-mined intervals and the results should be recorded and retained. All monitor-ing records should be kept for at least one year after the end of the shelf-life of the stored material or product, or as long as required by national legisla-tion. Temperature mapping of the facility should be well designed to support assurance of uniformity of the temperature across the storage facility. It is recommended that temperature monitors should be placed in the worst-case areas of the facility. Recorded temperature monitoring data should be avail-able for review.

Equipment used for monitoring should be calibrated at defi ned intervals.

On the label Means:

Do not store over 30 °C From +2 °C to +30 °C



Do not store over 8 °C From +2 °C to + 8 °C

Do not store below 8 °C From +8 °C to +25 °C

Protect from moisture No more than 60% relative humidity under normalstorage conditions; to be provided to the patient ina moisture-resistant container

Protect from light To be kept in a light-resistant container

Table 1Meaning of storage instructions given on the labels of pharmaceutical products

Incertaincases,e.g.withfreeze-sensitivevaccines,productsthathavebeenstoredbelowthetemperaturespecifiedonthelabelshouldbedestroyed.Freeze-sensitiveproductsshouldbeequippedwitha“freeze-watch”monitoringdevice.


Theequipmentusedformonitoringshouldbecalibratedatsuitablepredeterminedintervalsandtheresultsshouldberecordedandretained.Allmonitoringrecordsshould be kept for at least one year after the end of the shelf-life of the storedmaterial or product, or as long as required by national legislation.Temperaturemappingofthefacilityshouldbewelldesignedtosupportassuranceofuniformityofthetemperatureacrossthestoragefacility.Itisrecommendedthattemperaturemonitorsshouldbeplacedintheworst-caseareasofthefacility.Recordedtemperaturemonitoringdatashouldbeavailableforreview.

Equipmentusedformonitoringshouldbecalibratedatdefinedintervals.

IV.4.4 Labelling and containers

Allmaterials andpharmaceutical products shouldbe stored in containerswhichdo not adversely affect the quality of the material or products, and which offeradequateprotectionfromexternalinfluences,includingbacterialcontaminationinsomecircumstances.

Allcontainersshouldbeclearlylabelledwithatleastthenameofthematerialorproduct, the batch number, the expiry date or retest date, the specified storageconditions and reference to the relevant pharmacopoeia where applicable. Onlyauthorizedabbreviations,namesorcodesshouldbeused.

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Storage areas should be kept clean and free of vermin and accumulated waste. A written sanitation programme should be available indicating the cleaning and pest-control methods used, and their frequency of use. Safe pest-control agents should be used which will not contaminate materials and pharmaceutical products. There should be appropriate procedures for the cleaning up of any spillage to eliminate any risk of contamination.

Storage conditions used for pharmaceutical products and materials should comply with the instructions on the label which are based on the results of stability testing.

In general, the instructions on the label have the meanings given in Table 1.

In certain cases, e.g. with freeze-sensitive vaccines, products that have been stored below the temperature specifi ed on the label should be destroyed. Freeze-sensitive products should be equipped with a “freeze-watch” moni-toring device.


The equipment used for monitoring should be calibrated at suitable predeter-mined intervals and the results should be recorded and retained. All monitor-ing records should be kept for at least one year after the end of the shelf-life of the stored material or product, or as long as required by national legisla-tion. Temperature mapping of the facility should be well designed to support assurance of uniformity of the temperature across the storage facility. It is recommended that temperature monitors should be placed in the worst-case areas of the facility. Recorded temperature monitoring data should be avail-able for review.

Equipment used for monitoring should be calibrated at defi ned intervals.

On the label Means:




Do not store over 8 °C From +2 °C to + 8 °C

Do not store below 8 °C From +8 °C to +25 °C

Protect from moisture No more than 60% relative humidity under normalstorage conditions; to be provided to the patient ina moisture-resistant container

Protect from light To be kept in a light-resistant container

Table 1Meaning of storage instructions given on the labels of pharmaceutical products

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IV.4.5 Miscellaneous and hazardous materials

Materialswhichmayaffectothermaterialsstoredintheirvicinityshouldbehandledin accordance with a written procedure. Rodenticides, insecticides, fumigatingagentsandsanitizingmaterialsshouldnotbepermittedtocontaminateequipment,startingmaterials,packagingmaterials, in-processmaterialsorfinishedproducts.Toxic substances andflammablematerials shouldbe clearlymarked as such andshouldbestoredinsuitablydesigned,separate,enclosedareasasrequiredbynationallegislation.Flammablesubstancesshouldbekeptawayfromcorrosiveoroxidantsubstancesatalltimes.

IV.4.6 Stock control

Stock rotation and control is best maintained by the use of a proprietary stockcontrol system.Caremustbe takentoselecta systemthatcanmanagetherigidrequirements forbatchnumbercontrolandexpirydatingwhichareessential forhandlingpharmaceuticalproducts.Manycommercialsystemslackthesefeatures.Incaseofdoubtadviceshouldbesoughtfromcompetentexperiencedpersonnel.

Periodicstockreconciliationshouldbeperformedcomparingactualandrecordedstocklevels.

Allsignificantstockdiscrepanciesshouldbesubjectedtoinvestigationasacheckagainstinadvertentmix-upsand/orincorrectissue.

Inmanufacturingfacilities,partlyusedcontainersofmaterialsandpharmaceuticalproducts should be securely reclosed and resealed to prevent spoilage and/orcontaminationduringsubsequentstorage.Materialsandpharmaceuticalproductsfrom containerswhich are openor partly used shouldbeusedupbefore anewcontainerisopened.

Damaged containers shouldnotbe issuedunless it is certain that thequalityofthematerial inside isunaffected.Wherepossible,damaged containers shouldbebroughttotheattentionofthepersonresponsibleforqualitycontrol.Anyactiontakenshouldbedocumented.

Control of obsolete and outdated materials and products

All stock should be checked regularly for obsolete and outdated materials andpharmaceuticalproducts.Alldueprecautionsshouldbeobservedtopreventissueofoutdatedmaterialsandpharmaceuticalproducts.Thehandlingofsuchmaterialsshouldbesubjecttoawrittenprocedure.

Recalled materials

Recalled materials should be handled in accordance with a written procedure.Writtenrecordsofallmajoractionswiththesignaturesofthepersonresponsibleforcarryingouteachactionshouldbemaintained.

Recalledproductsshouldbeidentifiedandstoredseparatelyinasecureareauntil

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a decision has been taken on their fate. The decision should be made as soonas possible. An assessment may be made only by an appropriately qualified andexperiencedmemberofstaff.

Returned goods

Returnedgoodsshouldbehandledinaccordancewithawrittenprocedure.Theyshould be placed in quarantine until a decision has been taken on their fate.Productsreturnedfromthemarketshouldbedestroyedunlessitiscertainthattheirqualityissatisfactory.Inthatcase,theymaybeconsideredforresale.Thenatureoftheproduct, any special storage requirements, its conditionandhistory, and thetimeelapsedsinceitwasissuedshouldallbetakenintoaccountinthisassessment.Whereanydoubtarisesoverthequalityoftheproduct,itshouldnotbeconsideredsuitable for reissue or reuse, althoughbasic chemical reprocessing to recover theactiveingredientmaybepossible.Anyactiontakenshouldberecorded.

Waste materials

Wastematerialsshouldbehandledinaccordancewithawrittenprocedure.Provisionshouldbemadefortheproperandsafestorageofwastematerialsawaitingdisposal.Toxic substances andflammablematerials shouldbe stored in suitablydesigned,separate,enclosedcupboards,asrequiredbynationallegislation.

Wastematerialshouldnotbeallowedtoaccumulate.Itshouldbecollectedinsuitablereceptaclesforremovaltocollectionpointsoutsidethebuildingsanddisposedofsafelyandinasanitarymanneratregularandfrequentintervals.

IV.4.7 Documentation: written instructions and records

Writteninstructionsandrecordsshouldbekeptwhichdescribethestorageproceduresanddefinetheroutesofmaterials,pharmaceuticalproductsandinformationthroughtheprocurementagency,includinghandlingofexpiredstock.Batchtraceabilityisessentialintheeventofaproductrecall.

Permanentinformation,writtenorelectronic,shouldexistforeachstoredmaterialor product to indicate recommended storage conditions, any precautions to beobservedandretestdates.Pharmacopoeialrequirementsandothercurrentnationalregulationsconcerninglabelsandcontainersshouldberespectedatalltimes.

Recordsshouldberetainedforeachdelivery.Theyshouldincludethedescriptionofthegoods,quality,quantity,supplier,supplier’sbatchnumber,thedateofreceipt,assigned batch number and the expiry date. National regulations which state aperiodforretentionofrecordsmustbeobserved.Wherenosuchregulationsexist,recordsshouldberetainedforoneyearaftertheendoftheshelf-lifeofincomingproducts.

Comprehensiverecordsshouldbemaintainedofallreceiptsandissuesofmaterialsand pharmaceutical products according to a specified system, e.g. by batchnumber.

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Module VDistribution

Introduction

Awell-manageddistributionsystemshouldachievethefollowingobjectives(1).• Maintainaconstantsupplyofdrugs.• Keepdrugsingoodconditionthroughoutthedistributionprocess.• Minimizedruglossesduetospoilageandexpiry.• Maintainaccurateinventoryrecords.• Rationalizedrugstoragepoints.• Useavailabletransportationresourcesasefficientlyaspossible.• Reducetheftandfraud.• Provideinformationforforecastingdrugneeds.

Thismodulefocusesonmeasurestobetakentoensureproductintegrityandqualityduring distribution, and outlines the main points. The principles established intheWHOguidelines for good trade and distribution practice(18)(seeAppendix15)shouldbefollowed.

V.1 Transport conditions

Materialsandpharmaceuticalproductsshouldbetransportedinsuchawaythattheintegrityofthematerialorpharmaceuticalproductisnotadverselyaffectedandthatappropriatestorageconditionsaremaintained.

Everyprecautionshouldbetakentominimizetheriskoftheftandfraud.

V.2 Cold chain

Specialcareshouldbeexercisedwhenusingdryiceincoldchains.Inadditiontoaddressingsafetyconcerns,itisnecessarytoensurethatthematerialorproductdoesnotcomeincontactwiththedryice,asthismayadverselyaffectthequalityoftheproduct,e.g.asaresultoffreezing.

V.3 Temperature monitoring and records

Whereappropriate,theuseofdevicestomonitorconditionssuchastemperatureduringtransportationisrecommended.Recordsshouldbeavailableforreview.

V.4 Delivery order

The dispatch and transport of materials and pharmaceutical products should becarriedoutonlyafterreceiptofadeliveryorder,whichhastobedocumented.Thereshouldbeaproceduretoensurethatproductsaresuppliedtoauthorizedrecipientsonly.

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V.5 Dispatch procedures and policies

Rules for dispatch procedures should be established according to the nature ofthematerialsandpharmaceuticalproductsbeingdispatchedandaftertakingintoaccountanyspecialprecautionstobeobserved.Anyspecialpackagingrequirementsformovementofgoodsmustbemet.Somegoodsmayrequirespecialprotectionbeforetheycanbeshippedbyboatorbyair.Alllegislationthatmayaffecttheserequirementsmustbefulfilled.

V.6 Dispatch containersTheoutsidecontainershouldofferadequateprotectionfromallexternalinfluencesandshouldbeindeliblyandclearlylabelled.Productsshouldbepackedinsuchawayastominimizetheriskoftheft,e.g.byusinglockedcontainersorbyshrink-wrappingentirepalletsinplastic.

V.7 Dispatch records

Recordsfordispatchshouldberetained,statingatleastthefollowing:➣ dateofdispatch;➣ customer’snameandaddress;➣ productdescription, e.g.name,dosage formand strength (if appropriate),

batchnumberandquantity;and➣ transportandstorageconditions.

V.8 TraceabilityRecordsofdistributionshouldcontainsufficientinformationtoenabletraceabilityoftheproductfromthepointofsupplytotheenduser.Traceabilityofgoodsiscrucialincaseoftheneedforproductrecalls.Itwillalsohelptodetecttheftandfraud.Anydiscrepanciesshouldbeinvestigatedandfollowedupbyappropriatemeasurestotacklepossiblesecuritybreaches.

V.9 Port of entryAll conditions required for storage should be achievable at the port of entry ofgoods.Thisisparticularlyimportantforalltemperature-sensitiveproductsshippedtoportswheretemperaturesmaybelesswellcontrolled.Specificarrangementsmayneedtobemadewithlocalhandlingagentsandcustomstoensurespeedyhandlingandclearance.Security measures to prevent theft, fraud and bribery should be in place duringstorageattheportofentry.

V.10 Packaging of products and materials

Ifanypackagingor repackaging is requiredbecauseofbreakages,all thepoliciesandproceduresdescribedinWHOGMPguidelines(3)shouldbefollowedintheirentirety.

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Module VIReassessment

Introduction

Thequalityofallproductsand servicesprocured inaccordancewith thisModelshouldbe continuouslymonitored.Reassessmentwillbe required to ensure thatthe products procured continue to meet the norms and standards defined. Thismodule briefly outlines the principles of routine and non-routine assessment ofmanufacturers,productsandcontracted-outservices.

VI.1 Re-evaluation of manufacturers

Re-inspectionofmanufacturersshouldtakeplaceatregularintervalsatleasteverythreeyears.

Manufacturers should inform the procurement agency immediately of anychanges to themanufacturingsiteorequipmentthatmayhavean impacton itsprequalification.

Non-routinerequalificationmayberequiredinthefollowingsituations:• incaseofanyomissionofinformationintheinitialassessment;• if false or misleading information is suspected during the follow-up

assessment;• ifchangesareimplementedthatmayhaveanimpactontheprequalification

ofthemanufacturingsite,suchaschangestokeypersonnelororganizationalstructure,changestoequipment,apparatusorthemanufacturingprocess,ortherenovationoradditionoffacilitiesthatneedvalidation,commissioningorre-inspection;or

• ifacomplaintconsideredtobeseriousinnaturehasbeenreceived.

Theprocurementagencyshouldsuspendorwithdrawaprequalifiedfacilityfromtheprequalificationlistifthereisevidenceofnon-compliancewiththerequirementsforprequalification.

VI.2 Re-evaluation of products

Productinformationshouldbereviewedeverythreeyears,orsoonerifmajorchangesoccurinthemeantime.

Underroutinecircumstancestherewillbenorequirementforthemanufacturertoretesttheproductaspartofthere-evaluationprocess.However,circumstancesmayariseinwhichretestingisnecessary.

Manufacturersshouldinformtheprocurementagencyofanycontemplatedchangestotheproductthatmayaffectitssafety,performance,efficacyorquality.Withregardtotheproduct,manufacturersshouldforinstancereportthefollowingchanges:➣ changeofmanufacturingprocess,siteorequipmentrelatingtotheproduct;

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➣ changeofcontractmanufacturers;➣ changeofpharmaceuticalproductreleasecontrollaboratories;➣ changedsuppliersofstartingmaterialsorcontainerorclosure;➣ changestotheformulationorcompositionoftheproduct;➣ newanalyticalmethodinthetestingofstartingmaterial,intermediateorfinal

product;or➣ changeofspecifications.

Sufficient timemustbeallowed for thenecessary testing, e.g. stability testingorbioequivalencetesting.Basedontheinformationsubmitted,thepersonresponsibleforprequalificationshoulddecidewhethertoapprovethechangesorwhethertorequestadditionaldatawhichdemonstratetheequivalenceof theproducttotheonethathasbeenprequalified.

The section or department responsible for prequalification of products andmanufacturersshouldinformthepurchasingofficeaboutthechangesandtheresultoftheevaluationofsuchchanges.

Non-routinere-evaluationofproductsshouldbedoneinthefollowingcases.• Ifanyomissionbythemanufacturerintheinitialevaluationprocedure,or

during the follow-up activities, is evident in relation to the requirements,including compliance with quality system standards and failure to notifycomplaints.

• If any batch or batches of supplied product(s) are documented by theprocurementagencynottobeincompliancewiththeagreedspecificationsoftheproductortorevealfailure(s)regardingsafety,performanceorqualityofthedevice.

• Iftheinvestigationofacomplaintconsideredleadstotheconclusionthatthequalityand/orsafetyoftheproductisinquestion.

• Ifanyfraudormisconductbythemanufacturerisevident.• Ifanybatchorbatchesofproduct(s)wassuppliedandisconsiderednottobe

incompliancewiththeagreedspecificationoftheproduct.• Ifacomplaintconsideredtobeserious innaturehadbeenreceivedbythe

organization.• Incasesofchangesorvariationstoproducts,theWHOguidelinesMarketing

authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for drug regulatory authorities(6)giveguidanceonwhentoproceedwithwhichtypeofre-evaluation.

• If,intheopinionoftheorganization,changesmadeinthesourcingoftheAPI,formulation,manufacturingmethod,facilityorotherproductionaspectsrequirethatareassessmentbemade.

• Ifsupplyhasbeensuspendedforoneyearorlonger.

VI.3 Monitoring of contracted-out services

VI.3.1 Storage and distribution

Monitoringof theperformanceof contractors and follow-upofnon-compliance

Module VI

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shouldbecarriedoutaccordingtoawrittenprocedure.Itshouldincludecontinuousmonitoring,aswellasperiodicreviewandrenewalofthecontract.

Continuousmonitoringshouldincludetrackingofcost,orderanddeliverystatus,lead-time and compliance with contract terms and conditions. A managementinformationsystemshouldbeinplaceforthispurpose.Thereshouldbecontinuousqualitycontrolofpharmaceuticalproductssuppliedincludingrandomsamplingandaprocedurefordealingwithcomplaints.Theprocurementagencyshoulddocumentanyreportedproblemswithqualitycontrolor serviceand informthecontractorof eachproblem.Continuousmonitoring shouldalso includecomplianceof thecontract-giverwithcontractconditions,andcorrectionofanyfactorsthatpreventthecontract-acceptorfromfulfillingthespecifiedduties.

Periodicreviewofthecontractshouldbebasedonanassessmentofthecontractor’soverallperformance.Thecriteriaoutlinedformonitoringofprequalifiedproductsandmanufacturers(seeSectionIII.6)alsoapplytomonitoringofcontract-acceptorswhostoreanddistributepharmaceuticalproducts.

VI.3.2 Quality control laboratories

Contracted laboratories should comply with the principles of good laboratorypractice(GLP)(19).Theaccreditationstatusalonedoesnotguaranteecompliancewith GLP. The performance of contracted laboratories should be continuouslymonitored.

VI.3.3 Contract research organizations

Contract research organizations (CROs) should be inspected as part of theassessmentprocess to verify that rawdata correspond to submitteddata, and toassesscompliancewithstandardsduringtheconductofclinicalandbioequivalencestudies.Monitoringandrequalificationshouldensurethattheprinciplesofgoodclinicalpractices(GCP)(20),goodpractices forqualitycontrol laboratories(10)andGLP(19)areadheredto.

Conclusion

A trend towards the introduction of quality systems principles in the internaloperationsoforganizationsconcernedwithpharmaceuticalqualityassurancehasled to the publication of the WHO document Quality systems requirements for national good manufacturing practice inspectorates (21), which outlines principlesfor implementing a quality management system (see Appendix 16). The qualitymanagement principles described are valid for all key aspects of procurementand have been considered in designing and testing the model quality assurancesystempresentedinthisdocument.ItisrecommendedthatprocurementagenciesimplementthisModeltoensureaharmonizedapproachtoqualityassuranceinallkeyactivitiesofprocurement.

Theestablishmentandoperationofaqualitysystemisanessentialelementinthemutualrecognitionoftheoutcomesofprequalificationactivities.Onceaharmonized

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systemisinplace,agencieswillbeabletoexchangeinformationonassessmentofproductinformationandinspectionfindings.

Sharingthisinformationwilleliminatetheneedforduplicationofprequalificationprocedures. Reliance on a harmonized system for the procurement of productsmeeting predefined norms and standards will expedite procedures for obtainingquality products at competitive prices. The benefit will be greatest for thosemedicinesforwhichdemandishigh,e.g.medicinesforprioritydiseasesaffectingalargepartoftheworld’spopulationinareaswheredrugregulatorycapacitiesandhealthbudgetsarelimited.

Module VI

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References1. Quick JD, et al. (eds). Managing drug supply. 2nd ed. revised and expanded.

Hartford,CT,KumarianPress,1997.

2. Quality assurance of pharmaceuticals: a compendium of guidelines and related materials.Volume1.Geneva,WorldHealthOrganization,1997.

3. Quality assurance of pharmaceuticals: a compendium of guidelines and related materials. Volume 2, updated edition. Good manufacturing practices andinspection.Geneva,WorldHealthOrganization,2004.

4. 14th Model List of Essential Medicines.Geneva,WorldHealthOrganization,2005(http://www.who.int/medicines/organization/par/edl/expcom13/eml13_en.pdf).

5. Procedure for assessing the acceptability, in principle, of pharmaceuticalproductsforpurchasebyUnitedNationsagencies.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-seventh report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.908),Annex8(http://www.who.int/medicines/qsm/trs908/trs908.pdf).

6. Marketing authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for drug regulatory authorities.Geneva,WorldHealthOrganization,1998(WHO/DMP/RGS/98.5).

7. Modelapplicationformfornewmarketingauthorizations,periodicreviewsandvariations,withnotestotheapplicant.In:Marketing authorization of pharmaceutical products with special reference to multisource (generic) products: a manual for drug regulatory authorities. Geneva,World Health Organization, 1998, Annex6 (WHO/DMP/RGS/98.5) (http://mednet3.who.int/prequal/documents/WHO_DMP_RGS_98_5_R.pdf).

8. WHO Certification scheme on the quality of pharmaceutical products moving in international commerce. Geneva, World Health Organization, 2000 (WHO/EDM/QSM/2000.2) (http://www.who.int/medicines/organization/qsm/activities/drugregul/certification/certifscheme.shtml).

9. Guide for a quality systems manual in a control laboratory.Geneva,WorldHealthOrganization,1998(WHO/VSQ/98.04)(http://www.who.int/vaccines-documents/DocsPDF/www9840.pdf).

10. Goodpracticesfornationalpharmaceuticalcontrollaboratories.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-sixth report. Geneva,World Health Organization, 2002 (WHOTechnical Report Series, No.902),Annex3.

11. GuidanceonGoodManufacturingPractices(GMP):inspectionreport.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-seventh report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.908),Annex6.

12. Operational principles for good pharmaceutical procurement. Geneva, WorldHealthOrganization,1999(WHO/EDM/PAR/99.5).

13. Standard bidding documents. Procurement of health sector goods (pharmaceuticals, vaccines, and condoms).Washington,DC,WorldBank,2000(revised February 2001, March 2002 and March 2003) (http://siteresources.worldbank.org/PROCUREMENT/Resources/health-ev4.pdf).

14. Technical note. Procurement of health sector goods.Washington, DC,WorldBank,2000(http://siteresources.worldbank.org/INTPROCUREMENT/Resources/health-tn-ev2-a4.doc).

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15. Model formulary 2004.Geneva,WorldHealthOrganization,2004 (http://www.who.int/medicines/organization/par/formulary.shtml).

16. Guidelines for drug donations.Geneva,WorldHealthOrganization,1999(WHO/EDM/PAR/99.4).

17. Guidetogoodstoragepracticesforpharmaceuticals.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-seventh report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.908).Annex9(http://www.who.int/medicines/library/qsm/good_storage.pdf).

18. Goodtradeanddistributionpractices forpharmaceuticalstartingmaterials. In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-eighth report.Geneva,WorldHealthOrganization,2003 (WHOTechnicalReport Series, No. 917), Annex 2 (http://www.who.int/medicines/strategy/quality_safety/tr917ann2.pdf).

19. Handbook.Good laboratory practice (GLP).Qualitypracticesforregulatednon-clinical research and development. Geneva, UNDP/World Bank/WHO SpecialProgrammeforResearchandTraininginTropicalDiseases(TDR),2001(TDR/PRD/GLP/01.2).

20. Guidelinesforgoodclinicalpractice(GCP)fortrialsonpharmaceuticalproducts.In:WHO Expert Committee on the Use of Essential Drugs, Sixth report.Geneva,WorldHealthOrganization,1995(WHOTechnicalReportSeries,No.850),Annex3.

21. Quality systems requirements for national good manufacturing practiceinspectorates.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-sixth report.Geneva,WorldHealthOrganization,2002(WHOTechnicalReportSeries,No.902),Annex8.

References

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Appendix1

Example of a Code of Conduct

1. Introduction

ThisCodeofConductmustbefollowedbyappointedstaffmembersaswellasallotherstaffinvolved.

AllmembersofstaffincludingtemporaryadvisersandexpertsappointedtocarryoutevaluationsandinspectiononbehalfofWHOshouldkeepinmindatalltimestheimageofWHO.

(InthecontextofthisCodeofConduct,staffandmembersofstaffincludecontractappointments,short-termstaff,advisersandexpertsappointedfortheperformanceofwork.)

2. Key responsibilities

Eachmemberofstaff,expertandtemporaryadviserhaskeyresponsibilitiestofulfil.TheoverallobjectiveistoperformthesekeyresponsibilitieswithintheframeworkofthisCodeofConduct.

AninternaloversightframeworkhasexistedwithinWHOsincetheearlydaysoftheOrganization.Itisnecessaryperiodicallytoensurethatallstaffunderstandthisfunction.TheWHOsummarystatementonWHO’sOfficeofInternalAuditandOversight(IAO)whichdescribesitspurpose,authorityandscopeofwork,shouldbereadbyeachmemberofstaff.ThisdocumentsummarizestheexpectationsforIAOanditfurnishesdirectionforinternalauditatWHO.

By accepting appointment, staff members pledge themselves to discharge theirfunctionsandtoregulatetheirconducttoservethebestinterestsofWHO.

In the performance of their duties staff members shall neither seek nor acceptinstructions from any government or from any other authority external to theOrganization.

Nostaffmembershallaccept,holdorengageinanyofficeoroccupation,whichisincompatiblewiththeproperdischargeofhisdutieswithWHO.

Staffmembersshallconductthemselvesatalltimesinamannercompatiblewiththeirstatusasinternationalcivilservants.

Staffshallavoidanyactionand inparticularanykindofpublicpronouncementwhichmayadverselyreflectontheirstatus.Whiletheyarenotexpectedtogiveuptheirnationalsentimentsortheirpoliticalandreligiousconvictions,theyshallatalltimesbearinmindthereserveandtactincumbentuponthembyreasonoftheirinternationalstatus.

Appendix 1

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Staffmembersshallexercisetheutmostdiscretioninregardtoallmattersofofficialbusiness.They shallnot communicate to anyperson any informationknown tothembyreasonoftheirofficialposition,whichhasnotbeenmadepublic,exceptin the course of their duties or by authorizationof theDirector-General.Atnotimeshalltheyinanywayusetoprivateadvantageinformationknowntothembyreasonoftheirofficialposition.Theseobligationsdonotceasewithseparationfromservice.

AnystaffmemberwhobecomesacandidateforapublicofficeofapoliticalcharactershallresignfromtheSecretariat.

The immunitiesandprivilegesattaching toWHObyvirtueofArticle67of theConstitutionareconferredintheinterestsoftheOrganization.Theseprivilegesandimmunitiesfurnishnoexcusetostaffmembersfornon-performanceoftheirprivateobligationsorfailuretoobservelawsandpoliceregulations.ThedecisionwhethertowaiveanyprivilegesorimmunitiesofthestaffinanycasethatarisesshallrestwiththeDirector-General.

AllstaffmembersshallsubscribetotheoathordeclarationassetoutinWHOStaffRegulations.

Astaffmembermaynotactasadelegateorobserverfor,oradviserto,hisorhergovernment.

A staffmembermayparticipate in international ornational societieswhen suchparticipationisnotinconflictwiththestandardsreferredtoinWHOStaffRulesand may represent such societies at an international meeting with the Director-General’sauthorization.

A staffmember shall obtain theDirector-General’spermissionbeforepublishingarticleswhosecontentsreflectworkperformedfortheOrganizationorinformationobtainedarisingoutofsuchwork.

All rights, including title, copyrightandpatent rights, inanyworkor inventionproducedordevelopedbyastaffmemberaspartofhisofficialdutiesshallbevestedintheOrganization.

“Misconduct”means:• anyimproperactionbyastaffmemberinhisofficialcapacity;• anyconductbyastaffmember,unconnectedwithhisofficialduties,tending

tobringtheOrganizationintopublicdiscredit;and• anyimproperuseorattempttomakeuseofhisorherpositionasanofficial

forhisorherpersonaladvantage.

Anyconductcontrarytothetermsofhisoathordeclaration.

2.1 Personal responsibilities

StaffmembersmustbecommittedtoastrongoversightenvironmentandmustgiveIAOtheirfullcooperation.

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Staffmustobserve,implementandmaintaintheresponsibilitiesinrelationtothepositioninwhichtheyhavebeenappointed.

StaffmustperformtheworktheyhavebeenallocatedtothebestoftheirabilityandfinalizetasksinaccordancewiththetimeframessetbyWHO.

2.2 Safety

SafetyistheresponsibilityofWHOstaff,supervisorsandWHOmanagement.Itincludesreportingofpossiblehazardsandsuspectedhazardsandtakingthenecessaryprecautionsandimplementingsafeguardstominimizesafetyproblems.

Staffinvolvedinactivitieswheresafetyproblemsmayarise,e.g.theinspectionofamanufacturingsite,shouldobservesafetyrulesandregulationsasrecommendedbyWHO,themanufacturerandnationallegislation.

Staffmustwearprotectivedevices suchasprotectiveclothing, shields,eyecovers(glasses),earplugs,whererelevant,toprotectthebody,organsandextremitiesfrompossibleharm.Staffmustusetheirprofessionalknowledgetoensurethattheytakeappropriatecareof theirownsafety.Thismeans that shouldamanufacturernotprovide what is deemed to be adequate personal protection, then the inspectorsshouldrefusetoenteranareaonthegroundsoflackofsafety.

Staffmustobservenationalregulationswhendrivingvehicles.

Staff must be aware of, and take, the necessary precautions when collectingsamples.

Specialattentiontosafetyrequirementsisnecessarywhenperformingsiteinspections.These includeaspects in relationto thedosage formandactivitiesobserved(e.g.radioactivepharmaceuticals,hazardousmaterials, laboratory reagents, equipmentand apparatus, explosions, personnel lifts, ladders, glassware, freezers, steam,radiation, microbiological hazards, viral and biological products and waste, andotherrelevantpossiblehazards).

3. Professional competence

3.1 Qualifications and experience

Thestaffappointedmusthavetherequiredqualificationsandexperiencetoperformthetasksrequired.AnypersonappointedtoperformworkfororonbehalfofWHOmustindicateifhe/sheisnotsuitablyqualifiedtoperformthetask,ordoesnothavetherelevantexperience,beforetakingontheworkorbeingappointed.

WhenpeopleareapproachedtoperformworkonbehalfofWHO,theymustbetruthfulinprovidingevidenceoftheirqualificationsandexperience.

Staff must not mislead WHO or procurement agencies in relation to theirqualifications and/or experience. Any case of misrepresentation of qualifications

Appendix 1

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orexperiencewillbetreatedasfraudandmayeventuallyleadtoprosecution.NofutureemploymentinanycapacitybyanyWHOorUnitedNationsorganizationwillbepossibleatanytime.

4. Conduct

Duringdailyactivities,staffmustmaintainhighstandardsofethicalconduct.

StaffmustobservetheWHOconstitutionandareresponsibleforcomplyingwiththeWHOregulationsandguidelines.

4.1 Integrity and attitude

ToensurethatthebusinessofWHOisconductedeffectively,andwithoutimproperinfluence,allstaffmembersmustbepersonsof integrityandobservethehigheststandardsofconduct.• WHOmustbeabletorelyuponstafftodotherightthings.• Staffmustbehonestanddependable.• Staffmustbedevotedtoaccuracy,truthfulness,objectivenessandfairness.• Staffmustnotuserestrictedinformationnotavailabletothegeneralpublic

forgainortoadvanceprivateinterests.• Staff must report findings such as presentation of false, misleading and

fraudulentinformationprovidedtoWHO.• StaffshouldmaintainapositiveattitudetowardsWHOanditspoliciesand

projects.• Staffmustbedignified,diplomatic,tactfulandcourteous.Strong-armtactics

mustbeavoided.• Staffmustnotactwithanairofsuperiorityorspecialauthority.• Staff must use a firm approach when requesting necessary and authorized

information.• StaffmembersarethecontactpersonsofWHOandtheiractionwillbethe

basisuponwhichthepublicwilljudgetheorganization.Staffmustexhibitexemplarybehaviouratalltimes.

Astaffmemberwhohasanyfinancialinterestinanybusinessconcernwithwhichhe may be required, directly or indirectly, to have official dealings on behalf oftheprocurementagency shall report such interests to theDirector-General,whoshalldecideontheapplicabilityofStaffRegulations.Staffmaynothavefinancialinterestsincompaniestobeevaluatedorinspected.Shareholdingsthroughpensionschemesandothersuch“arm’slength”arrangementswillnotnormallybetakenasafinancialinterestinthiscontext.AnydoubtsonthismattershouldbereferredtotheWHOInternalAuditOfficeforclarification.

4.2 Attire, health and hygiene

Good public relations require that all members of staff dress appropriately forthe activities to be performed. Staff should observe WHO guidelines regardingappropriatedresscode.

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Staffshouldnormallywearprotectiveclothingforinspections.Inspectorsmustwearprotectiveclothingatleastequivalenttothatwornbyemployeesofmanufacturingsites (e.g. head covering or masks, when appropriate). Staff should conform tocompanyproceduresatalltimes.However,ifcompanyproceduresareconsideredinappropriatethenthisfactshouldberecorded.

Staffinvolvedininspectionsmustinformsupervisorsormanagersoftheirhealthstatuswhenthiscouldhaveimpactoninspections,aspersonswithcommunicablediseases,woundsandopenlesionsmaynotbeallowedinareaswhereproductsandmaterialareexposed.

Staffareresponsiblefortakingthenecessaryprecautionswhentravelling(e.g.havingtheappropriateinoculations).

Staffmustpracticegoodhygieneatalltimes.

4.3 Gifts, meals and favours

Nostaffmembershallacceptanyhonour,decoration,favour,giftorremunerationfromanygovernment,or fromanyother sourceexternal to theOrganization, ifsuchacceptanceisincompatiblewithhisstatusasaninternationalcivilservant.

Astaffmemberwhoisofferedanyhonour,decorationorgiftfromsourcesexternaltotheOrganizationshallreportthisoffertotheDirector-GeneralwhoshalldecideontheapplicabilityofStaffRegulations.

Nomemberofstaffshallreceiveoracceptanythingofvaluefromanymanufacturerfororbecauseofanyofficialactthathasbeenperformedoristobeperformed.

Staff will not solicit or accept directly or indirectly any gift, gratuity, favour,entertainmentloanoranyotheritemofmonetaryvaluefrommembersofthepublicwithwhomstaffmembershaveofficialrelationships.

Whenperforminginspections,staffmustpayfortheirownmealswheneverpossibleand must make an effort to pay for their own meals even when invited by themanufacturer,unlessthesituationissuchthatitwillprovokeasceneorcreateanembarrassmenttoWHO.

4.4 Management relationship

Staffmustpromoteapositiverelationshipwithsupervisorsandmanagers.

4.5 Standard operating procedures

Staff must follow authorized standard operating procedures (SOPs) for theperformanceoftasks.

4.6 Travel and accommodation

StaffmustobserveWHOregulations,guidelinesandSOPswhentravelling.Therelevantproceduresshallbefollowedforplanningofvisits,meetings,inspectionsandotheractivitiessuchasmakingreservationsandpayingforaccommodation.

Appendix 1

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4.7 Confidentiality and conflict of interest

StaffmustobservetheWHOpolicy,countryrulesandregulations,andcompanypolicywithrespecttoconfidentiality.

Staff must sign and abide by the conflict of interest and confidentialityundertaking.

4.8 Documentation and records

Staff shall follow SOPs and maintain appropriate records as required in theprocedures.

Allinformationprovidedbystaffmembersmustbetruthfulandcorrect,includingreportsandrelateddocumentation.

4.9 Contracts and terms of reference

Staffshallperformactivitiesasstipulatedinthecontractoragreementforperformanceofwork(APW)andtermsofreference(TOR).

4.10 Product files, evaluation and inspection

Staffshallhandleproductfileswithcareandtreatall informationasconfidentialrelatingtothetasktobeperformed.

All data submitted initially and as a result of the evaluation, shall bedealtwithinaccordancewithSOPsandbeconsideredasconfidential informationbetweenWHOandthemanufacturer.AllaspectsrelatingtotheinspectionperformedshallbeconsideredasconfidentialbetweenWHOandthemanufacturer.

Staff members shall observe the requirements and undertaking with regard toconfidentialityandconflictofinterest.

4.11 Samples

SamplestakenduringinspectionsshallbeinaccordancewithaWHOSOP,withtheapprovalofthemanufacturer.

4.12 Evaluation and inspection reports

Thereshallbewrittenevaluationandinspectionreportsforeveryproductevaluated,andeverymanufacturingsiteinspected.

The reports shall be a true reflection of the findings of the evaluation andinspection.

4.13 Provision of information and advice

Staffshallnotactasconsultantstoindividualcompaniesormanufacturerswhenappointedforthepurposesofevaluationorinspectionforaparticularproject,wherethecompanycaninparticularbenefitfromsuchadvice,unlesstheinformationisinthepublicdomainorgiventoallmanufacturers.

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Appendix2

Example of a guideline on confidentialityThe evaluators and inspectors will treat all information submitted and observedduring the inspections and otherwise in connection with the discharge of theirresponsibilitieswithregardtotheabove-mentionedproject,asstrictlyconfidentialandproprietarytoWHOorpartiescollaboratingwithWHOinaccordancewiththetermssetforthbelowandthosecontainedintheattachedprovisionsforteammembersparticipatinginsitevisitswithinthescopeoftheprequalificationprocedureofpharmaceuticalproducts.AnexampleofaconfidentialityundertakingisshownattheendofAppendix3.

Evaluatorsandinspectorswilltakeallreasonablemeasurestoensure:➣ thattheconfidentialinformationisnotusedforanypurposeotherthanthe

evaluationactivitiesdescribedinthisdocument;and➣ thatconfidentialinformationisnotdisclosedorprovidedtoanypersonwhois

notboundbysimilarobligationsofconfidentialityandnon-useascontainedherein.

Evaluators and inspectors will not, however, be bound by any obligations ofconfidentialityandnon-usetotheextenttheyareclearlyabletodemonstratethatanypartoftheconfidentialinformation:➣ wasknowntothempriortoanydisclosurebyoronbehalfofWHO(including

bymanufacturers);or➣ wasinthepublicdomainatthetimeofdisclosurebyoronbehalfofWHO

(includingbymanufacturers);or➣ hasbecomepartofthepublicdomainthroughnofaultoftheirs;or➣ hasbecomeavailabletothemfromathirdpartynotinbreachofanylegal

obligationsofconfidentiality.

All personnel involved in prequalification and related matters, having access toconfidential information regarding products and manufacturers, should treatall information submittedandobservedduring the inspections andotherwise inconnectionwiththedischargeoftheirresponsibilitieswithregardtotheseactivities,as strictly confidential andproprietary to theprocurement agencyor thepartiescollaboratingwiththeprocurementagency.

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Appendix3

Example of a guideline on conflict of interest

IntroductionThis document presents policy on “conflict of interest” as it applies to externalevaluatorsandmembersofadvisorycommittees.Thesetwocategoriesaretogetherreferredtoas“consultants”forthepurposesoftheseguidelines.AnexampleofasignedstatementonconflictofinterestisshownattheendofthisAppendix.

Definitions and principlesThecommonmeaningof“conflictofinterest”isaconflictbetweenanindividual’sprivate or personal interest andhis or her duty.However, itmay also refer to asituationwhereanindividualhasseveraldutieswhichconflictwithoutinvolvementofanyprivateorpersonalinterests.

A conflicting private or personal interest may be financial or non-financial asexplainedbelow.

Whenadecision-makerorconsultanthasadirectfinancialinterest,howeverslight,in the matter to be decided, there is a conclusive presumption of bias and thedecision-makerorconsultantwillthusbedisqualifiedfromacting.

Where a decision-maker or consultant has a non-financial interest, which givesrise to a reasonable presumption of bias, the decision-maker or consultant willbedisqualifiedfromacting.Thetesthereiswhetherareasonableobserverwouldsuspect that there isapossibilityofbias,notwhether thatbiasactuallyexists.Arelevant non-financial interest may arise, for example, out of personal or familyinvolvementbetweenadecision-makerorconsultantandapartywhoseinterestsareaffectedbythedecisionorrecommendations.Suchaninterestmayalsoarisewhereadecision-makerorconsultantisseentohaveprejudgedtheissues,eitherthroughpreconceivedopinionsorpriorinvolvementwiththefactsofacaseonwhichheorsheisrequiredtomakeadecisiononrecommendations.

Conflict of interest in relation to consultantsThere are a variety of situations in which consultants may find themselves in asituationofconflictofinterestbetweentheirprofessionalactivities(e.g.preparationofobjectiveandindependentevaluationsormembershipofindependentcommittees)andpersonalandprivateinterest(e.g.privateconsultancies,grantstocovertravelandaccommodationatcompany-sponsoredconferences,shareholdings,researchgrantsorhonoraria).Itisrecognizedthatalmostallconsultantshavesomepotentialconflictofinterestbecauseoftheirpresentorpastassociationwiththepharmaceuticalindustry.

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Some situations of conflict of interest are clear-cut and some are more difficultto determine. If an individual is an employee of, or a retained consultant to, apharmaceutical company, there is a clear possibility of conflict of interest. If anindividualisanemployeeofagovernmentorganization,doesnoworkonbehalfofpharmaceuticalcompanies,andisnotinreceiptofgratuitiesorfunding,thereisaminimalrisk.Betweenthesetwosituationsisaspectrumofpossibilitieswherethedecisionastowhetherthereisaconflictofinterestmaybelessobvious.

Contractsareunlikelytobeofferedtoconsultantsinanyoneofcategories1to6listedbelow.1. Theconsultantworksinthepharmaceuticalindustry,eitherasanemployeeor

asanownerorpartowner(e.g.shareholderinthepharmaceuticalcompanytobeassessed).

2. Theconsultantreceivesaretainer(fee)fromoneormoreofthepharmaceuticalcompanieswhoseproductssheorhehastoassessorwhichthenewproductislikelytoreplace.

3. The consultants have a significant direct current relationship with one ormorecompanies.Thismaytaketheformof(a)financialsupportforacurrentresearch project or projects; (b) sponsorship of graduate or postgraduatestudents;or(c)companyemployeeswhoareunderthedirectresponsibilityoftheconsultant.

4. Heorshereceivessubstantialfinancialassistanceorexpensiveequipmenttoconductresearchonbehalfofthepharmaceuticalcompany.

5. Theconsultantactsorhasactedasaconsultantforapharmaceuticalcompanyon the product she or he has agreed to assess.Suchaconsultancymayincludesponsorship as a speaker, or appointment as chairperson at professionalmeetingsconcerningtheproduct,orattendanceonbehalfofthesponsoringcompanyatnationalor internationalprofessionalmeetingsconcerning theproduct.

6. The consultant has provided significant input to the planning or conductof a clinical trial of theproduct to be assessed, for example as a principalinvestigator, signatory to the study report, or author of any published orunpublishedpaperorotherreportofthestudy.Participationlimitedtotheinclusion of patients in a large-scale multicentre study is not considered asignificantconflictofinterest.

Aconflictofinterestislesslikelytobeseeninsituations7to10(seebelow).7. The consultant has occasional contracts with one or more companies for

particular projects, but does not have a significant relationship with anyonecompany.Sheorhehasnotbeendirectlyinvolvedwiththeproductinquestion.

8. Theconsultantownsorworksforaconsultancy,whichdoesnotprovideadvicetothepharmaceutical industrybutmayprovideadvicetoother industries,suchasthedevices,foodorpaintindustries.Howeveritisunlikelythatsuchconsultantswillhavethetechnicalknowledgeorexperiencetoqualifyasaconsultantinthepharmaceuticalsfield.

9. Theconsultantoccasionallyprovidesadvicetooneormorecompaniesonthedesignofclinicaltrialstobeconductedpriortosubmissionofanapplicationfor

Appendix 3

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marketingauthorization,butdoesnothaveasignificantcurrentrelationshipwithanyonecompany(e.g.points1to6above).

10. The consultant has been invited to attend and contribute to national orinternationalmeetingsorganizedbyprofessionaloracademicassociations.

The responsibility of consultantsAdrugregulatoryauthoritycannotbeawareofalloftheconsultant’sinvolvementsand their ramifications when a contract is offered. The onus is therefore on theconsultant todeclare inwriting anypotential conflictorwhatmaybe seen as apotentialconflicttothestaffmemberofthedrugregulatoryauthoritywhonegotiatedthecontractorcommitteemembership.Ifthereisanydoubt,thepotentialconflictmustbedeclared.Theconsultantmayonlyproceedwiththeevaluationofthedataortakeupcommitteemembershipafteranypotentialconflicthasbeendiscussedwiththedrugregulatoryauthorityandfoundnottobesignificant.

Forthisreason,eachevaluationcontractrequirestheevaluatortosignastatementtotheeffectthatsheorhehasnocurrentconflictofinterestandthat,iftheriskofsuchaconflictarisesduringtheevaluation,thedrugregulatoryauthoritywillbenotifiedimmediatelyinwriting.

The evaluator is expected to cease reading the application immediately she or he becomes aware of a conflict of interest,andreturnitpromptlytothedrugregulatoryauthority.Thisclauseappliesalsotothoseinvolvedintheinspectionoffacilities.

ConfidentialityAnydataconcerningacompany’sproductwhicharesuppliedbythedrugregulatoryauthoritytoaconsultantforreviewarestrictlyconfidential.Asstatedinthecontract,all materials related to or referred to in the contract must be accepted in strictconfidenceandheldinsafeandsecurecustodyatalltimes.Anapplicationmaybediscussedonlywiththestaffmembersofthedrugregulatoryauthority.

Consultants must be aware of and avoid the possibility of indirect breaches ofconfidence.There is clearly apotential, consciouslyor subconsciously, tomisuseinformationgainedfromaconsultancyinotherpapersorscientificpresentationsontheproductinquestion.Suchacasewouldalsoconstituteaconflictofinterest.Theconsultantmustnotuseinformationgainedinthiswayinfuturescientificpapersorpresentationswithouttheagreementofthecompanyorindividualthatsubmittedthedata.

ImpartialityTo protect impartiality, the company concerned is not informed by the drugregulatoryauthorityoftheidentityoftheconsultanttowhomapplications,dataorcommitteepapersareforwarded.Forthisreason,theconsultantshouldhavenodirectcommunicationwiththecompanyconcerningtheproduct.Theconsultantmaynot

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disclosehisorher role to the company, evenafter adecisionon the applicationhasbeencompleted.Thisisclearlynotpossibleinthecaseofaninspectorofthemanufacturingfacility.

Subcontracting the evaluationA consultant is not allowed to subcontract part or all of an evaluation to anysecondpersonwithoutwrittenpermission fromthedrugregulatoryauthority. Ifthedrugregulatoryauthorityagreestosuchanarrangement,theconsultantmustensurethatthesubcontractorisfullyawareoftheprovisionsonconflictofinterest,confidentialityandimpartialitysetoutinthesenotes.

Ifanypartofanevaluationissubcontracted,thepersonwhoactuallyundertakestheworkmustalsosignallthereportstowhichsheorhehascontributed.

Appendix 3

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Example of a confidentiality undertakingand declaration of Conflict of Interest

PROVISIONS FOR EVALUATORS OF PRODUCT INFORMATIONAND FOR INSPECTORS (TEAM MEMBER PARTICIPATING IN

SITE VISITS) WITHIN THE SCOPE OF THE QUALITYASSESSMENT PROCEDURE OF PHARMACEUTICAL PRODUCTS

In the course of discharging your functions as an expert adviser to WHO under the attached agreement for performance of work (APW), you will gain access to certain information, which is proprietary to WHO or entities collaborating with WHO, including the manufacturers of the product(s) which need to be assessed as part of the quality assessment procedure by WHO. You undertake to treat such information (hereinafter referred to as “the Information”) as confidential and proprietary to WHO or the aforesaid parties collaborating with WHO. In this connection, you agree:

(a) not to use the Information for any other purpose than discharging your obligations under the above-mentioned APW; and

(b) not to disclose or provide the Information to any person who is not bound by similar obligations of confidentiality and non-use as contained herein.

However, you will not be bound by any obligations of confidentiality and non-use to the extent that you are clearly able to demonstrate that any part of the Information:

(i) was known to you prior to any disclosure by or on behalf of WHO (including by the manufacturer(s)); or

(ii) was in the public domain at the time of disclosure by or on behalf of WHO (including the manufacturer(s)); or

(iii) becomes part of the public domain through no fault of your own; or(iv) becomes available to you from a third party not in breach of any legal obligations

of confidentiality.

You also undertake not to communicate your deliberations and findings and/or those of the team(s) of experts in which you will participate, as well as any resulting recommendations to, and/or decisions of, WHO to any third party, except as explicitly agreed by WHO.

You will discharge your responsibilities under the above-mentioned APW exclusively in your capacity as an expert adviser to WHO. In this connection, you confirm that the information disclosed by you in the declaration of interest is correct and that no situation of real, potential or apparent Conflict of interest is known to you, including that you have no financial or other interest in, and/or other relationship with, a party, which:

(i) may have a vested commercial interest in obtaining access to any part of the Information referred to above; and/or

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(ii) may have a vested interest in the outcome of the evaluation of the product(s), in which you will participate (such as the manufacturers of those products or of competing products).

You undertake to promptly advise WHO of any change in the above circumstances,includingifanissuearisesduringthecourseofyourworkforWHO.

I hereby accept and agree with the conditions and provisions contained in thisdocument.

Signed

Name(typewritten)

Organization

Place Date

Appendix 3

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Appendix4

Example of a standard operating procedure (SOP) for writing an SOP

1. Title

Standardprocedureforwritingastandardoperatingprocedure(SOP)

285

Appendix 4Example of a standard operating procedure (SOP) for writing an SOP

1. TitleStandard procedure for writing a standard operating procedure (SOP)

2. Policy and objective2.1 The procurement agency should have an SOP for each activity per-formed by the procurement agency. All SOPs should be in the required format and distributed with care to a predetermined list of personnel. SOPs should be authorized, implemented and kept up to date.

2.2 All SOPs should be written in English if any international use is expected, or in the local language if required only by local staff,

2.3 Documentation is a prime necessity in quality assurance. Its purpose is to defi ne the system of control, to reduce the risk of error inherent in oral communication, to ensure that personnel are instructed in the details of, and follow the procedures concerned in a logical, reproducible manner.

2.4 There should be a written SOP for every critical or important activ-ity in the procurement agency. SOPs should be written in the standardized format as attached.

2.5 A list should be kept of all SOPs required by the procurement agency.

2.6 Management should authorize SOPs prior to their distribution and implementation.

3. ResponsibilityAll members of staff should adhere to the SOP when drawing up the SOP.The project manager should supervise its implementation.

Signature Date

Prepared by 9 May 2005

Authorized by

2. Policy and objective

2.1 TheprocurementagencyshouldhaveanSOPforeachactivityperformedbytheprocurementagency.AllSOPsshouldbeintherequiredformatanddistributedwith care to a predetermined list of personnel. SOPs should be authorized,implementedandkeptuptodate.

2.2 AllSOPsshouldbewritteninEnglishifanyinternationaluseisexpected,orinthelocallanguageifrequiredonlybylocalstaff.

2.3 Documentationisaprimenecessityinqualityassurance.Itspurposeistodefinethesystemofcontrol,toreducetheriskoferrorinherentinoralcommunication,toensurethatpersonnelareinstructedinthedetailsof,andfollowtheproceduresconcernedinalogical,reproduciblemanner.

2.4 There should be a written SOP for every critical or important activity inthe procurement agency. SOPs should be written in the standardized format asattached.

2.5 AlistshouldbekeptofallSOPsrequiredbytheprocurementagency.

2.6 Management should authorize SOPs prior to their distribution andimplementation.

3. Responsibility

Allmembersof staff should adhere to theSOPwhendrawingup theSOP.Theprojectmanagershouldsuperviseitsimplementation.

4. Action

4.1 AnypersonmayinitiatethefirstdraftofanSOP.Theheadings(listedbelow)shouldconformtotheattachedformatandshouldbeusedwhenwritingtherelevantsectionsoftheSOP.

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4.2 TheSOPshouldincludeatleastthefollowingheadings: A.Title B.Policyandobjective C. Responsibility D.Action E.Addenda F. Distribution G.Reviewdate H.Revisionhistory

Thefollowinginformationshouldappearundereachheading.

A. Title

Writeinclear languagethetitleoftheproceduretoensureunderstandingoftheprocessthattheSOPwillbedescribing.Theprocedureshouldalsocontainaclearindicationofwhowasresponsibleforthepreparation,reviewandapprovaloftheprocedure.

B. Policy and objective

DescribetheWHOorprocurementagencypolicyregardingthemattertobedealtwithundertheSOP.DescribetheobjectivetobereachedinfollowingtheSOP.

C. Responsibility

DescribeandlistthepeopleresponsibleforperformingtheactivitieslistedintheSOP.Whereverpossible,itispreferabletousejobdescriptionsorpositionnamesforthesepeopleratherthannamesofindividuals.UseofthepersonalnamesofstaffmembersmeanstheSOPhastobechangedeverytimepersonnelchangesoccur.

D. Action

4.1 Describethesequenceofactionsneededtoperformthetask.

4.2 Listtheactionsintheorderinwhichtheyneedtobeperformedandnumberthemfrom1totheend.

4.3 Explainallthestepsindetailinclear,unambiguous,language.

4.4 Puttheinitialsoftheresponsiblepersoninbracketsnexttotheactionstepifaspecificpersonisresponsiblefortheactionstep.

4.5 Read thecompletedSOPtodeterminewhether itdescribesall theactionstepstobefollowedfromthestartoftheprocesstotheend.

4.6 IfastepleadstoanotherSOP,thenrefertotherelevantSOPinthatstep.

4.7 IftheSOPrequiresanyrecordstobekept,drafttherequiredformatofthedocumenttobecompletedandattachittotheSOPasanaddendum.

Appendix 4

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4.8 ForwardtheSOPtothesupervisororpersonresponsiblefordocumentationandqualityassurance.

4.9 ReadtheSOPandassessitssuitabilityandapplicability.4.10 Ifanychangesaretobemade,makeamendmentstotheSOPininkandreturnittothepersonwhowrotetheSOPfortheircomments.4.11 ReturntheSOPtothesupervisor.4.12 SignanddatetheSOPifsatisfiedwithitscontents.4.13 Forward the SOP to the second person who is responsible for approvingdocumentation.4.14 TheSOPshouldbesignedanddatedbythesecondpersonwhoisresponsibleforapprovingthedocumentationifheorsheisinagreementwiththecontents.4.15 ReturntheSOPtothepersonresponsibleformaintainingthedocumentationinfrastructure.4.16 If applicable, proceed with the steps for distribution and retrieval of thepreviousversionoftheSOP.4.17 FiletheoriginalSOPintheSOPfile.

E. Addenda

4.18 Drafteachaddenduminsuchamannerthatitleadsthepersonresponsibleforcompletingtheaddendumtodocumentalltherequiredinformation.

4.19 EachaddendumshallformpartoftheauthorizedSOPandshallbereviewedwhentheSOPisreviewed,orwhennecessary.

F. Distribution

4.20 Records shall be maintained of the distribution and retrieval of SOPs toensurethatsupersededSOPsarenotstillinuseanywhere.

4.21 Completethetable(seeAddendumA,point6)toindicatethenameofthepersontowhomtheSOPwillbesent.

4.22 MakeacopyoftheoriginalSOPandstampitinredinkas“officialcopy”.

4.23 OnlyofficialcopiesofSOPsshallbecontrolled.SOPsnothavingaredstampwillbeconsiderednon-officialanduncontrolledSOPs.

4.24 Theperson shall sign anddate (in the appropriate space in the table (seeAddendumA,point6)ontheoriginalSOP),asproofofreceiptoftheSOP.

4.25 WhentheSOPisreviewedandamended,copiesofthesupersededSOPshouldberetrievedfromallthosewhoholdacopywhenthenewversionisdistributed.

4.26 When replacing the supersededSOP, thepersons fromwhom ithasbeenretrievedshouldsign(anddate)theappropriatespaceonthedistributiontableintheoriginalSOP.

4.27 MarktheoriginalSOPas“superseded”oneachpageandfileinthe“supersededSOP”file.

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4.28 DestroyallretrievedcopiesofsupersededSOPs.

G. Review date

AdateshouldbeassignedonwhichtheSOPwillbereviewedtodeterminewhetheranychangesarerequiredtokeepituptodate.

H. Revision history

4.29 TomaintainarecordofthehistoryoftheinformationontheSOP,completethetableregardingthehistoryofthechangestotheSOP(seeAddendumA,point7).

4.30 Each SOP should have a time limit for validity and should be reviewedbeforetheendoftheperiodofvalidity.ThisisanopportunitytoconsiderwhethertheSOPstillmeetsallitsobjectivesandisappropriatefortheworktobedoneandthemethodsofworking.TheupdatedSOPshouldgothroughthesamewritingandrevisionprocess.

5. Addenda

AddendumAcontainsanoutlineoftheformatofanSOP.

6. Distribution and retrieval

289


7. History

Distribution Retrieval

Name Signature Date Signature Date

Date Reason for change

New SOP

Appendix 4

History

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290

Addendum A: Format of a standard operating procedure

1. Title(indicate title)

2. Policy and objective

3. Responsibility

4. Action4.1

4.2

4.3

5. Addenda


7. History




WHO Logo Document no. Review date: 2006Standard operating procedure

Signature Date


Authorized by

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Appendix5

Example of an invitation for expression of interest

SIXTH INVITATION FOR EXPRESSION OF INTEREST (EOI)

Inthecontextofdramaticallyincreasingtheaccessto,andaffordabilityof,HIV/AIDS-relatedcareandtreatment,WHO,togetherwithUNICEF,UNAIDSandUNFPAareinvitingexpressionsofinterestfrommanufacturersofpharmaceuticalproductsinrespecttotheprovisionofdrugsforthemanagementofHIV-relateddiseases.TheWorldBankisinsupportofthiseffort.

Thissixthinvitationispublishedinordertoincreasetherangeofpossibleproductsandsourcesasafollowuptotheinterestthatwasexpressedasaresultofthefirst,second,third,fourthandfifthinvitationspublishedin2000,2001,2002,2003and2004.

Manufacturersshouldbecommittedtoprovidingtheabove-mentionedproductsatpreferentialpricestodevelopingcountries.Interestedmanufacturersareencouragedtosubmitdocumentationandsamplesasspecifiedbelowforvariousdosageformsandstrengthsoftheproductsinthefollowingcategories:

I) Antiretrovirals as single-ingredient formulations for use in adults and adolescents:

• Nucleoside/Nucleotide.Reverse.Transcriptase.Inhibitors,.including Abacavir Didanosine Lamivudine Stavudine Tenofovir Zidovudine• Non-Nucleoside.Reverse.Transcriptase.Inhibitors,.including Efavirenz Nevirapine• Protease.Inhibitors,.including Indinavir Nelfinavir Ritonavir Saquinavir

Applications are also encouraged for single-ingredient formulations suitable foruse inpaedatricpopulations, that support existing international andornationaltreatmentguidelinesforpaediatricantiretroviraltherapy(ART).

As soliddosage formulations are thepreferred formulations for treatingchildrenexceptforintheveryyounginfant,manufacturersshouldalsoapplyforreducedand/orscoredsoliddosageformulationsof:

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Zidovudine Abacavir Lamivudine Nevirapine Efavirenz

Also sought are syrups, solutions or dissolvable nucleoside/nucleotide and non-nucleosideformulationsofthefollowingproducts: Zidovudine Abacavir Lamivudine Nevirapine

Forfurtherinformationonpaediatricformulationspleaseconsult:http://www.who.int/3by5/paediatric/en/

II) Antiretrovirals as fixed-dose combinations (FDC):

Applicationsarealsoencouragedforfixed-dosecombinationsofanyfirstlineARVregimensasdescribedintheWHO Guidelines for Scaling Up Antiretroviral Therapy in Resource Limited Settings – 2003 Revision.Forfurtherinformationpleaseconsult:http://webitpreview.who.int/entity/3by5/publicatons/documents/arv_guidelines/en/

Fixed-dosecombinationslistedbelow:

Foruseinadultsandadolescents:• Reverse.Transcriptase.Inhibitors Lamivudine+Stavudine Lamivudine+Zidovudine Lamivudine+Stavudine+Efavirenz Lamivudine+Stavudine+Nevirapine Lamivudine+Zidovudine+Efavirenz Lamivudine+Zidovudine+Nevirapine Lamivudine+Zidovudine+Abacavir Tenofovir+Emtricitabine

• Protease.Inhibitors Lopinavir+Ritonavir

Forpaediatricuse,reducedand/orscoredsoliddosageformulationsof:• Reverse.Transcriptase.Inhibitors Lamivudine+Stavudine Lamivudine+Zidovudine Lamivudine+Stavudine+Nevirapine Lamivudine+Zidovudine+Nevirapine Lamivudine+Zidovudine+Abacavir

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• Protease.Inhibitors Lopinavir+Ritonavir

Co-packaged. preparations. of the standard ARV combinations, for adult,adolescent and paediatric use are also sought. for further information onpaediatric fixed-dose and/or co-packaged formulations please consult:http://www.who.int/3by5/paediatric/en/

• Anti-infective.drugs.listed.below:.. Antibacterial.and.antimycobacterial.agents.(other.than.MTB) Azithromycin Ceftriaxone Cefixime Ciprofloxacin Clarithromycin Clindamycin Rifabutin Spectinomycin

.. Antiprotozoal.and.Antifungal.agents AmphotericinB Dapsone Folinicacid Fluconazole Itraconazole Pentamidine Pyrimethamine Sulfadiazine Trimethoprim/Sulphamethoxazole

.. Antiviral.agents Acyclovir Ganciclovir

•.. Anti-cancer.drugs Bleomycin Etoposide Vinblastine Vincristine

• Palliative.care.drugs Amitriptyline Codeine Chlorpheniramine Ibuprophen Loperamide Morphine(oralformulation)

Appendix 5

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ThemedicineslistedinthisInvitationforExpressionofInterestarethoseforwhichaneedhasbeenidentifiedbytheHIV/AIDSdepartment,WHO.Thesubmittedproductsshouldbeofassuredpharmaceuticalqualityandrelevantdatatosupportefficacyshouldbeprovided.

ProcedureforsubmissionofEOI

1. Submitacoveringletterexpressingtheinterestinparticipatingintheproject,confirmingthattheinformationsubmittedintheproductdossiersiscorrect.

2. Submit aproductdossier in the recommended format* as specified in theGuidelineforsubmissionofaproductfilewhichcanbeobtainedbyelectronicmailfromoakesl@who.int,alsoavailableonthethewebpagehttp://mednet3.who.int/prequal.Thedossiershouldbeaccompaniedbyasampleoftheproducttoenableanalyses(e.g.1×100tablets).

*Ifthedossieriscompiledinadifferentformat(e.g.EU),thensuchadossiercanbesubmittedwithacoveringlettercross-referencingthepageswheretherelevantdatacanbefoundinaccordancewiththeabove-mentionedGuideline.

SubmitteddocumentationreachingUNICEFSupplyDivisionwillbeevaluatedduringMarch,May,July,SeptemberandNovember2005.DocumentationshouldbeprovidedinEnglish.Interestedmanufacturersshouldsubmittheabove-mentionedinformationto:

.. UNICEF.Supply.Division

.. Reference:.Accelerated.Access.to.HIV/AIDS.Care

.. SIXTH.EOI

.. UNICEF.Plads.-.Freeport

.. DK-2100.Copenhagen

.. Denmark

.. E-mail:[email protected]

.. Tel:.(45).35.27.35.27.Fax:.(45).35.26.50.48

3. Submitasitemasterfileforeachmanufacturingsiteaslistedintheproductdossier,intherecommendedformat,alsoavailablebyelectronicmailandonthewebpagehttp://mednet3.who.int/prequal/to

The.Secretary.. WHO/HTP/PSM/QSM.. 20.Ave.Appia.. 1211.Geneva.27.. Switzerland

Productsandmanufacturingsitesassessedforacceptabilityandmeetingthespecifiedstandardswillbeaddedtothelistpublishedontheprojectwebpage(http://mednet3.who.int/prequal/).Productsandmanufacturersincludedinthis list may be invited to bid for the supply of products, individually orcollectively,directlybymembergovernments,bytheaforesaidUnitedNationsagenciesand/orbyassociatedNGOs.

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Thefollowingcriteriawillbetakenintoaccountinthequalityassessmentprocess.• Validmanufacturer’slicenceforproduction.• Productregisteredorlicensedinaccordancewithnationalrequirements.• ProductsmanufacturedincompliancewithGMPascertifiedbythenational

regulatoryauthorityand/orcertifiedGMPinspectors.• ProductcertificatesexistinaccordancewiththeWHOCertificationschemeon

thequalityofpharmaceuticalproductsmovingininternationalcommerce.• Productdossiersofacceptablequalitysubmittedandoutcomeoftheassessment

inrespectoftheprequalificationprocedure.• Outcomeoftheinspectionperformedbyoronbehalfoftheabovementioned

agencies.• Manufacturerdemonstratessoundfinancialstanding.

Only manufacturers THAT CAN SUPPLY APPROPRIATE PRODUCTS OFACCEPTABLEQUALITYCOMPLIANTWITHAPPLICABLEREGULATORYREQUIREMENTS, WHO GUIDELINES AND LEGISLATION will beconsidered.

TheUnitedNationsprocurementagenciesreservetherighttodeterminespecificconditions,asforexampletheexclusionofcompaniesusingchildlabour,orengagedinthemanufactureoflandminesorpartsthereof.

Further references

ForbackgroundinformationondrugsforthetreatmentofopportunisticinfectionsinHIV/AIDS,pleaserefertowww.aidsinfo.nih.gov/guidelines.

Forbackground informationonpalliativecaredrugs,pleaserefer tohttp://www.who.int/3by5/publications/documents/en/genericpalliativecare082004.pdf

Appendix 5

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Appendix6Pharmaceuticalproductquestionnaire

I Product identificationActivepharmaceuticalingredient(s)(useINNifany):Genericnameoftheproduct:(TradenamerequirespriorapprovalbyUNICEF)Dosageform:q Tablets q Capsules q Ampoules q Vials q Other:Strengthperdosageunit:Routeofadministration:q Oral q IM q IV q SC q Other:Packsize(ml): q 50q 100q 1000q Other:Descriptionofprimarypackagingmaterials:Descriptionofsecondarypackagingmaterials:

II Manufacturer of the productName,addressandactivitiesofthemanufacturer(s)(orcontractmanufacturer(s)):

296

Appendix 6Pharmaceutical product questionnaire

I Product identifi cationActive pharmaceutical ingredient(s) (use INN if any): _______________Generic name of the product: ___________________________________(Trade name requires prior approval by UNICEF)Dosage form:

Tablets Capsules Ampoules Vials Other: _________Strength per dosage unit: ______________________________________Route of administration:

Oral IM IV SC Other: _______________________Pack size (ml): 50 100 1000 Other: _______________Description of primary packaging materials: _______________________Description of secondary packaging materials: _____________________

II Manufacturer of the productName, address and activities of the manufacturer(s) (or contract manufacturer(s)):

Are all sites listed above licensed by the relevant authority to perform the activity?

Yes No

Is the manufacturing site for THIS product prequalifi ed by the procurement agency?

Yes No

Has the manufacturing method for each standard batch size been validated? Yes No

List the standard batch size quantities: ____________________________

Name Physical address Telephone number, Facsimile number and e-mail contact details

Activity (e.g. packaging)

Areallsiteslistedabovelicensedbytherelevantauthoritytoperformtheactivity?q Yes q No

IsthemanufacturingsiteforTHISproductprequalifiedbytheprocurementagency?q Yes q No

Has the manufacturing method for each standard batch size been validated?q Yes q No

Listthestandardbatchsizequantities:

III Supplier identification(to be filled in if not identical to that indicated in question II)Name:Address:Telephonenumber:Facsimilenumber:E-mailcontactdetails:

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Linkwiththeproduct:q Marketinglicenceholder q Distributor q Manufacturerq Other:

IV Regulatory situation (licensing status) in the country of manufacture

q Productregisteredandcurrentlymarketed:Licencenumber:q Productregisteredformarketinginthecountryofmanufacturebutnotcurrently marketed:Licencenumber:q Productregisteredforexportonly:Licencenumber:q Productnotregistered(pleaseclarify):

Please attach a Certificate of Pharmaceutical Product according to the WHO Certification scheme (WHO Technical Report Series, No. 863). Earlier version is not acceptable.

V Regulatory situation (licensing status) in other countriesListothercountrieswheretheproductisregisteredandiscurrentlymarketed:

VI Finished product specificationsq BritishPharmacopoeiaEdition(BP)q UnitedStatesPharmacopeiaEdition(USP)q InternationalPharmacopoeiaEditionq Other:

Please attach a copy of the finished product specification, if different from BP, USP or International Pharmacopoeia specification.

Limitsin%fortheassayinactiveingredient(s):q 95–105% q 90–110% q Other:Additional specifications to those in the pharmacopoeia (e.g. dissolution,syringeability):

Please attach a copy of the model certificate of analysis for batch release.

Areyouwillingtoprovidenecessaryinformation(analyticalmethod)fortheteststobereplicatedbyanothercontrollaboratory?q Yes q No

Appendix 6

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VII StabilityStabilitytestingdataavailable:q Yes q No

Ifyes,typeandconditionsoftesting:q Acceleratedtesting q 40°C/75%RH/6months q Other:InthesamepackagingasspecifiedunderpointI(page1): q Yes q No

Real-timetestingtemperature:q ambient q 25°C q 30°C q Other:

Relativehumidity:q non-controlled q 45% q 65% q Other:

Periodoftime:q 1year q 2years q 3years q Other:

InthesamepackagingasspecifiedunderpointI(page1): q Yes q No

Canastabilityreportbeforwardedwithinoneweekofbeingrequested?q Yes q No

Wasthestabilitytestingdoneonaproductofthesameformula,manufacturedonthesamesiteandpackedinthesamepackagingmaterialastheproductthatwillbesupplied?q Yes q No

VIII Label and insert informationShelf-life(years): q 2 q 3 q 4 q 5 q Other:

Storageconditions(e.g. “Do not store above 30 °C – Protect from light”):

Labellanguage:q BilingualEnglish/French q English q French q Other:

Packageinsert: q Yes(attachacopy) q No

IX SamplesCan free non-returnable samples be obtained upon request within one week ofbeingrequested? q Yes q No

X Therapeutic equivalenceq Demonstrated:q byinvivobioequivalencestudies:Referenceproduct:Numberofvolunteers: Countryofstudy:

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Yearperformed:q by another method claimed by the supplier/manufacturer (please describebriefly):

q byinvitrodissolutiontests: Referenceproduct:

q notdemonstrated q notrelevant q unknown

Can a copy of the report be obtained upon request within one week of beingrequested?q Yes q No

Istheproductusedinthetrialortestessentiallythesameastheonethatwillbesupplied(samematerialsfromthesamesuppliers,sameformula,samemanufacturingmethod)?q Yes q No

XI Active pharmaceutical ingredient(s) (APIs)(In case more than one active ingredient is used, please replicate this question.)

DospecificationsandstandardtestmethodsexistforeachAPIandexcipient?q Yes q No

EachAPIused(inINNifany):q hasaCertificateofsuitabilitytotheEuropeanPharmacopoeia(CEP) Certificateno.: q TheCEPisinourpossession(includingannexifany) q TheCEPisinthepossessionofthefinishedproductmanufacturer(including annexifany)

q hasadrugmasterfile(DMF) registeredin:(country) registrationno. q ThefulloropenpartoftheDMFisinourpossession q ThefulloropenpartoftheDMFisinthepossessionofthefinishedproduct manufacturer

Qualitystandard:q BP q USP q EP q InternationalPharmacopoeiaq Other(e.g.“in-house”;specify):q Nopharmacopoeiamonographexists**If there is no monograph in a recognized pharmacopoeia, then the followinginformationshouldbeprovidedandevaluated:• chemicalstructure;• ifrelevant,theisomericnatureoftheactiveingredient,includingstereochemical

Appendix 6

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configuration(e.g.racmate,pure(S)-isomer,50/50mixtureof(Z)-and(E)-isomers;

• thesolubilityoftheactiveingredientinwaterat25or35°C;• thesolubilityoftheactiveingredientinothersolventssuchasether,ethanol,

acetone and buffers of different pH (if the active ingredient is acidic orbasic);

• other relevant physicochemical characteristics of the active ingredientsuch as partition coefficient (usually octanol/water) and the existence ofpolymorphs;

• copiesofinfrared,nuclearmagneticresonance(protonandC-13),ultravioletandmassspectra;

• informationon the chemical stabilityof theAPI, andonphysicochemicalstability if relevant (e.g. formation of a hydrate, change of polymorphicform).

Manufacturer(name,physicaladdress+country):

GMPcertified:q Yes(attach a copy of the GMP certificate if any) q No q UnknownCertifiedby:

XII CommitmentI,theundersigned,

(position in the company, e.g. General Manager, Authorized Person, Responsible Pharmacist),actingasresponsibleforthecompany: (name of the company),certifythattheinformationprovided(above)iscorrectandtrue.

(If the product is marketed in the country of origin, tick the following boxes as applicable:)q andIcertifythattheproductofferedisidenticalinallaspectsofmanufacturingandqualitytothatmarketedin:(countryoforigin),includingformulation,methodandsiteofmanufacture,sourcesofactiveandexcipientstartingmaterials,qualitycontroloftheproductandstartingmaterial,packaging,shelf-lifeandproductinformation;

q andIcertifythattheproductofferedisidenticaltothatmarketedin: (nameofcountry),except:

(e.g. formulation, method and site of manufacture, sources of active and excipient starting materials, quality control of the finished product and starting material, packaging, shelf-life, indications, product information)

Date: Signature:

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Appendix7

Example of a standard operating procedure for screening and assessing product information

1. TitleAssessingproductfiles

302

Appendix 7Example of a standard operating procedure for screening and assessing product information

1. TitleAssessing product fi les

2. Policy and objective2.1 Each product fi le submitted by an interested manufacturer should be assessed as part of the prequalifi cation process.

2.2 Each product fi le should go through a screening procedure.

2.3 Product fi les found to comply with the screening requirements will be retained for assessment.

2.4 The objective is to screen product fi les to determine whether these comply with the requirements. This will prevent loss of valuable assessment time, should the product fi les be incomplete when received.

2.5 The objective of the assessment process is to verify that the re-quired information regarding safety, effi cacy and quality of the product is documented and submitted in the required format. Where possible during inspections, and as a part of the verifi cation process, the data and results should be verifi ed to ensure that correct, accurate and reliable data have been submitted to the procurement agency.

3. ResponsibilityProject ManagerEvaluators

Signature Date


Authorized by

2. Policy and objective2.1 Eachproductfilesubmittedbyaninterestedmanufacturershouldbeassessedaspartoftheprequalificationprocess.2.2 Eachproductfileshouldgothroughascreeningprocedure.2.3 Product files found to comply with the screening requirements will beretainedforassessment.2.4 Theobjectiveistoscreenproductfilestodeterminewhetherthesecomplywiththerequirements.Thiswillpreventlossofvaluableassessmenttime,shouldtheproductfilesbeincompletewhenreceived.2.5 The objective of the assessment process is to verify that the requiredinformation regarding safety, efficacy and quality of the product is documentedandsubmittedintherequiredformat.Wherepossibleduringinspections,andasapartoftheverificationprocess,thedataandresultsshouldbeverifiedtoensurethatcorrect,accurateandreliabledatahavebeensubmittedtotheprocurementagency.

3. ResponsibilityProjectManagerEvaluators

4. Action

A. Screening

4.1 Unpackeachproductfileontotheworkingsurfaceinthepresenceofatleasttwootherpersons.Signasheetindicatingthenamesofthepersonsresponsibleforopeningthecontainersonthatdate.4.2 Completetherelevantdetailsinthe“productreceivedregister”.4.3 Record details such as the product number, date, product detail (INN),nameofsupplier,nameofmanufacturer(s),countryofmanufacturer(s),screeningoutcome,datemanufacturerinformed(AddendumA).4.4 Allocatetheproductnumberinnumericalorderstartingfrom001.

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4.5 Thenumbershouldstartwiththeyear,e.g.01(for2001).4.6 Identifytheprojectforwhichtheproductwassubmitted,e.g.HAforHIV/AIDS.Thefirstproductfortheprojectwouldthusbenumbered01HA001.4.7 OpenaWHOfilefortheproduct.Writetheproductname,numberandthenameofthemanufacturerontheouterpage.4.8 Writetheproductnumberontheproductfileandscreeningformfortheproduct.4.9 Screentheproductfiletoassessitscompleteness.Confirmthatalltherequiredinformation,dataandformshavebeensubmittedbythemanufacturer/supplier.4.10 Usetheattachedscreeningformforthispurpose(AddendumB).4.11 Entertherelevantinformationintheappropriatecolumnofthescreeningformaspartofthescreeningprocess.4.12 Oncethescreeningiscomplete,makeacopyofthescreeningform.4.13 Filethecopyofthescreeningforminthescreeningformfile.4.14 Placetheoriginalofthecompletedscreeningforminthefrontoftheproductfile.4.15 Iftheproductfileiscomplete,placetheproductfileinnumericalorderinthedesignatedareamarked“Forevaluation”.4.16 Iftheproductfileisincomplete,placethefileinthedesignatedarea,marked“Incompletefiles”.4.17 Entertheoutcomeinthe“productreceivedregister”.4.18 Foreachproductfilereceived,sendaletterofacknowledgementofreceipttothemanufacturer.Foran“Incompletefile”,informthemanufacturerinwritingthattheproductfilesubmittedwasincompleteandcannotbeconsideredforevaluationorassessment(seeAddendumCforamodelletter).

B. Assessing product files

Note: Eachproductfilemustbeassessedbyatleastthreeevaluators.ThreeevaluatorsshouldevaluatePartI(qualityaspects)andatleasttwoevaluatorsshouldevaluatePartII(bioavailability,safetyandefficacyaspects).

Step 1 (Evaluator 1)

4.19 Takeaproductfilefromthesectionmarked“Forevaluation”.4.20 Usetheattachedproductassessmentreport(AddendumD)forthepurposeofevaluatingtheproductinformation.4.21 Gothrougheachsectionandassesscompliancewiththerequiredstandardsforthesubmissionoftherelevantinformation.4.22 Recordyourfindingsinthereportform.4.23 Oncompletionoftheassessmentrecordyourname,signatureandthedateonthereportform.4.24 Recordanyspecificproblemassociatedwiththeevaluationoftheproductonaseparatereportform,entitled“Product-specificproblemreport”(AddendumE).IfyouareevaluatingPart2,“Bioequivalence(safetyandefficacy)”,andtheefficacy

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partofthedossierisnotincludedforalloralpreparations,exceptaqueoussolutions,atthetimeofadministration,informthemanufacturerinwritingthattheproductfile was submitted without bioavailability aspects and cannot be evaluated atpresent.4.25 Placethereportformsinthefrontoftheproductfile.4.26 Replacethefileinthesection“Forevaluation”.


Performstepsequivalenttosteps4.19to4.26above.


Performstepsequivalenttosteps4.19to4.26above.

Step 4

4.27 Ifafilecontains theevaluationreports signedby threeevaluators (qualityaspects) and two evaluators (bioavailability), place the file in the area marked“Evaluationcompleted”.4.28 Assesswhethertherelevantnumberofevaluators(threeforqualityaspects,andtwoforbioavailability)haveevaluatedeachproductadequately.4.29 Collatetheinformationinthereports.Ifadditionalinformationisrequiredfromthemanufacturerorsupplier,drafttheletteronthebasisoftheinformationcontainedinthereports.4.30 Request the additional information to be submitted within the specifiedperiod.Remindthemanufacturerthatfailuretosupplytherequestedinformationwithinthetimescalerequestedmayleadtoexclusionoftheproductfromfurtherconsideration.4.31 Recordtherecommendationofevaluatorsonthelistfortheinspectionofthemanufacturingsite.

5. AddendaAddendumA: ProductdetailsAddendumB: ScreeningformtoassessthequalityofthesubmissionofEOIAddendumC:ProductinformationreceiptAddendumD:ProductassessmentreportAddendumE:Product-specificproblemreport

6. Distribution and retrievalTherecordofdistributionandretrievaloftheSOPshouldbeenteredinatable;seethemodelbelow.

305

4.28 Assess whether the relevant number of evaluators (three for quality aspects, and two for bioavailability) have evaluated each product adequately.

4.29 Collate the information in the reports. If additional information is required from the manufacturer or supplier, draft the letter on the basis of the information contained in the reports.

4.30 Request the additional information to be submitted within the speci-fi ed period. Remind the manufacturer that failure to supply the requested information within the timescale requested may lead to exclusion of the product from further consideration.

4.31 Record the recommendation of evaluators on the list for the inspec-tion of the manufacturing site.

5. AddendaAddendum A: Product detailsAddendum B: Screening form to assess the quality of the submission of EOIAddendum C: Product information receiptAddendum D: Product assessment reportAddendum E: Product-specifi c problem report

6. Distribution and retrievalThe record of distribution and retrieval of the SOP should be entered in a table; see the model below.

7. HistoryThe history of changes to the SOP should be recorded in a table; see the model below.




Appendix 7

��


7. HistoryThehistoryofchanges to theSOPshouldbe recorded ina table; see themodelbelow.

305

4.28 Assess whether the relevant number of evaluators (three for quality aspects, and two for bioavailability) have evaluated each product adequately.

4.29 Collate the information in the reports. If additional information is required from the manufacturer or supplier, draft the letter on the basis of the information contained in the reports.

4.30 Request the additional information to be submitted within the speci-fi ed period. Remind the manufacturer that failure to supply the requested information within the timescale requested may lead to exclusion of the product from further consideration.

4.31 Record the recommendation of evaluators on the list for the inspec-tion of the manufacturing site.

5. AddendaAddendum A: Product detailsAddendum B: Screening form to assess the quality of the submission of EOIAddendum C: Product information receiptAddendum D: Product assessment reportAddendum E: Product-specifi c problem report


7. HistoryThe history of changes to the SOP should be recorded in a table; see the model below.




Addendum A: Product details

306


Addendum B: Screening form to assess the quality of the submission of an expression of interest

Access to drugs and diagnostics of acceptable qualityPilot procurement quality and sourcing project

Complete the following:

Product name

Active pharmaceutical ingredient

Strength

Dosage form

Pack size

Name of supplier of drug products

Address of supplier of drug products

Name and address of manufacturer if different from that of the supplier above

Name and address of manufacturer (and if appropriate of supplier) of the active pharmaceutical ingredient

Date of submission

Country of origin of the submission Supplier: ___________________________________Manufacturer: ______________________________

Is the product licensed in JapanUSAEU*

YESYESYES

NONONO

If “Yes”, proceed to Appendix 1If “No”, proceed to Appendix 2

* (EU countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, United Kingdom)

ProductNumber

Date Product details(INN)

Name ofsupplier

Name of manufac-turer(s)

Country of manu-facture

Screen-ingoutcome

Datemanu-facturer informed

Inspec-tionplanned(Y/N)

Product submission number:


AccesstodrugsanddiagnosticsofacceptablequalityPilotprocurementqualityandsourcingproject

306





Product name


Strength

Dosage form

Pack size





Date of submission



YESYESYES

NONONO



ProductNumber


Name ofsupplier



Screen-ingoutcome




��

Appendix 1Thefollowingisincludedinthesubmission:

306





Product name


Strength

Dosage form

Pack size





Date of submission



YESYESYES

NONONO



ProductNumber


Name ofsupplier



Screen-ingoutcome




307

Appendix 1

The following is included in the submission:

A WHO-type certifi cate of a pharmaceutical product (CPP) issued by one of the regulatory authorities of ICH regions

YES NO

The summary of product characteristics (SmPC)

Assessment report(s) issued by the respective regulatory authority

WHO-type batch certifi cate from the manufacturer

The packaging of the product is the same as that approved by the drug regulatory authorities of the ICH regions

1

The product information is the same as on the WHO-type CPPfor at least:

________ ________

Formulation 2

Strength 2

Specifi cations 2

1 Stability testing data are submitted

2 Arguments and/or data to support the applicability of the certifi cate(s) despite the differences are submitted.

If the answers to 1 and 2 are “no”, then the EOI should be rejected.

Appendix 7

(continued)

* (EU countries: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia,Finland,France,Germany,Greece,Hungary,Ireland,Italy,Latvia,Lithuania,Luxembourg,Malta,Netherlands,Poland,Portugal,Romania,Slovakia,Slovenia,Spain,Sweden,UnitedKingdom).

��


Appendix 2

Check that the followinghasbeen submitted in theproductdocumentation forEOI:

308

Appendix 2

Check that the following has been submitted in the product documentation for EOI:

YES NO

Details of the product(Name of the product; approved generic name(s) (use INN, if any); visual description of the product; visual description of the packaging; strength per unit dosage and dosage form)

Regulatory situation in other countries(Marketing authorization, withdrawn from the market, application rejected, deferred or withdrawn.)

API

PropertiesChemical structure; solubility in water, other solvents such as ether, ethanol, acetone and buffers of different pH; its isomeric nature including stereochemical confi guration; partition coeffi cient and the existence of polymorphs; copies of infrared, nuclear magnetic resonance (proton and C-13), ultraviolet and mass spectra; information on the chemical and physico-chemical stability if relevant (e.g. formation of a hydrate, change of polymorphic form)

Sites of manufactureName and street address of each facility of manufacture (synthesis, production), including any alternative manufacturersGMP certifi cate attached (including for all alternative sites of manufacture being submitted)

Route(s) of synthesis1. Including reagents and reaction conditions; specifi cations for starting materials, reagents, solvents, catalysts and intermediates in the synthesis; synthetic by-products and degradation products2. If a European certifi cate of suitability with any appendices is submitted, then an outline of the route of synthesis is suffi cient3. The manufacturer of the fi nished product should know the full details of the synthesis of the substance so that they are able to conduct a full set of tests on each batch. The results of such testing should be presented for at least two batches. The last option can be used only if the quality of API is described in a pharmacopoeia

Specifi cations

Pharmacopoeial requirements: copy of the monograph and tests, additional specifi ca-tions, certifi cates of analysis, two batches, including results for impurities

Non-pharmacopoeia: tests and limits, methods, results of validation

Stability testingResults of stability, physical as well as chemical tests, methodology used (WHO guide-lines or ICH guidelines), validation

Finished product

FormulationFormulation and administration unit, excipients not present in fi nal formulation, the qualita-tive and quantitative composition, overages, function(s) of each excipient, ranges in the content of excipients justifi ed and explained

Sites of manufactureName and street address of each facility. Indicate the activity, alternative manufacturers, major production step(s) – certifi cate issued, product information approved, summary basis of approval

)

��

309

YES NO

Manufacturing procedureOutline of manufacturing and packagingCopy of the master formula and a copy of a manufacturing recordDetails of sterilizationStages of sampling and in-process control tests

Specifi cations for excipientsPharmacopoeia: copy of the monograph, test methods referencedAdditional specifi cationsNon-pharmacopoeia: list of tests and for each excipient, including solvents, liquids to adjust pH, coatings, capsule shell, and inked imprint (on the dosage form), description of test methods, microbiological limits, colours EU/FDA/Japan

Specifi cations for the fi nished productTwo specifi cations: at release and end of shelf-lifeList general characteristics, specifi c standards: tests and limits for results for the fi nished product must be providedAnalytical test procedures described (physicochemical properties, identity of API)Quantitative determination of active, deviations, purity tests, pharmaceutical tests, colour-ing antimicrobial or chemical preservatives, results of validation studies, comments on the choice of routine tests and standards providedCopy of pharmacopoeia monograph and verifi cation dataResults of batch analysis (inc. date of manufacture, place of manufacture, batch size and use of batch tested)

Container/closure system(s) and other packagingDetailed description (inc. liner or wadding, details of composition); describe other (e.g. outer) packaging; state materials and specifi cations for part in contact with the product, or if protective.Parenteral: BP, EP, JP or USP

Stability testingResults for each pack, methodology, validated (accuracy and precision recorded)Related compounds and decomposition: sensitivity, accelerated and real-time data, accelerated 40 °C and 75% RH for six months, real time 30 °C and 70% RH

Container labellingName, active ingredients, amount of each, batch number, expiry date, storage conditions, directions, warnings or precautions, name and address of the manufacturer, excipients known to be a safety concern

Product informationCopy approved by competent authority

Patient information and package insertsCopies of package inserts and information for distribution

Justifi cation for any differencesArguments provided and/or data to support, validation data. Only minor differences are likely to be acceptable

InterchangeabilityMultisource (generic): bioequivalence study. Bioequivalence of all oral preparations except aqueous solutions. Orally or parenterally administered aqueous solutions: chemical–pharmaceutical characteristics. Comparative clinical trial using clinical or pharmacodynamic end-points can be presented. End-points justifi ed and validated for the compound and trial should be designed to show equivalence. Trial showing the absence of signifi cant difference cannot be acceptedBioequivalence study report included

Appendix 7

�00


310

YES NO

ReportStudy design, investigators, study site, study dates, preparations used, characterization of study subjects, study procedures, drug determination methods, measured drug concen-trations, calculation methodology of pharmacokinetic parameters, statistical methodology and results of statistical calculations

Summary of pharmacology, toxicology and effi cacy of the productNew active ingredients and new combinations of active ingredients: full safety and effi cacy (EU, FDA, Japan)

Accept Reject Hold

Reasons for rejecting or holding an application: ____________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

�0�

Addendum C: Product information receipt

Dear…

Prequalificationofmanufacturersandsuppliersofdrugproducts

Thankyouforsubmittingaproductfileafterhavingindicatedyourcompany’sinterestinsupplyingdrugproductsaspartoftheprequalificationprocessofdrugproductstotheUnitedNationsorganizationsandinterestedprocurementagencies.

Weherewithacknowledgereceiptofyourproductinformationsenttothisofficeaspartoftheprequalificationprocess.

The product information submitted has been screened to assess completenessof the submission in accordance with the guidelines that were sent to you afterreceivingyourExpressionofInterest(EOI)inparticipatingintheprequalificationprogramme.Kindlynotethatyoursubmissionisnowpendingthefullassessment.Itispossiblethataninspectionofthemanufacturingsite(s)willbeperformedinduecourse.Detailsofthiswillbeadvisedtoyouonceallthenecessaryarrangementshavebeencompleted.

OR

Kindlynotethatyoursubmissionwasfoundtobeincomplete.Wethereforeregrettoinformyouthatnofurtherevaluationwilltakeplacewithregardstoyourproductfile, and that the manufacturer will be not be included in the prequalificationprocess.Wouldyoukindlycontactthisofficewithin30daystoenableustomakethenecessaryarrangementsforthereturnoftheinformationalreadysubmitted.

OR

Kindlynote thatyour submissionwas found tobe incomplete. It ismissing thefollowinginformation.

IfyouprovidethemissingdatawithinXdays,anditisofsatisfactoryquality,thenyoursubmissionwillgoforwardtofullassessment.

Yourcooperationisappreciated.

Appendix 7

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Addendum D: Product assessment reportAccesstodrugsanddiagnosticsofacceptablequalityPilotprocurementqualityandsourcingproject

312

Addendum D: Product assessment report


Product number:

Product name (API):

Manufacturer:

Product manufactured and registered/licensed in EU, Japan or USA YES1 NO2

This product evaluation report consists of two parts. Both parts should be completed as part of the assessment. The report should be written in clear unambiguous language referring to shortcomings or lack of data submitted, as communication with the manufacturer may result from the assessment.

Part One should be completed by at least three evaluators from different countries, responsible for assessing product quality including pharmaceuti-cal and analytical aspects. (The report should be no longer than six pages.)

Part Two should be completed by an evaluator responsible for the assess-ment for bioavailability. (The report should be no longer than two pages.)

The report should be signed off by the person responsible for the evaluation and assessment of the product fi les.

Part I: Quality aspects

1 Product licensed/registered in the EU, Japan or the USA. Review the data submitted and comment (see also guidelines):

A WHO-type certifi cate of a pharmaceutical product (CPP) issued by one of the regulatory authority of ICH regions (EU, Japan, USA)




The packaging of the product is the same as those approved by the drug regulatory authorities of the ICH regions

The product information is the same as on the WHO-type CPP for at least:

Thisproductevaluationreportconsistsoftwoparts.Bothpartsshouldbecompletedas part of the assessment. The report should be written in clear unambiguouslanguagereferring toshortcomingsor lackofdata submitted,ascommunicationwiththemanufacturermayresultfromtheassessment.

PartOneshouldbecompletedbyatleastthreeevaluatorsfromdifferentcountries,responsible forassessingproductquality includingpharmaceutical andanalyticalaspects.(Thereportshouldbenolongerthansixpages.)

PartTwoshouldbecompletedbyanevaluatorresponsiblefortheassessmentforbioavailability.(Thereportshouldbenolongerthantwopages.)

Thereportshouldbesignedoffbythepersonresponsiblefortheevaluationandassessmentoftheproductfiles.


1Productlicensed/registeredintheEU,JapanortheUSA.Reviewthedatasubmittedandcomment(seealsoguidelines):

312

Addendum D: Product assessment report


Product number:

Product name (API):

Manufacturer:

Product manufactured and registered/licensed in EU, Japan or USA YES1 NO2

This product evaluation report consists of two parts. Both parts should be completed as part of the assessment. The report should be written in clear unambiguous language referring to shortcomings or lack of data submitted, as communication with the manufacturer may result from the assessment.

Part One should be completed by at least three evaluators from different countries, responsible for assessing product quality including pharmaceuti-cal and analytical aspects. (The report should be no longer than six pages.)

Part Two should be completed by an evaluator responsible for the assess-ment for bioavailability. (The report should be no longer than two pages.)

The report should be signed off by the person responsible for the evaluation and assessment of the product fi les.


1 Product licensed/registered in the EU, Japan or the USA. Review the data submitted and comment (see also guidelines):

A WHO-type certifi cate of a pharmaceutical product (CPP) issued by one of the regulatory authority of ICH regions (EU, Japan, USA)




The packaging of the product is the same as those approved by the drug regulatory authorities of the ICH regions

The product information is the same as on the WHO-type CPP for at least:

�0�

313

Formulation

Strength

Specifi cations

2 Product not licensed/registered in the EU, Japan or the USA. Review the data submitted and comment:

Details of the product

Regulatory situation in other countries

Active pharmaceutical ingredient(s) (API) Properties of the API(s)

Sites of manufacture

Route(s) of synthesis

Specifi cations API described in a pharmacopoeia (specify the pharmacopoeia, its edition, and any supplement if relevant). The latest edition of the relevant pharmacopoeia should always be used. API not described in a pharmacopoeia

Stability testing

Finished product

Formulation


Manufacturing procedure

Specifi cations for excipients

Appendix 7

313

Formulation

Strength

Specifi cations

2 Product not licensed/registered in the EU, Japan or the USA. Review the data submitted and comment:

Details of the product

Regulatory situation in other countries

Active pharmaceutical ingredient(s) (API) Properties of the API(s)


Route(s) of synthesis

Specifi cations API described in a pharmacopoeia (specify the pharmacopoeia, its edition, and any supplement if relevant). The latest edition of the relevant pharmacopoeia should always be used. API not described in a pharmacopoeia

Stability testing

Finished product

Formulation


Manufacturing procedure

Specifi cations for excipients

�0�


314

Specifi cations for the fi nished product

Container/closure system(s) and other packaging

Stability testing

Container labelling

Product information

Patient information and package inserts

Justifi cation for any differences of the product in the country or countries issuing the submitted WHO-type certifi cate(s)

Evaluator (name): Signature: Date:

1

2

3

Part II: Bioavailability (safety and effi cacy)

(See also guidelines)

Bioequivalence study report

Summary of pharmacology, toxicology and effi cacy

Evaluator (name): Signature: Date:

1

2

3

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Addendum E: Product-specific problem report

AccesstodrugsanddiagnosticsofacceptablequalityPilotprocurementqualityandsourcingproject

315

Addendum E: Product-specifi c problem report


API:

This product-specifi c problem report should highlight any specifi c prob-lems identifi ed during the evaluation of products. No mention should be made of the specifi c manufacturer’s product. The objective is to identify any problems associated with a specifi c product containing a specifi c API, or specifi c to any dosage form.

Dosage form

Problems

General recommendations

This product-specific problem report should highlight any specific problemsidentifiedduringtheevaluationofproducts.Nomentionshouldbemadeofthespecificmanufacturer’sproduct.TheobjectiveistoidentifyanyproblemsassociatedwithaspecificproductcontainingaspecificAPI,orspecifictoanydosageform.

315

Addendum E: Product-specifi c problem report


API:

This product-specifi c problem report should highlight any specifi c prob-lems identifi ed during the evaluation of products. No mention should be made of the specifi c manufacturer’s product. The objective is to identify any problems associated with a specifi c product containing a specifi c API, or specifi c to any dosage form.

Dosage form

Problems

General recommendations

Appendix 7

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Appendix8

Technical questionnaire for pharmaceutical manufacturers

1. General information on the manufacturerName,address,telephone,telefax,Internetaddressofthecompany:

316

Appendix 8 Technical questionnaire for pharmaceutical manufacturers

1. General information on the manufacturerName, address, telephone, telefax, Internet address of the company:

Name

Postal address

Physical address

Telephone

Fax number

Web site URL

Contact e-mail address

2. Affi liatesIf the company is owned by another company, or belongs to a group of companies,Please describe your position within the structure: __________________ __________________________________________________________

3. Regulatory issues3.1 Good manufacturing practice (GMP)

Indicate the GMP standards (WHO, PIC/EU, FDA or other) with which the company complies: ___________________________________________

Provide a copy of the latest inspection report or certifi cate whichever is appropriate.

3.2 Manufacturing licence for medicinal products

Please list the pharmaceutical dosage forms you are licensed to manufac-ture by the national regulatory authority and attach a copy of the manufac-turing licence(s): _____________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

2. AffiliatesIf the company is owned by another company, or belongs to a group ofcompanies,Pleasedescribeyourpositionwithinthestructure:

3. Regulatory issues

317

3.3 Inspection

Date of last inspection by a national or other competent drug regulatory authority:

Drug regulatory authority Date

Please attach a copy of the last inspection report(s) or certifi cates for re-view on a confi dential basis.

4. Manufacturing4.1 Manufacturing site

Please state all the names and addresses at which manufacturing of pharma-ceutical products to be prequalifi ed takes place, and indicate in which year the factory was built. Include dates of upgrading and adaptation, as well as a description of the activity:

Name Physical address Year built and recent upgrades

Activity (e.g. all, compression, pack-aging, etc.)

4.2 Personnel

Please indicate the name, qualifi cation and years of experience of the fol-lowing key staff:

Position Name Qualifi cation Experience

Managing Director

Technical Director

Production Manager

Quality Control Manager

Quality Assurance Manager

Number of personnel in total: ___________________________________Number of personnel in production: ______________________________Number of personnel in quality assurance/control: __________________

3.1 Good manufacturing practice (GMP)Indicate the GMP standards (WHO, PIC/EU, FDA or other) with which thecompanycomplies:

Provide a copy of the latest inspection report or certificate whichever is appropriate.

3.2 Manufacturing licence for medicinal productsPleaselistthepharmaceuticaldosageformsyouarelicensedtomanufacturebythenationalregulatoryauthorityandattachacopyofthemanufacturinglicence(s):

3.3 InspectionDateoflastinspectionbyanationalorothercompetentdrugregulatoryauthority:

�0�

Please attach a copy of the last inspection report(s) or certificates for review on a confidential basis.

4. Manufacturing 4.1 Manufacturing site

Pleasestateallthenamesandaddressesatwhichmanufacturingofpharmaceuticalproductstobeprequalifiedtakesplace,andindicateinwhichyearthefactorywasbuilt. Includedatesofupgrading and adaptation, aswell as adescriptionof theactivity:

317

3.3 Inspection








4.2 Personnel



Managing Director

Technical Director

Production Manager




4.2 PersonnelPleaseindicatethename,qualificationandyearsofexperienceofthefollowingkeystaff:

317

3.3 Inspection








4.2 Personnel



Managing Director

Technical Director

Production Manager




Numberofpersonnelintotal:Numberofpersonnelinproduction:Numberofpersonnelinqualityassurance/control:

4.3 Ventilation system

Please indicate whether the manufacturing areas are equipped with controlledventilationsystems qYes qNo

If “Yes”, please give a brief description of the ventilation system. (A diagramcomplementingthedescriptioncanbesubmitted.)

If“No”,explainreasons:

Appendix 8

�0�


4.4 Quality control

Instrumentation?

Chemicallaboratory in-houseq contractedoutq

Biologicallaboratory in-houseq contractedoutq

Microbiologicallaboratory in-houseq contractedoutq

4.5 Contract manufacture

Doyouundertakecontractmanufactureforothercompanies? qYesqNo

If“Yes”,pleaseindicatethetypeofproducts(e.g.pesticides,antibiotics,hormones,cytotoxics,etc.)

Doyousubcontracttoothercompanies? qYesqNo

If“Yes”,pleaselistproductsand/orservicesthataresubcontracted:

4.6 Sterile productsDoyoumanufacturesterileproducts? qYesqNoGiveabriefdescriptionofthemethodofsterilizationused:

4.7 Beta-lactam, highly sensitizing compounds, hormones, cytotoxic .. products

Doyoumanufacturepenicillinsorotherbeta-lactam,highlysensitizingcompounds,hormonesorcytotoxicproducts? qYesqNo

Ifyes,doesthisproductiontakeplaceinaseparatebuildingprovidedwithitsowndedicatedair-handlingsystem? qYesqNo

4.8 Complaints and recalls

Do you have a recall procedure, which enables you to recall any producteffectively and promptly within 24 hours from the distribution pointsormarket? qYesqNo

Doyouhaveaprocedureforhandlingcomplaints? qYesqNo

Doesitcoveranalysisoftrends? qYesqNo

Please list significant product complaints and any recalls during the last threeyears:

�0�

4.9 Research and development activitiesPleaseindicatethetypeofactivitiesandannualinvestment:.

4.10 Production capacity

319


Do you have a recall procedure, which enables you to recall any product effectively and promptly within 24 hours from the distribution points or market? Yes No

Do you have a procedure for handling complaints? Yes No

Does it cover analysis of trends? Yes No

Please list signifi cant product complaints and any recalls during the last three years:

Product List complaints

Year 1 Year 2 Year 3

4.9 Research and development activities

Please indicate the type of activities and annual investment: . __________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________


Product No. of units per year Last year’s production units

Tablets

Capsules

Ampoules

Vials, liquids

Vials, dry powder

Vials, lyophilized

Ointments

Liquids

Powder for oral suspensions

Suppositories

Penicillin, tablets/capsules

Penicillin, powder for oral suspension

319


Do you have a recall procedure, which enables you to recall any product effectively and promptly within 24 hours from the distribution points or market? Yes No

Do you have a procedure for handling complaints? Yes No

Does it cover analysis of trends? Yes No

Please list signifi cant product complaints and any recalls during the last three years:

Product List complaints

Year 1 Year 2 Year 3

4.9 Research and development activities

Please indicate the type of activities and annual investment: . __________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________


Product No. of units per year Last year’s production units

Tablets

Capsules

Ampoules

Vials, liquids

Vials, dry powder

Vials, lyophilized

Ointments

Liquids

Powder for oral suspensions

Suppositories

Penicillin, tablets/capsules

Penicillin, powder for oral suspension

Are production capacity figures based on one or more shifts? (Tick appropriatebox)

qOne qTwo qThree

4.11 Stock

Doyoumaintainapermanentstock? qYesqNo

320

Penicillin, powder for injection

Other, specify

Are production capacity fi gures based on one or more shifts? (Tick appro-priate box)

One Two Three

4.11 Stock

Do you maintain a permanent stock? Yes No

4.12 Quality systems (including quality management and quality assurance)

Give a brief description of the quality management system, with specifi c reference to aspects such as procurement agency, documentation infrastruc-ture, validation, training, statistical analysis, and other related aspects: __ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

5. Products5.1 Product licences

Please enclose a list of all products manufactured by your company for which you seek prequalifi cation and which are authorized for sale. For each licensed product, please complete the table below and categorize as shown.

If possible, please attach an indicative price list.

Product Marketed in the domestic

market(Yes or No)

For export only (Yes or No)

Licences are held in the fol-

lowing countries

Name of con-tract manu-facturer and

country

5.2 Documentation

The following product documentation must be made available upon re-quest for each product offered. Please indicate if this documentation

Appendix 8

��0



Giveabriefdescriptionofthequalitymanagementsystem,withspecificreferencetoaspects suchasprocurementagency,documentation infrastructure,validation,training,statisticalanalysis,andotherrelatedaspects:

5. Products

5.1 Product licences

Pleaseenclosealistofallproductsmanufacturedbyyourcompanyforwhichyouseekprequalificationandwhichareauthorizedforsale.Foreachlicensedproduct,pleasecompletethetablebelowandcategorizeasshown.

320

Penicillin, powder for injection

Other, specify

Are production capacity fi gures based on one or more shifts? (Tick appro-priate box)

One Two Three

4.11 Stock

Do you maintain a permanent stock? Yes No


Give a brief description of the quality management system, with specifi c reference to aspects such as procurement agency, documentation infrastruc-ture, validation, training, statistical analysis, and other related aspects: __ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

5. Products5.1 Product licences

Please enclose a list of all products manufactured by your company for which you seek prequalifi cation and which are authorized for sale. For each licensed product, please complete the table below and categorize as shown.

If possible, please attach an indicative price list.

Product Marketed in the domestic

market(Yes or No)

For export only (Yes or No)

Licences are held in the fol-

lowing countries

Name of con-tract manu-facturer and

country

5.2 Documentation

The following product documentation must be made available upon re-quest for each product offered. Please indicate if this documentation

5.2 Documentation

The followingproduct documentationmust bemade available upon request foreachproductoffered.PleaseindicateifthisdocumentationisNOTavailableforanyoftheproductsonthelistshownunderpoint5.1:

Productcomposition–masterformula

Startingmaterialsspecification

Manufacturingandpackagingspecification

In-processtestspecificationsandmethods

Finishedproductspecification

Packagingandlabellingspecifications

Analyticalprocedures

��

Upon request, “the common product questionnaire” must be completed andreturned.

5.3 Samples

Are you willing to provide product samples and batch documentation (on aconfidentialbasis)whenrequested? qYesqNo

5.4 Starting materials

Liststartingmaterialsmanufacturedbythecompanyorbyaffiliates,andindicatein the tablebelowwhether approveddrugmasterfiles (DMF)orCertificates ofsuitabilityoftheMonographoftheEuropeanPharmacopoeia(CEP)areavailable.

321

is NOT available for any of the products on the list shown under point 5.1:

Product composition – master formula ____________________________

Starting materials specifi cation __________________________________

Manufacturing and packaging specifi cation ________________________

In-process test specifi cations and methods _________________________

Finished product specifi cation __________________________________

Packaging and labelling specifi cations ____________________________

Analytical procedures _________________________________________

Upon request, “the common product questionnaire” must be completed and returned.

5.3 Samples

Are you willing to provide product samples and batch documentation (on a confi dential basis) when requested? Yes No

5.4 Starting materials

List starting materials manufactured by the company or by affi liates, and indicate in the table below whether approved drug master fi les (DMF) or Certifi cates of suitability of the Monograph of the European Pharmaco-poeia (CEP) are available.

Starting material DMF(Mark ✓, and state number)

CEP(Mark ✓)

5.5 Stability studies and shelf-life

Do you perform initial and continuous stability studies on your products? Yes No

Give a brief description of the stability procedure and programme. If “No”, explain reasons: _____________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

5.5 Stability studies and shelf-life

Doyouperforminitialandcontinuousstabilitystudiesonyourproducts? qYesqNo

Giveabriefdescriptionofthestabilityprocedureandprogramme.If“No”,explainreasons:

Whattype(s)ofstudiesdoyoucarryout?

322

What type(s) of studies do you carry out?

Type (Mark with ✓) Test conditions

Temperature(indicate)

Relative humidity(indicate)

Accelerated studies

Real-time studies

Explain if necessary: _________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

How do you determine the shelf-life of your products? _______________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

5.6 Bioequivalence

Have you conducted in vivo bioequivalence studies for some of your products? Yes No

If “yes”, list the products studied and the reference products:

Product Reference product Country of study

5.7 Retention samples

Do you keep retention samples? Yes No

Samples: Yes No Retention period Storage conditions

Every fi nished product

Active pharmaceutical ingredients

Excipients

6. AuditCan we or any other representative designated by us perform a GMP audit of the manufacturing site? Yes No

Explainifnecessary:

Howdoyoudeterminetheshelf-lifeofyourproducts?

Appendix 8

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5.6 Bioequivalence

Have you conducted in vivo bioequivalence studies for some of your products? qYesqNo

If“yes”,listtheproductsstudiedandthereferenceproducts:

322





Accelerated studies

Real-time studies



5.6 Bioequivalence









Excipients



Doyoukeepretentionsamples? qYesqNo

322





Accelerated studies

Real-time studies



5.6 Bioequivalence









Excipients


6. Audit

CanweoranyotherrepresentativedesignatedbyusperformaGMPauditofthemanufacturingsite? qYesqNo

Can (a) representative(s) from the national regulatory authority participate asobserver(s)intheaudit? qYesqNo

Maywesharetheinspectionreportwiththeotherprocurementagencies“signatory”tothisquestionnaire? qYesqNo

Isasitemasterfile(PICorWHOformat)availableuponrequest? qYesqNo

Will any required additional information be provided if we wish to perform anauditofthecompany? qYesqNo

7. Other informationContactperson(commercialissues):

323

Can (a) representative(s) from the national regulatoryauthority participate as observer(s) in the audit? Yes No

May we share the inspection report with the otherprocurement agencies “signatory” to this questionnaire? Yes No

Is a site master fi le (PIC or WHO format) availableupon request? Yes No

Will any required additional information be providedif we wish to perform an audit of the company? Yes No

7. Other informationContact person (commercial issues):

Name:

Telephone no.:

Fax:

e-mail:

Contact person (quality issues):

Name:

Telephone no.:

Fax:

e-mail:

Any additional information: ____________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

I hereby certify that the information given in this questionnaire and the at-tachments is correct.

__________________ ________________________________ Date Signature

__________________ ________________________________ Name Position in company

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Anyadditionalinformation:

Iherebycertifythattheinformationgiveninthisquestionnaireandtheattachmentsiscorrect.

Date.. . . . . Signature

Name Positionincompany

323

Can (a) representative(s) from the national regulatoryauthority participate as observer(s) in the audit? Yes No

May we share the inspection report with the otherprocurement agencies “signatory” to this questionnaire? Yes No

Is a site master fi le (PIC or WHO format) availableupon request? Yes No

Will any required additional information be providedif we wish to perform an audit of the company? Yes No

7. Other informationContact person (commercial issues):

Name:

Telephone no.:

Fax:

e-mail:

Contact person (quality issues):

Name:

Telephone no.:

Fax:

e-mail:

Any additional information: ____________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________ __________________________________________________________

I hereby certify that the information given in this questionnaire and the at-tachments is correct.

__________________ ________________________________ Date Signature

__________________ ________________________________ Name Position in company

Appendix 8

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Appendix9

Example of a standard operating procedure for planning of inspections1. Title

Inspection,planningofsiteinspections

324

Appendix 9Example of a standard operating procedurefor planning of inspections

1. TitleInspection, planning of site inspections

Signature Date

Prepared by 1 July 2006

Authorized by

2. Policy and objective2.1 Manufacturing sites should be inspected as part of the prequalifi ca-tion process. To enable the procurement agency to perform the inspections, they should be properly planned.

2.2 The objective is proper planning of site inspections to ensure that products will be sourced only from manufacturers that comply with inter-national standards.

2.3 Proper planning of inspections should save time and resources (e.g. fi nancial and human) through procurement agency planning.

3. ResponsibilityHead of the Section or Department Project ManagerEvaluator

4. Action4.1 When assessing product information, make a list of all the products received (see Addendum A). Complete the table.

4.2 On the basis of the outcome of the assessment of the product informa-tion, decide which manufacturers should be inspected for prequalifi cation.

4.3 Dossiers lacking information, or of unacceptably low quality, may lead to the manufacturing site failing to qualify for the inspection.

2. Policy and objective2.1 Manufacturing sites should be inspected as part of the prequalificationprocess.Toenabletheprocurementagencytoperformtheinspections,theyshouldbeproperlyplanned.

2.2 Theobjectiveisproperplanningofsiteinspectionstoensurethatproductswillbesourcedonlyfrommanufacturersthatcomplywithinternationalstandards.

2.3 Properplanningofinspectionsshouldsavetimeandresources(e.g.financialandhuman)throughprocurementagencyplanning.

3. Responsibility

HeadoftheSectionorDepartmentProjectManagerEvaluator

4. Action4.1 Whenassessingproductinformation,makealistofalltheproductsreceived(seeAddendumA).Completethetable.

4.2 Onthebasisoftheoutcomeoftheassessmentoftheproductinformation,decidewhichmanufacturersshouldbeinspectedforprequalification.

4.3 Dossierslackinginformation,orofunacceptablylowquality,mayleadtothemanufacturingsitefailingtoqualifyfortheinspection.

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4.4 Groupallthemanufacturersinonecountrytogethertoensurethatwhenatripisundertakentoonecountry,morethanonemanufacturercanbeincludedintheinspectiontripwhererelevant.

4.5 Consultamaptoseewherethesitesarelocatedandplanthetripsoastopreventunnecessarylossoftimethroughtravelling.

4.6 Plotthesitesonatable(calendar)andallocateatleast3daysforinspectionofeachmanufacturingsite,dependingonthedosageformsmanufacturedandthesizeofthefacilities.

4.7 Writealettertothecompanyinformingthemofthetentativedateallocatedfor the site inspection. Request the company to indicate whether the dates aresuitabletothem,andalsorequestthemtosubmitasitemasterfile.

4.8 Appoint inspectors for the inspection team. There should be at least twoinspectorsontheteam,includingtherepresentativefromWHO.

4.9 Sendalettertothenationalregulatoryauthorityinvitinganinspectorfromtheinspectoratetoparticipateintheinspection.

4.10 Informtheinspectorsoftheproposeddatesfortheinspection.

4.11 WhenthemanufacturerconfirmsthedatesforinspectionconfirmthedatewiththecompanyandrequesttheinformationlistedinAddendumB.

4.12 Confirmthedateswiththeinspectors.

4.13 SendtheinspectorscopiesoftheSOPsneededtoperformtheinspections,as well as the terms of reference, confidentiality clause, no conflict of interestdeclarationandagreementforperformanceofwork.

4.14 Maketherelevantbookings(airtravel,transportinthecountrywheretheinspectionwillbeperformedandhotelaccommodation).

5. AddendaAddendumA:Summarylistofdossiersreceived

AddendumB:Manufacturerinformation

Appendix 9

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326




7. HistoryThe history of changes to the SOP should be entered in a table; see the model below.


7. HistoryThe history of changes to the SOP should be entered in a table; see the modelbelow:

326






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Addendum A: Summary list of dossiers received

327

Addendum A: Summary list of dossiers received

No API Strength Dosage form

Supplier/Manu-facturer

Manu-facturing site

Country Sample

Appendix 9

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Addendum B: Manufacturer information

1. General information

328



Name

Physical address of head offi ce

Postal address

Telephone number

Fax number

Contact person

E-mail address

2. Manufacturing licencePlease attach the manufacturing licence.

3. Product listPlease attach a list of products manufactured at this particular manufactur-ing site.

4. Inspections by the national regulatory authority

Date of last inspection by the national regulatory authority (NRA)

List the NRA of other countries that have inspected the site, and dates of inspection

Country Date

5. Manufacturing and testing

Physical address of manufacturing sites for the prod-ucts indicated in the submission

Telephone number

Fax number

Physical address of quality control laboratories (chemical and microbiological) used for testing the products in the submission

Telephone number

Fax number

E-mail


3. Product listPlease attach a list of products manufactured at this particular manufacturing site.


328



Name


Postal address

Telephone number

Fax number

Contact person

E-mail address






Country Date



Telephone number

Fax number


Telephone number

Fax number

E-mail


328



Name


Postal address

Telephone number

Fax number

Contact person

E-mail address






Country Date



Telephone number

Fax number


Telephone number

Fax number

E-mail

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6. RecallsPlease list the products and reasons for implementing a product recall in the last 5 years.

329


Product and batch number(INN, strength and dosage form)

Reason Date of recall

7. ComplaintsIf the company has had any product complaints in the last year, please com-plete the table below.

Products and batch number(INN, strength and dosage form)

Complaint and source Corrective action taken

8. Site master fi le (SMF)If the SMF for the manufacturing site was submitted previously:

Date submitted

SMF number

If the SMF has not yet been submitted to WHO, please attach it now. Please note that the SMF must conform to the requirements specifi ed previously.

9. Audit/inspectionWe herewith grant WHO permission to perform the inspection of the manu-facturing site to assess compliance with good manufacturing practice, for the purpose of the prequalifi cation of the manufacturing site and product.

I declare that the information given above is true and correct.

__________________________________ __________________

Signature: Date:

Name: _____________________________________________________

Position: ___________________________________________________

7. ComplaintsIf the company has had any product complaints in the last year, please complete the table below.

329








Date submitted

SMF number




__________________________________ __________________

Signature: Date:

Name: _____________________________________________________

Position: ___________________________________________________

8. Site master file (SMF)If the SMF for the manufacturing site was submitted previously:

329








Date submitted

SMF number




__________________________________ __________________

Signature: Date:

Name: _____________________________________________________

Position: ___________________________________________________

If the SMF has not yet been submitted to WHO, please attach it now. Please note that the SMF must conform to the requirements specified previously.

9. Audit/inspectionWeherewithgrantWHOpermissiontoperformtheinspectionofthemanufacturingsitetoassesscompliancewithgoodmanufacturingpractice,forthepurposeoftheprequalificationofthemanufacturingsiteandproduct.Ideclarethattheinformationgivenaboveistrueandcorrect.

Signature: Date:

Name:

Position:

Appendix 9

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Appendix10

Example of a standard operating procedure for preparing for an inspection

1. TitlePreparationforaninspection

330

Appendix 10Example of a standard operating procedurefor preparing for an inspection

1. TitlePreparation for an inspection

Signature Date


Authorized by

2. Policy and objective2.1 Each manufacturer should be inspected by the procurement agency to assess compliance with good manufacturing practices.

2.2 All inspectors should follow the SOP in preparing for the inspection(s).

2.3 The objective is to ensure that a standardized procedure is followed by all inspectors when preparing for the inspections to prevent inspections being performed by different inspectors in different ways. This should en-sure consistency in performance between inspectors.

3. ResponsibilityProject ManagerInspectors

4. ActionAll actions described here are taken from the details provided by the WHO publication Quality assurance of pharmaceuticals, Volume 2, Chapter 4: Inspection of pharmaceutical manufacturers and inspection of drug distri-bution channels. These guidelines or other similar systems operated by na-tional drug regulatory agencies should be followed in detail.

4.1 Once the inspection has been allocated to the inspector, he or she should plan for the performance of the inspection according to the steps outlined below.

4.2 Verify the objective of the inspection that is to be carried out.

2. Policy and objective2.1 Eachmanufacturershouldbeinspectedbytheprocurementagencytoassesscompliancewithgoodmanufacturingpractices.

2.2 AllinspectorsshouldfollowtheSOPinpreparingfortheinspection(s).

2.3 The objective is to ensure that a standardized procedure is followed byall inspectors when preparing for the inspections to prevent inspections beingperformedbydifferentinspectorsindifferentways.Thisshouldensureconsistencyinperformancebetweeninspectors.

3. ResponsibilityProjectManagerInspectors

4. ActionAll actions described here are taken from the details provided by the WHOpublicationQuality assurance of pharmaceuticals,Volume2,Chapter4:Inspectionofpharmaceuticalmanufacturersandinspectionofdrugdistributionchannels.Theseguidelinesorothersimilarsystemsoperatedbynationaldrugregulatoryagenciesshouldbefollowedindetail.

4.1 Once the inspectionhasbeenallocated to the inspector,heor she shouldplanfortheperformanceoftheinspectionaccordingtothestepsoutlinedbelow.

4.2 Verifytheobjectiveoftheinspectionthatistobecarriedout.

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4.3 Clarifywhich typeof inspectionwill beperformed, e.g. routineGMPorfollow-upinspection.

4.4 Decidewhethertheinspectionwillcovertheentirefactoryorjustpartofit.

4.5 Determinewhatthescopeanddepthoftheinspectionwillbetoenableyoutoprepareforitproperly.(Foracompanyproducingsterileproducts,preparebyreviewingtheguidelinesforsterileproductmanufactureinadditiontothegeneralGMPguidelines.)

4.6 Scrutinizetheproductinformationfortheproductsintheprequalificationproceduremanufacturedatthismanufacturingsite.

4.7 Decidehowlongitwilltaketocarryouttheinspectionandplanthedatewhentheinspectionwilltakeplace.

4.8 Inform the manufacturer(s) in question of the proposed date for theinspection.

4.9 Ensurethattheproposeddatefortheinspectionissuitableforallmembersoftheinspectionteam.

4.10 Decideonachieforleadinspectortocoordinateandleadtheinspection.

4.11 The lead inspector will be the main spokesperson during the closing orexitmeetingattheendofaninspection,andhastheoverallresponsibilityfortheinspectionreport.

4.12 Informotherinterestedpartiesoftheproposedorplannedinspection,e.g.aregionalofficeoftheprocurementagencyoragency,orthenationalregulatoryauthority.

4.13 Reviewdocumentationrelatingtothemanufacturertobeinspectedsuchasacompletedquestionnaire.

4.14 In case of a follow-up inspection, and where the procurement agency oragencyhasacompanyfileinwhichgeneralcorrespondenceandpreviousinspectionreportsarefiled,reviewthecorrespondence.

4.15 Ifasitemasterfile(SMF)existsandisavailable,studytheSMFandmakenotestobefollowedupduringtheinspection(e.g.availableequipment,SOPsandrecords).

4.16 Study the layout and design of the manufacturing facility, and some ofthe systems the manufacturer has in place to ensure quality in manufacture ofproducts.

4.17 Lookattheinformationprovidedonthemanufacturinglicenceandproductlicence.Makenotesoftheaspectsthatneedtobeinspectedtoconfrmcompliancewithlicenceconditions,andtoverifydataduringtheinspection.

Appendix 10

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4.18Reviewthereportsofpreviousinspections,reportsofadversedrugexperiencesandcomplaints, if anyexist, as investigations andcorrective action takenby themanufacturershouldbeverifiedduringinspections.

4.19Foraspecialinspection,reviewrecordsofthecompanyinrelationtocomplaintsandrecalls,andregulatorytestresults(surveillance)whereavailable.

4.20Ifanannualreportisavailable,scrutinizethereportandnotetheinformationin relation to financial aspects of the company, personnel issues and productsmanufactured.

4.21 If any complaints had been received about the manufacturer or productspreviouslysupplied,reviewthecontentsofthecomplaint,investigation,outcomeandcorrectiveaction.

4.22 Ifself-inspection/internalauditreportswererequestedfromthemanufacturer,reviewthecontents.(Suchreportsarenormallynotrequestedassomemanufacturersconsider that the inspectors should assessGMPcompliance themselves, andnotlookatthecompany’sownfindingsofinspections.Requestingsuchreportswouldbedependentonthepolicyoftheprocurementagency.)

4.23 Studythediagramofthefacilitytogetabetterunderstandingoftheflowofmaterial,personnelandprocessesinthefacility.

4.24 If any manuals and/or procedures were submitted by the manufacturer,reviewtheseandpreparespecificquestionsrelatingtothequalitypolicy,validationpolicyandprocedureforperformingcertainactivities.

4.25 Draw up a checklist or aide-memoire of points to be verified during theinspection.

4.26 Drawupaprogrammefortheinspection.Produceanoutlineofwhatwillbecoveredeachdayandclarifywhateachmemberoftheteamwillbedoingeverydayorhalf-dayofthevisit.Indicateintheprogrammewhichsectionsordepartmentswillbeinspected,andwhen(foranexample,seeAddendumA).

4.27 Distributetheprogrammetotheteammembers.Inthecaseofanannouncedinspection,formthecompanyoftheproposedinspectionprogramme.

5. AddendaAddendumA:Exampleofaninspectionplan

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333






7. HistoryThe history of changes to the SOP should be entered in a table; see the modelbelow.

333






Appendix 10

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Addendum A: Example of an inspection plan

334

Addendum A: Example of an inspection plan

Manufacturer

Address

Date

Inspectors

Day 1

Time Activity08:30 Arrival08:45 Opening meeting and company presentation09:15 Receiving area and stores10:15 Sampling11:00 Tea11:15 Weighing12:00 Packaging components13:00 Lunch14:00 Manufacturing (organize time depending on the dosage form(s))17:00 Summary of the day’s observations

Day 2

08:30 Manufacturing, continued10:00 Tea10:15 Quality control12:00 Heating, ventilation and air-conditioning, water and other utilities13:00 Lunch14:00 Documentation17:00 Summary17:30 Closing meeting

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Appendix11

Example of a standard operating procedure for performing an inspection

1. TitlePerformanceofinspection

335

Appendix 11Example of a standard operating procedure for performing an inspection

1. TitlePerformance of inspection

Signature Date

Prepared by 1 July 2006

Authorized by

2. Policy and objective2.1 Each manufacturer should be inspected by the procurement agency to assess compliance with good manufacturing practices.

2.2 All inspectors should follow the SOP for performing inspections.

2.3 The objective is to ensure that a standardized procedure is followed by all inspectors when performing inspections to prevent inspections be-ing performed by different inspectors in different ways. This should ensure consistency in performance between inspectors.

2.4 One of the objectives is to control and enforce the general standards of production for products that may be sourced as a result of the prequali-fi cation procedure.

2.5 Through sequential examination of production and control activities of the manufacturer, the manufacturer of pharmaceutical products may be included on the prequalifi cation list as a manufacturer of pharmaceutical products for possible supply of specifi ed products to procurement agencies and other agencies.

2.6 During inspections, the performance of manufacture of products and data submitted in the relevant product information fi les should be verifi ed.

3. ResponsibilityProject Manager Inspectors

2. Policy and objective2.1 Eachmanufacturershouldbeinspectedbytheprocurementagencytoassesscompliancewithgoodmanufacturingpractices.

2.2 AllinspectorsshouldfollowtheSOPforperforminginspections.

2.3 Theobjective is toensure thata standardizedprocedure is followedbyallinspectorswhenperforminginspectionstopreventinspectionsbeingperformedbydifferentinspectorsindifferentways.Thisshouldensureconsistencyinperformancebetweeninspectors.

2.4 One of the objectives is to control and enforce the general standards ofproduction for products that may be sourced as a result of the prequalificationprocedure.

2.5 Throughsequentialexaminationofproductionandcontrolactivitiesofthemanufacturer, themanufacturerofpharmaceuticalproductsmaybe includedontheprequalificationlistasamanufacturerofpharmaceuticalproductsforpossiblesupplyofspecifiedproductstoprocurementagenciesandotheragencies.

2.6 Duringinspections,theperformanceofmanufactureofproductsanddatasubmittedintherelevantproductinformationfilesshouldbeverified.

3. Responsibility

ProjectManagerInspectors

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4. ActionAll actions described here are taken from the details provided in the WHOpublicationQuality Assurance of Pharmaceuticals,Volume2,Chapter4:Inspectionofpharmaceuticalmanufacturersandinspectionofdrugdistributionchannels.Theseguidelinesorothersimilarsystemsoperatedbynationaldrugregulatoryauthoritiesshouldbefollowedindetail.

4.1 Clarificationanddefinitions

4.1.1 Different types of inspections are identified in theWHO text referred toabove.Theseinclude:➣ routineinspection;➣ conciseinspection;➣ follow-upinspection;➣ specialinspection;and➣ qualitysystemsreview.

4.2 Theperformanceoftheinspectionisdependentonthetypeofinspection;however, in principle, the basic aspects of this procedure can be followed forperformanceofaninspection.

4.3 AroutineinspectionisafullreviewofallaspectsandcomponentsofGMPwithinafacility.Itisappropriatetoperformaroutineinspectionunderthefollowingcircumstances:• Whenthereisanewexpressionofinterest(EOI)fromamanufacturerora

newlyestablishedmanufacturer.• Whenthelistingontheprequalificationlistisdueforrenewal.• Iftherehavebeensignificantchangessuchasnewproductsornewproduct

lines;modificationtomanufacturingmethodsorprocesses;orchangesinkeypersonnel,premisesand/orequipment.

• Ifaninspectionhasnotbeencarriedoutwithinthepast3–5years.

4.4 Aconcise inspection is the evaluationof limited aspects relating toGMPcompliance within a facility. (It is known as an abbreviated inspection in somecountries.)AlimitednumberofGMPrequirementsareselectedbytheinspectortoserveasindicatorsofoverallGMPcompliancebythemanufacturer.Theinspectoralso has to identify and evaluate any significant changes that could have beenintroducedbythemanufacturersincethelastinspection.

4.4.1 Collectively,theselectedindicatorsandthechangesidentifiedindicatethemanufacturer’sattitudetowardsGMP.

4.4.2 Aconciseinspectionisappropriateunderthefollowingcircumstances:• Where a manufacturer has a consistent record of compliance with GMP

throughroutineinspectionsinthepast.• Whereasampleofaspectscanbetakenasagoodindicationoftheoverall

levelofcompliancewithGMP.

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4.4.3 However,iftheconciseinspectionuncoversevidencethatthelevelofGMPcompliancehas fallen, amore comprehensiveor fullGMP inspection shouldbeperformedsoonaftertheconciseinspection.

4.5 Afollow-upinspectionisalsoreferredtoasare-inspectionorareassessmentofthemanufacturer.

4.5.1 A follow-up inspection is performed specifically to monitor the result ofcorrectiveactionsofthemanufacturerfollowingapreviousinspection.

4.5.2 Dependingonthenatureofthedefectsandtheworkrequired,thefollow-upinspectioncouldbecarriedoutbetween6weeksand6monthsaftertheoriginalinspectiontookplace.

4.5.3 The follow-up inspection is limited to specific GMP requirements thathave not been observed or that have been inadequately implemented by themanufacturer.

4.6 Thereareanumberofcircumstancesinwhichspecialvisitsorinspectionsmaybenecessary.Aspecialinspectionisundertakentodospotchecks.Spotcheckscouldfocusononeproduct,agroupofrelatedproducts,orspecificoperationse.g.mixing,or labelling. If therehavebeen complaints about a specificproduct that suggesttheremaybedefects, a special inspection couldbeperformed to investigate thequalitydefectsoftheproduct.Iftherehasbeenaproductrecall,thiscanalsotriggeraninspection,aswouldadversedrugreactions.Intheabovecases,theinspectionwouldfocusonthespecificproductoraspectofproductionthatissuspect.Aspecialinspectioncouldalsobeperformedtogatherspecificinformation,ortoinvestigatespecificoperationsofthemanufacturer.

4.7 Thepurposeofaqualitysystemsreviewistoreviewthemanufacturer’squalitysystemandtoascertainwhetherithasbeenshowntooperatesatisfactorily.

4.8 Plantheinspectiontoensurethatallareasforassessmentarecoveredintheallocatedtimeframe.Thelengthoftimeneededforaninspectionisdeterminedbyanumberoffactors,includingthetypeofinspectiontobeperformed,thenumberofinspectors,thesizeofthecompanyandthepurposeoftheinspectionorvisit.

4.9 An inspection can be performed over a period of a few days to severalweeks.

4.10 Thetimetakenwillalsodependonthesizeoftheinspectionteam.Oneormoreinspectorscanperformtheinspectionaspartofaninspectionteam.

4.11 Ifnecessary,appointaspecialisttoaccompanytheteamduringtheinspection,e.g.forparticulardosageforms,chemistryoranotheraspect,e.g.themanufactureofbiologicals.

Appendix 11

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5. AddendaAddendumA:Inspectionprogramme

AddendumB:Documentationrequiredforverificationduringtheinspection


338

4.11 If necessary, appoint a specialist to accompany the team during the inspection, e.g. for particular dosage forms, chemistry or another aspect, e.g. the manufacture of biologicals.

5. AddendaAddendum A: Inspection programme

Addendum B: Documentation required for verifi cation during the inspection






7. HistoryThe history of changes to the SOP should be entered in a table; see the modelbelow.

338

4.11 If necessary, appoint a specialist to accompany the team during the inspection, e.g. for particular dosage forms, chemistry or another aspect, e.g. the manufacture of biologicals.

5. AddendaAddendum A: Inspection programme

Addendum B: Documentation required for verifi cation during the inspection






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Addendum A: Inspection programme

339

Addendum A: Inspection programme

Manufacturer

Address

Date

Inspectors

Day 108:30 Arrival08:35 Opening meeting08:45 Company presentation09:00 Receiving area and stores10:30 Tea10:45 Sampling and weighing areas11:15 Packaging material stores and control12:30 Lunch13:15 Manufacturing areas15:30 Tea15:45 Manufacturing (cont.)16:30 Summary of fi ndings, day 1

Day 208:30 Arrival08:35 Manufacturing area (cont.)10:30 Tea10:45 Laboratories12:30 Lunch13:15 Laboratories (cont.)15:30 Tea15:45 Utilities16:30 Summary of fi ndings, day 2

Day 308:30 Arrival08:35 Utilities (cont.)10:30 Tea10:45 Documentation12:30 Lunch13:15 Documentation (cont.)15:30 Tea15:45 Preparation for closing meeting16:00 Closing meeting

Appendix 11

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Addendum B: Documentation required for verification during the inspection

1. Organigram2. Jobdescriptions3. Qualitypolicy(e.g.qualitymanual)4. Validationpolicy(e.g.validationmasterplanorprogramme)5. Rawmaterialspecifications(forspecificproducts)6. Packagingmaterialspecifications7. Manufacturingformulaandmethodmasters8. Packinginstructionsmaster9. Batchmanufacturingrecords(verificationagainstmasterdocuments)10. SOPindex11. SOP:selfinspection12. SOP:recalls13. SOP:complaintsplusrecords14. SOP:batchnumberallocation15. SOP:plannedpreventivemaintenance16. SOPandrecord:plannedpreventivemaintenanceofspecificequipment17. SOP:training(plusrecordofpersonnel)18. SOP:environmentalmonitoringplusrecords19. SOP:watersamplingandtestingplusrecords20. Validationprotocolandreportforspecificproducts21.22.23.24.25.26.27.28.29.30.

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Appendix12

Example of a checklist for good manufacturing practices

It is recommended that inspectors prepare an aide-memoire to remind them ofpointstobecheckedduringaninspection.

Aide-memoirescanbepreparedtocoveroneormoreaspects,e.g.• production• qualitycontrol• utilities• lyophilization

Theaide-memoireshouldcontainkeywordstoremindtheinspectorofaspectstobeinspected.

Anexampleofanaide-memoireisshownbelow.

Example: Aide-memoire for inspection of the lyophilization process:

341

Appendix 12Example of a checklist for good manufacturing practices

It is recommended that inspectors prepare an aide-memoire to remind them of points to be checked during an inspection.

Aide-memoires can be prepared to cover one or more aspects, e.g.

• production• quality control• utilities• lyophilization

The aide-memoire should contain key words to remind the inspector of aspects to be inspected.

An example of an aide-memoire is shown below.

Example: Aide-memoire for inspection of the lyophilization process:

Points to check Notes

DissolvingFiltrationFilling and stopperingTransferLoadingFreezingVacuumHeatingStopperingCapping

Validation:Design qualifi cation (DQ)Installation qualifi cation (IQ)Operational qualifi cation (OQ)CommissioningProcess qualifi cation (PQ)Media fi llsAir samplesSurface swabsOperator swabsDaily clothingSimulate process with media (not freeze)Smoke test (transport area)TransportFrequent fi ll volumePre-cooling of shelves (no ice)

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342

Points to check Notes

FreezingCycleRate – (slow = crystals, polymorphism)MannerDrying temp. < eutectic pointDetermine eutectic point, consistentShelf loading variationsValidate:shelf temperatureproduct temperaturecondenser temperaturepressure (chamber)pressure (condenser)time, temperature, pressureleakage incontamination (thermal fl uid, oil)cleaning

CycleEutectic point determinationScale upVial sizeBatch size

Sterilization of lyophilizerMoist heat usedEach cycleResidue if applicableBiological IndicatorsDesign: single door (double door, air class!)

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Appendix13

Guidance on good manufacturing practices: inspection report

GuidanceonGoodManufacturingPractices(GMP):inspectionreport.In:WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-seventh report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeriesNo.908),Annex6.

Availableat:http://www.who.int/medicines/areas/quality_safety/quality_assurance/inspections/en/

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Appendix14

Good storage practicesFor a guide to good storage practices for pharmaceuticals, see: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-seventh report.Geneva,World Health Organization, 2003 (WHOTechnical Report Series No.908),Annex9.

Availableat:http//:www.who.int/medicines/areas/quality_safety/quality_assurancedistribution/en/

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Appendix15

Good trade and distribution practicesFor a guide to good trade and distribution practices for pharmaceutical startingmaterials, see: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-eighth report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.917),Annex2.

Availableat:http://www.who.int/medicines/strategy/quality_safety/tr917ann2.pdf

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Appendix16

Quality system recommendations for pharmaceutical inspectorates

ForaguidetoQualitysystemsrequirementsfornationalgoodmanufacturingpracticeinspectorates, see: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-sixth report.Geneva,WorldHealthOrganization,2002(WHOTechnicalReportSeries,No.902),Annex8.

Availableat:http://who.int/medicines/areas/quality_safety/quality_assurance/inspections/en/

This publication is intended to assist procurement agencies to procure safe, effective pharmaceuticals of suitable quality. The model described here focuses on four key agency activities: prequalification, purchase, storage and distribution of pharmaceutical products. The long-term goal of the recommendations made is the design and implementation of a uniform and harmonized system that will ensure procurement of pharmaceutical products of defined quality for supply to patients. The system should be based on a mutually recognized process of prequalification of products and manufacturers.

The publication is divided into six modules, with the first addressing the general requirements for the quality assurance system that should be in place at all procurement agencies. Module II sets out recommendations for agencies when they are evaluating their product needs, assessing the products offered, and the manufacturing and supply arrangements provided by the manufacturers. The next module describes principles of purchasing pharmaceutical products, and is followed by recommendations on how to receive and store them. Good distribution practices are covered in Module V, while the final module describes monitoring and reassessment of products and contracted-out activities. In addition to a useful glossary, the publication includes a number of appendices with sample forms and questionnaires to use when implementing the model, as well as the text of relevant WHO guidelines.

This is an interagency document published by the WHO Department of Medicines Policy and Standards on behalf of the organizations listed. The text was previously included as Annex 6 of the 40th Report of the WHO Expert Comittee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series No. 937, Geneva, World Health Organization, 2006).


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