Model Quality Assurance

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: prequalifcation,
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 defned
quality for supply to patients. The system should be based on a
mutually recognized process of prequalifcation of products and
manufacturers.
The publication is divided into six modules, with the frst 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 fnal 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 40
th
Report
of the WHO Expert Comittee on Specifcations for Pharmaceutical
Preparations (WHO Technical Report Series No. 937, Geneva, World
Health Organization, 2006).
a model quality assurance
system for procurement
agencies
World Bank
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agencies
Recommendations for quality assurance systems
focusing on prequalifcation of products and manufacturers,
purchasing, storage and distribution of pharmaceutical products
World HealtH organization
United nations CHildrens FUnd
United nations development programme
United nations popUlation FUnd
World Bank
WHO/PSM/PAR/2007.3
Acknowledgements

Tis document was previously published as Annex 6 of the 40
th
Report of the WHO Expert
Comittee on Specifcations 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
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whether for sale or for noncommercial distribution should be addressed to WHO Press, at the above
address (fax: +41 22 791 4806; e-mail: permissions@who.int).
Te 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
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Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
Te mention of specifc 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
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reader. In no event shall the World Health Organization be liable for damages arising from its use.

Tis 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.
1
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 Guidelinesonconfictofinterest.............................................................23
I.2.6 Listofprequalifedproductsandmanufacturers......................................23
I.2.7 Maintenanceofrecords...........................................................................24
Module.II..Prequalifcation................................................................................... 25
Introduction. ...................................................................................................... 25
II.1 Principlesforprequalifcation.............................................................................25
II.1.1 WHOModelListofEssentialMedicines................................................26
II.2 Standardsforprequalifcation.............................................................................26
II.3 Keypersonsandresponsibilities..........................................................................26
II.3.1 Stafresponsibleforprequalifcation........................................................26
II.3.2 Stafresponsibleforevaluationofproductinformation...........................27
II.3.3 Stafresponsibleforinspectionofmanufacturingsites.............................27
II.4 Keystepsinprequalifcation...............................................................................28
II.4.1 Step1:solicitandreceiveexpressionsofinterest......................................28
II.4.2 Step2:receiveproductinformation.........................................................32
Contents
2
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:fnalizeassessmentprocessandupdateprequalifcationlist..........38
II.5 Requalifcationandmonitoring..........................................................................40
II.6 Monitoringofcomplaints...................................................................................40
II.7 Costrecovery......................................................................................................40
Module.III..Purchasing.......................................................................................... 41
Introduction. ...................................................................................................... 41
III.1 Strategiesforhealthsystems................................................................................41
III.2 Procurementmethods.........................................................................................42
III.2.1Restrictedtender.....................................................................................43
III.2.2Competitivenegotiation..........................................................................43
III.2.3Directprocurement.................................................................................43
III.2.4Opentender............................................................................................43
III.3 Qualityassuranceinpurchasing..........................................................................43
III.4 Keyactivitiesinpurchasing.................................................................................44
III.4.1Productselectionandspecifcation..........................................................44
III.4.2Productquantifcation.............................................................................44
III.4.3Selectionofsuppliers...............................................................................45
III.4.4Adjudicationoftenders...........................................................................45
III.5 Organizationandresponsibilities........................................................................46
III.5.1Procurementagencystructure..................................................................46
III.5.2Responsibilities........................................................................................47
III.6 Monitoringofperformanceofprequalifedmanufacturers..................................48
III.7 Patents .........................................................................................................48
III.8 Donations.........................................................................................................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
3
IV.3.1Sampling.................................................................................................51
IV.3.2Rejectedmaterials....................................................................................51
IV.4 Storageofmaterialsandproducts........................................................................52
IV.4.1Staf.........................................................................................................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.1 Re-evaluationofmanufacturers...........................................................................58
VI.2 Re-evaluationofproducts...................................................................................58
VI.3 Monitoringofcontracted-outservices.................................................................59
VI.3.1Storageanddistribution..........................................................................59
VI.3.2Qualitycontrollaboratories.....................................................................60
VI.3.3Contractresearchorganizations...............................................................60
Conclusion.. ...................................................................................................... 60
References. . ...................................................................................................... 62
Contents
4
Appendix1 Exampleofacodeofconduct.............................................................65
Appendix2 Exampleofaguidelineonconfdentiality...........................................71
Appendix3 Exampleofaguidelineonconfictofinterest.....................................72
Appendix4 Exampleofastandardoperatingprocedure(SOP)
forwritinganSOP.............................................................................78
Appendix5 Exampleofaninvitationforexpressionofinterest..............................83
Appendix6 Pharmaceuticalproductquestionnaire................................................88
Appendix7 Exampleofastandardoperatingprocedureforscreening
andassessingproductinformation......................................................93
Appendix8 Technicalquestionnaireforpharmaceuticalmanufacturers...............106
Appendix9 Exampleofastandardoperatingprocedureforplanning
ofinspections...................................................................................114
Appendix10Exampleofastandardoperatingprocedureforpreparing
foraninspection..............................................................................120
Appendix11Exampleofastandardoperatingprocedure
forperforminganinspection............................................................125
Appendix12Exampleofachecklistforgoodmanufacturingpractices..................131
Appendix13Guidanceongoodmanufacturingpractices:inspectionreport.........133
Appendix14Goodstoragepractice.......................................................................134
Appendix15Goodtradeanddistributionpractices...............................................135
Appendix16Qualitysystemrecommendationsforpharmaceutical
inspectorates.....................................................................................136
5
Introduction
Te World Health Organization (WHO), the United Nations Childrens Fund
(UNICEF) and many other organizations are involved in the procurement of
pharmaceuticalproducts.Inparticular,thesupplyofpharmaceuticalproductsused
in the treatment of human immunodefciency virus/acquired immunodefciency
syndrome(HIV/AIDS),malariaandtuberculosishasbecomeamajorconcernatboth
theinternationalandcountrylevels.CommitmentsbytheEuropeanCommission
and G8 countries, among others, ofer the potential for signifcant increases in
funding for eforts to combat communicable diseases. Low-cost pharmaceutical
productsofassuredqualityhavethegreatestpotentialformaximizingtheimpact
oftheseeforts.
The need for a model quality assurance system
Eforts to accelerate access to pharmaceutical products used in the treatment of
HIV/AIDS through negotiation and generic competition have highlighted the
importanceofqualityassuranceforprocurementofpharmaceuticalproductsand
diagnostics.Considerablesumsofmoneyareinvestedinprocuringpharmaceutical
productsfromvariousmanufacturersindiferentcountries.However,evaluationof
product-specifcdataandinformationonqualityisoftenlacking,andinspections
at manufacturing sites are not routinely performed to a consistent standard. At
present,someorganizationsinvolvedinprocurementofpharmaceuticalproductsdo
havequalitysystemsforthediferentactivitiesinplace.However,thesesystemsvary
greatlybetweenorganizations.Someprocurementagenciesrequestmanufacturersto
submitachecklistorquestionnairecontainingproductinformationforassessment.
In some cases, these checklists fail to address important aspects that should be
evaluatedaspartofprequalifcation.Othersusedetailedquestionnairesorrequest
product dossiers for evaluation. Some procurement agencies contract inspectors
toperforminspectionsattheplaceofmanufacture,buttheextentandqualityof
theseinspectionsmayvaryaccordingtotheresourcesavailable.Moreover,mutual
recognition and coordination of such inspections is an exception rather than the
rule.
Without a quality assurance system, organizations risk sourcing substandard,
counterfeitorcontaminatedpharmaceuticalproducts,leadingtocomplaintsabout
productsandproductrecalls,wastageofmoneyandserioushealthriskstopatients.
Suchproblemsafectthecredibilityofprocurementagencies,causefnanciallosses
andputpatientssafetyindanger.
Background
A preparatory study carried out by a team of experts emphasized the substantial
diferencesbetweenprequalifcationofvaccinesandpharmaceuticals.Apilotproject
tostudythefeasibilityofprequalifyingmanufacturersofessentialpharmaceutical
productsfortreatingprioritydiseaseswasrecommended.Teaccumulatedexperience
ofexpertsfromUNICEF,theUnitedNationsPopulationFund(UNFPA),WHO
and the World Bank has identifed the necessary elements to ensure appropriate
proceduresforprocurement.
Introduction
6
WHO therefore undertook a project with the above-mentioned United Nations
partners, which was supported in principle by the World Bank. Te project
focusedontheprequalifcationofproductsandmanufacturersofHIVandAIDS-
related products, and the drafting of a model quality assurance system (hereafter
referredtoastheModel).TisModelisintendedtoassistorganizationspurchasing
pharmaceutical products, vaccines, or other health sector goods or which are
otherwise involved in the prequalifcation, purchasing, storage and distribution
of such products, hereafter referred to as procurement agencies, to procure safe,
efectivepharmaceuticalsofsuitablequality.
Goal and objectives
Telong-termgoaloftheserecommendationsisthedesignandimplementationof
auniformandharmonizedsystemthatwillensureprocurementofpharmaceutical
productsofdefnedqualityforsupplytopatients,basedonamutuallyrecognized
process of prequalifcation of products and manufacturers by means of product
dossier evaluation and inspection of manufacturing sites. Such a process, as
defnedintheGlossaryanddescribedinModuleII,willhereafterbereferredtoas
prequalifcation.
Establishing, harmonizing and implementing a quality assurance system for
prequalifcation, purchasing, storage and distribution of pharmaceuticals is a task
of considerable magnitude, which should be undertaken in stages. Te following
objectiveswereidentifed:
creation of a model quality assurance system (MQAS) to be adopted and
implementedbyprocurementagencies;
creationofguidelinestoharmonizetheevaluationofdataandinformationon
productsaspartoftheprequalifcationprocedure;and
creationofunifedstandardsforinspectionofmanufacturersandsuppliersto
assesscompliancewithgoodmanufacturingpractices(GMP).
Quality assurance in procurement
Qualityassuranceisawide-rangingconceptwhichcoversallmattersthatindividually
orcollectivelyinfuencethequalityofaproduct.Itisthetotalityofthearrangements
madetoensurethatpharmaceuticalproductsareofthequalityrequiredfortheir
intended use. Quality assurance therefore incorporates several factors and it is an
integralpartofallkeyactivitiesinprocurement.
Te implementation of a quality assurance system in procurement, including
systems for prequalifcation, storage and distribution, may afect costs. However,
thebeneftsofensuringqualityoutweighthecostinvestmentbecausetheyreduce
thepossiblelossescausedbythepurchaseandsupplyofsubstandardproducts.
Prequalifcationofproductsandmanufacturers,purchasing,storageanddistribution
arecomplexprocessesthatmayinvolvemanyofces,procurementagencies,sections
7
ordepartmentsandseveralstagesofadministration,fnanceandtechnicaldecisions.
Pharmaceuticalproductsarenotordinarycommoditiesoftradeandrequirespecial
attention.Supportfromtheofcesresponsibleforqualityassuranceiscrucial.Te
efciencyoftheproceduresdependsingreatpartontheuseofaprovenmethodin
aconsistentmanner.Teuseofastandardapproachwillensureconsistencyinall
activitiesinvolvedinprocurementofpharmaceuticalproductsofdefnedacceptable
quality.
TisModelfocusesonthefollowingfourkeyactivitiesofprocurementagencies:
prequalifcationofpharmaceuticalproductsandmanufacturers;
purchaseofpharmaceuticalproducts;
storageofpharmaceuticalproducts;and
distributionofpharmaceuticalproducts.
Procurement agencies are ultimately responsible for the outcomes of all four key
activities. In some cases, one or more of the activities may be contracted out.
Wherethisoccurs,awrittencontractwhichdescribes theresponsibilities of both
partiesshouldbeagreeduponbetweenthetwoparties.Tecontract-giverremains
responsibleforensuringthatthecontract-acceptormeetsthenormsandstandards
refectedinthisModel.
Recommendations
Itisrecommendedthatprocurementagenciesinvolvedinanyofthekeyactivitiesof
procurementdevelopandimplementtheirowninternalqualityassurancesystems
onthebasisoftheModel,includingtheelementsdescribedandtechnicaldetails
specifed.Itisimportanttoensurethatthesystemisadaptedtorefecttheactivities
of each specifc procurement agency. Te system should cover all aspects of the
agencysactivitiesandshouldbecomprehensiveenoughtoensurethatinterrelated
activitieswhichimpactonthequalityofpharmaceuticalproductsarelinked.
TisdocumentprovidesguidelinesforUnitedNationsprocurementagencies,but
theymayalsobeusedbyotherprocurementagenciestoestablishqualityassurance
systemsfortheirownactivities.
Tese guidelines are designed for procurement of pharmaceutical products. Tey
mayalsobeapplicabletotheprocurementofdiagnostickitsormedicaldevices.
Overview
Tis document is divided into six modules. Module I addresses the general
requirements for the quality assurance system that should be in place at all
procurement agencies, irrespective of the number of key activities performed.
ModuleIIsetsoutrecommendationsthatprocurementagenciesshouldimplement
when evaluating their product needs, assessing the products ofered and the
manufacturing and supply arrangements provided by the manufacturers. Module
Introduction
8
IIIdescribesprinciplesofpurchasingpharmaceuticalproducts.ModuleIVcontains
recommendationsonhowtoreceiveandstorepurchasedproducts.InModuleV,
gooddistributionpracticesaredescribedandModuleVIdealswithmonitoringand
reassessmentofproductsandcontracted-outactivities.Tisdocumentalsoincludes
documentation examples of elements of this Model as well as relevant existing
WHOguidelines.
Troughout this document, reference will be made to existing WHO norms,
standards, guidelines and texts. An efort has been made to avoid duplication
whereverpossible.Whererelevant,referenceismadetorelateddocuments.
TestandardtextManaging drug supply (1)providesacompleteanddetailedoverview
oftechnicalaspectsofpharmaceuticalsmanagement,includingallthekeyactivities
ofprocurement.
9
Glossary
accountability
Teobligationtoaccountforonesconductandactions,usuallytoanindividual
orgroup,butultimatelytothepublic.Bothindividualsandorganizationsmaybe
accountable. Tere is some overlap between accountability and transparency (see
below).
active pharmaceutical ingredient (API)
Asubstanceorcompoundintendedtobeusedinthemanufactureofapharmaceutical
productasatherapeuticallyactivecompound(ingredient).
afordability
Teextenttowhichpharmaceuticalproductsareavailabletothepeoplewhoneed
thematapricetheycanpay.
authorized person
Aperson(amongkeypersonnelofamanufacturingestablishment)responsiblefor
the release of batches of fnished products for sale. In some good manufacturing
practice(GMP)guidesandlegaltexts,thetermqualifedpersonisusedtodescribe
analogousfunctions.
bioequivalence
Two pharmaceutical products are bioequivalent if they are pharmaceutically
equivalentorpharmaceuticalalternativesandtheirbioavailabilities,intermsofpeak
(C
max
andT
max
)andtotalexposure(areaunderthecurve(AUC)),afteradministration
inthesamemolardoseunderthesameconditions,aresimilartosuchadegreethat
theirefectscanbeexpectedtobeessentiallythesame.
bioavailability
Terateandextentatwhichtheactivepharmaceuticalingredientoractivemoiety
isabsorbedfromapharmaceuticaldosageformandbecomesavailableatthesite(s)
ofaction.
competitive tender
A procedure for procuring pharmaceutical products which puts a number of
suppliersintocompetition.Purchasingisdoneonthebasisofquotationssubmitted
bythesuppliersinresponsetoapublicnotice.
drug
Anysubstanceorpharmaceuticalproductforhumanorveterinaryusethatisintended
tomodifyorexplorephysiologicalsystemsorpathologicalstatesforthebeneftof
therecipient.Inthisdocument,thetermsdrug, medicineandpharmaceutical product
(seebelow)areusedinterchangeably.
drug legislation
Te legal conditions under which pharmaceutical activities should be organized.
(Seealsolegislationbelow.)
Glossary
10
drug regulatory authority
A national body that administers the full spectrum of drug regulatory activities,
includingatleastallofthefollowingfunctionsinconformitywithnationaldrug
legislation:
marketingauthorizationofnewproductsandvariationsofexistingproducts;
qualitycontrollaboratorytesting;
monitoringofadversedrugreactions;
provisionofdruginformationandpromotionofrationaldruguse;
good manufacturing practice(GMP)inspectionsandlicensingof
manufacturers,wholesalersanddistributionchannels;
enforcementoperations;
monitoringofdrugutilization.
efectiveness
Anexpressionofthedegreetowhichactivitieshaveproducedtheefectsplanned.
efciency
Te relationship between the results of activities and the corresponding efort
expendedintermsofmoney,resourcesandtime.
essential pharmaceutical products
Tosepharmaceuticalproductsthatsatisfythehealthcareneedsofthemajorityof
thepopulation.WHOsExpertCommitteeontheSelectionandUseofEssential
MedicinesupdatestheWHO Model List of Essential Medicinesattwo-yearintervals.
Eachcountrymayusethismodeltogenerateitsownlistofessentialpharmaceutical
products.
generic products
Tetermgeneric producthassomewhatdiferentmeaningsindiferentjurisdictions.
Teuseofthistermisthereforeavoidedasfaraspossible,andthetermmultisource
pharmaceutical product(seebelow)isusedinstead.Genericproductsmaybemarketed
either under the approved nonproprietary name or under a brand (proprietary)
name. Tey may be marketed in dosage forms and/or strengths diferent from
thoseoftheinnovator products(seebelow).Wherethetermgeneric productisused,
it means a pharmaceutical product, usually intended to be interchangeable with
theinnovatorproduct,whichisusuallymanufacturedwithoutalicencefromthe
innovator company and marketed after expiry of the patent or other exclusivity
rights.TetermshouldnotbeconfusedwithgenericnamesforAPIs.
generic substitution
Practiceofsubstitutingaproduct,whethermarketedunderatradenameorgeneric
name,withanequivalentproduct,usuallyacheaperone,containingthesameactive
ingredient(s).
11
good manufacturing practice (GMP)
Tatpartofqualityassurancewhichensuresthatproductsareconsistentlyproduced
and controlled to the quality standards appropriate to their intended use and as
requiredbythemarketingauthorization.
indicator
Criterion used to measure changes, directly or indirectly, and to assess the extent
to which the targets or objectives of a programme or project are being attained.
Indicators should meet the criteria of clarity, usefulness, measurability, reliability,
validity(seebelow)andacceptancebykeystakeholders.
innovator pharmaceutical product
Generally the pharmaceutical product which was frst authorized for marketing
(normallyasapatentedproduct)onthebasisofdocumentationofefcacy,safety
and quality according to requirements at the time of the authorization. When a
substancehasbeenavailableformanyyears,itmaynotbepossibletoidentifyan
innovatorpharmaceuticalproduct.
interchangeability
Aninterchangeablepharmaceuticalproductisonethatistherapeuticallyequivalent
toacomparator(reference)product.
International Nonproprietary Name
Teshortenedscientifcnamebasedontheactiveingredient.WHOisresponsible
forassigningINNstopharmaceuticalsubstances.
legislation
Tefrststageofthelegislativeprocess,inwhichlawsarepassedbythelegislative
bodyofgovernmentwithregardtoasubjectmatter,e.g.controlofpharmaceuticals.
Laws defne the roles, rights and obligations of all parties involved in the subject
matteringeneralterms(seealsoregulationsbelow).
licensing system
National legal provisions on who should manufacture, import or supply
pharmaceuticalproducts,whatqualifcationspeopleinthesupplyingagencyshould
have,andwhoshoulddispenseandsellpharmaceuticalproducts.
manufacture (manufacturing)
All or any operations of purchase of materials and products, production, quality
control, release, storage and distribution of fnished products and the related
controls.
marketing authorization
Alegaldocumentissuedbythecompetentdrugregulatoryauthorityforthepurpose
ofmarketingorfreedistributionofaproductafterevaluationforsafety,efcacyand
quality.Itmustsetout,interalia,thenameoftheproduct,thepharmaceuticaldosage
form,thequantitativeformula(includingexcipients)perunitdose(usingINNsor
nationalgenericnameswheretheyexist),theshelf-lifeandstorageconditions,and
Glossary
12
packagingcharacteristics.Itspecifestheinformationonwhichauthorizationisbased
(e.g.Teproduct(s)mustconformtoallthedetailsprovidedinyourapplication
and as modifed in subsequent correspondence.). It also contains the product
information approved for health professionals and the public, the sales category,
thenameandaddressoftheholderoftheauthorization,andtheperiodofvalidity
of the authorization. Once a product has been given marketing authorization, it
isincludedonalistofauthorizedproductstheregisterandisoftensaidtobe
registeredortohaveregistration.Marketauthorizationmayoccasionallyalsobe
referredtoasalicenceorproductlicence.
medicine
Seedrug.
multisource (generic) pharmaceutical product
Pharmaceuticallyequivalentor pharmaceuticallyalternativeproductsthat may or
may not be therapeutically equivalent. Multisource pharmaceutical products that
aretherapeuticallyequivalentareinterchangeable.
national list of essential pharmaceutical products
Telistofessential pharmaceutical products(seeabove)thathasbeendefned,adopted
andpublishedatcountrylevel.Itisnormallyusedbyallhealthfacilities,including
themainhospitals.
pharmaceutical product
Seedrug.
prequalifcation
Teactivitiesundertakenindefningaproductorserviceneed,seekingexpressions
of interest from enterprises to supply the product or service, and examining the
product or service ofered against the specifcation and the facility where the
product or service is prepared against common standards of good manufacturing
practice (GMP).Teexaminationoftheproductorserviceandofthefacilitywhere
itismanufacturedisperformedbytrainedandqualifedinspectorsagainstcommon
standards.Oncetheproductisapproved,andthefacilityisapprovedforthedelivery
of the specifed product or service, other procurement agencies are informed of
thedecision.Prequalifcationisrequiredforallpharmaceuticalproductsregardless
of their composition and place of manufacture/registration, but the amount and
typeofinformationrequestedfromthesupplierforassessmentbytheprocurement
agencymaydifer.
procurement
Teprocessofpurchasingorotherwiseacquiringanypharmaceuticalproduct,vaccine,
or nutraceuticals for human use. For the purpose of this document, procurement
means the pre-selection of products and manufacturers through a procedure of
qualifcation, including prequalifcation (see above) and continuous monitoring
thereafter, purchase of the prequalifed products from prequalifed manufacturers
(linked to the specifc product) through defned purchasing mechanisms, storage
anddistribution.
13
procurement agency
Any organization purchasing or otherwise acquiring any pharmaceutical product,
vaccine or nutraceutical for human use. In the context of these guidelines it will
normallybeanot-for-proftorganization,anongovernmentalorganization(NGO)
or a United Nations organization. A procurement agency in the context of this
document is defned as any organization purchasing pharmaceutical products,
vaccines,orotherhealthsectorgoodsorotherwiseinvolvedintheirprequalifcation
(seeabove),purchasing,storageanddistribution.
product information
In the context of this document, product information means information on
pharmaceutical products submitted by manufacturers or suppliers in any of the
formats specifed in the procurement agencys guidelines (including product
dossiers,productquestionnairesorotherformats)toobtainprequalifcationforthe
products.
qualifcation
Action of proving and documenting that any premises, systems and equipment
are properly installed and/or work correctly and lead to the expected results.
Qualifcation is often apart (the initial stage) of validation, but the individual
qualifcationstepsalonedonotconstituteprocessvalidation.Inthecontextofthis
documentitistheworkdonetoprovethatthesupplysystemwilldeliverproducts
ofthequalityrequiredandspecifedonaroutinebasis,meetingalltheapplicable
qualityrequirements.
quality assurance
Qualityassuranceisawide-rangingconceptcoveringallmattersthatindividuallyor
collectivelyinfuencethequalityofaproduct.Itisthetotalityofthearrangements
madewiththeobjectofensuringthatpharmaceuticalproductsareofthequality
requiredfortheirintendeduse.
quality control
Qualitycontrolisconcernedwithsampling,specifcationsandtesting,andwiththe
procurement agencys documentation and acceptance/rejection procedures which
ensurethatthenecessaryandrelevanttestsareactuallycarriedoutandthatstarting
materials, intermediates and fnished products are not accepted for use, sale or
supplyuntiltheirqualityhasbeenjudgedtobesatisfactory.
regulations
Tesecondstageofthelegislativeprocess(thefrststagebeinglegislation,seeabove).
Regulationsarespecifcallydesignedtoprovidethelegalmachinerytoachievethe
administrativeandtechnicalgoalsoflegislation.
reliability
Anexpressionofthedegreetowhichameasurementperformedbydiferentpeople
atdiferenttimesandunderdiferentcircumstancesproducesthesameresults(see
alsovalidity).
Glossary
14
reliable quantifcation of drug needs
Acarefulevaluationofthequantitiesneededofeachdrug,basedoneitheradjusted
pastconsumptionoranticipatedpatternofdiseasesandstandardtreatment,which
canbeexpectedtomatchactualneedsreasonablywell.
transparency
Tetermtransparencymeans:
defningpoliciesandproceduresinwritingandpublishingthewritten
documentation;and
givingreasonsfordecisionstothepublic(seealsoaccountabilityabove).
validation
Action of proving and documenting, in accordance with the principles of good
manufacturing practice, that any procedure, process, or method actually and
consistentlyleadstotheexpectedresults(seealsoqualifcationabove).
validity
Anexpressionofthedegreetowhichameasurementperformedactuallymeasuresthe
characteristicwhichtheinvestigatorwishestomeasure(seealsoreliability above).
WHO-type certifcate
AcertifcateofpharmaceuticalproductofthetypedefnedintheWHOCertifcation
Scheme on the quality of pharmaceutical products moving in international
commerce.
1
1
World Health Organization. WHO Certifcation 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/certifcation/certifschemes.
html).
15
Module I
General requirements for procurement agencies
Introduction
Procurementagenciesoftenhavetopurchaseandsupplypharmaceuticalproducts
using scarce resources. In many cases, product quality is compromised when
products are obtained from unqualifed sources. Procurement agencies will deal
withvarioustypesofsuppliersandcustomers,includingdrugregulatoryauthorities,
manufacturers, quality control laboratories, contract manufacturers, contract
laboratories, traders, brokers, distributors and pharmacies. A quality assurance
systemwillassistinensuringthattransactionswiththesepartnersultimatelyresult
inprocuringpharmaceuticalproductsofthebestpossiblequality.
Tismoduleaddressesthegeneralrequirementsforsuchasystem,includingphysical
resources such as premises, equipment and personnel, as well as the documented
policies, standards and procedures required to ensure consistency in all the key
activities of procurement. Te general requirements described in this module are
thereforeapplicabletoalltheactivitiescoveredinsubsequentmodules.
I.1 Physical resources
I.1.1 Premises
Offces
Te procurement agency should have sufcient ofce space to accommodate the
personnelrequiredandtheactivitiestobeperformed.
Storage
Teprocurementagencyshouldhavesufcientspaceforstorageandretentionof
commodities, including product documentation, product samples, stock, reports,
flesandotherrecordsrelatingtoallkeyactivitiesofprocurement.
Samplesandproductsshouldbestoredundersuitableconditionswhicharespecifed,
e.g.withregardtotemperature,humidityorprotectionfromlight.Detailsofstorage
requirementsaregiveninModuleIV.
Tere should be sufcient space for storage of equipment, stationery and
materialsforproperdistribution.Detailsofdistributionrequirementsaregivenin
ModuleV.
Module 1
16
I.1.2 Equipment
Computers
Te use of computers can facilitate, but not replace, efcient procedures in
pharmaceutical procurement.When implemented appropriately, computerization
willspeedupcomplextasks,increaseaccuracyandautomaterepetitivetasks.Staf
mustbetrainedadequatelyintheuseofcomputerizedsystems.
Manyaspectsofprocurementaresuitableforcomputerization,includingplanningof
requirements,budgetmanagement,fnancialanalysis,preparationofdocumentation
andreportsandinventorycontrol.Hardcopies(printouts)shouldbeproducedas
requiredtoprovidedocumentedevidenceoftheactivities.
Wherecomputersystemsarenotused,manualsystemsshouldprovidedocumented
evidenceoftheactivitiesperformed.
Software
Tesoftwareselectedshouldbesuitablefortheintendeduse.Teprogrammesused
shouldbeabletoprovidetherequiredqualityandmanagementinformationreliably
andaccurately.Teyshouldbeuser-friendlyandstafshouldbetrainedadequately
intheiruse.Wherepossible,diferentprogrammesusedshouldbecompatibleso
thatdatacanbetransferredbetweenthemwithouthavingtoberetyped.
Where information is exchanged between the procurement agency and the
manufacturer(s)byelectronicmeans,appropriateprogrammesshouldbeinplace.
Suitable security systems should be in place to prevent unauthorized access or
changes to computer records and reports. Back-up systems must be in place to
preventlossofdata.Agood-qualityvirusprotectionprogrammeandfrewallmust
beinstalled,confgured,usedandupdatedregularlytopreventunauthorizedaccess
andlossofdata.
Technicalsupportshouldbeavailabletoensurethatsoftwareandsecuritysystems
arekeptfunctionalanduptodate.
Hardware
Tehardwareselectedwhichshouldbeabletohandletherequiredsoftwareefciently.
Tesystemshouldhavesufcientcapacityandmemoryfortheintendeduse,aswell
asadequateinputandoutputdevices,includinggoodqualityprinters.Accesstothe
Internetandpossiblytoaninternalnetwork(LAN)shouldbeprovidedtofacilitate
exchangeofinformation.
A maintenance and upgrading plan must be in place to ensure that the system
remainsfunctional.
17
Telecommunications
Tere should be access to telephone and facsimile facilities to ensure instant
communication. If at all possible, electronic mailing (e-mail) systems should be
available.
Furniture
Suitable ofce furniture should be provided, including desks, chairs, shelves,
cupboards,flingcabinetsandotheritemsasrequired.
Offce equipment
Ofce equipment including copying machines, staplers and punches should be
provided.
I.1.3 Materials and consumables
Stationery and consumables
Teprocurementagencyshouldprovide stationerytoenablestaftoperformthe
relevanttasks,includingpaper,letterheads,businesscardsandpre-printedformsas
required.Computerconsumablestobeprovidedincluderemovablestoragedevices
(foppydisks,CDsand/orfashmemorysticks),printercartridges,printingpaper,
aswellasanyreplacementpartsnotcoveredbyamaintenancecontract.
Vehicles and transport
Ofcialtransportorreimbursementoftransportcostsincurredshouldbeprovided
fortripstomeetings,visits,inspectionsandperformanceofotherofcialduties.
Incaseswheretheprocurementagencyisresponsibleforlocaltransportationand
distribution of products, appropriate transport should be provided to ensure that
thequalityoftheproductsismaintained.
I.1.4 Financial systems
Teprocurementagencyshouldbeabletoefectnationalandinternationalfnancial
transactionsasrequired.Fundsmustbeavailabletoensurecontinuedoperations,
whetherornotcostrecoverymechanismsforkeyactivities,e.g.prequalifcation,are
inplace.
Adequatebankingfacilitiesmustbeavailable.Signatoriesofbankaccountsshould
beappointedtoensurecontrolononehand,andcontinuityofoperationsduring
theabsenceofkeypersonnelontheotherhand.
An accounting system should be in place. Regular fnancial audits should be
performed.
Iftheprocurementagencyispartofalargerorganization,itshouldhavesufcient
autonomyand/orsufcientlygoodcommunicationwiththemotherorganizations
Module 1
18
fnancial department to enable it to conduct all its fnancial transactions without
delay.
I.1.5 Human resources
Personnel
Tere should be a sufcient number of appropriately trained, educated and
experienced personnel to perform the key activities. Te number of members of
stafrequiredinthedepartmentresponsibleforthekeyactivitieswilldependonthe
volumeandvalueofproductssourcedandtobesupplied.Sufcientsupportstaf
forsecretarial,organizationalandaccountingdutiesaswellaslegalsupportshould
alsobeavailable.
Key personnel should include those responsible for prequalifcation, purchasing,
storageanddistribution.Tepersonresponsibleforprequalifcationcouldalsobe
responsibleforqualityassurance.Nationallegislationshouldbecompliedwith,e.g.
requirements for a responsible person for purchasing, storage and distribution of
pharmaceuticalproducts.
Tepersonresponsibleforprequalifcationandthepersonresponsibleforpurchasing
shouldbeindependentofoneanother.Oneshouldnotreporttotheother.
Teresponsibilitiesofthestafinchargeofthediferentkeyactivitiesaredescribed
inModulesIItoV.
Qualifcations and experience
Personnel responsible for prequalifcation, purchasing, storage and distribution
shouldhavesufcientqualifcations,knowledgeandexperienceoftheirrespective
felds(seeModulesIItoV).
Code of conduct
All staf members should comply with a code of conduct which should guide all
their professional activities. More detail on codes of conduct is given in section
I.2.4.AnexampleofacodeofconductisshowninAppendix1.
Confdentiality
It is essential that all information obtained by any person working for the
procurement agency is treated as confdential. Most of the information obtained
fromcompaniesandmanufacturersisproduct-specifc,maybepatentedandwill
becommerciallysensitive.Teevaluatorsandinspectorsmusttreatallinformation
submittedandobservedduringtheassessmentofproductdossiersandinspections
at manufacturing sites, and otherwise in connection with the discharge of their
responsibilitiesinregardoftheabove-mentionedproject,asstrictlyconfdentialand
proprietarytothepartycollaboratingwiththeprocurementagency.
Confdentialityagreementsshouldbesignedbyassessorsandinspectors.Anexample
19
of such an agreement is attached in Appendix 2. Additional information may be
foundinAppendix3(exampleofaguidelineonconfictofinterest).
Confict of interest
Before undertaking any work, assessors and inspectors (including contracted
personnel) should sign a declaration of interest. If, based on their declaration of
interest, it is deemed appropriate for them to undertake the work specifed, they
agreetocarryouttheirfunctionsexclusivelyfortheagency.Teyshouldconfrm
thattheinformationdisclosedbytheminthedeclarationofinterestiscorrect,that
nosituationofreal,potentialorapparentconfictofinterestisknowntothemand
that they have no fnancial or other interest in, and/or relationship with a party
which:
mayhavevestedcommercialinterestinobtainingaccesstoanyconfdential
information disclosed to them in the course of the evaluation activities
describedinthedeclaration;and/or
mayhaveavestedinterestintheoutcomeoftheevaluationactivitiesincluding,
but not limited to, parties such as the manufacturers whose products are
subjecttoevaluationormanufacturersofcompetingproducts.
Personnel should undertake to advise the procurement agency promptly of any
changeintheabovecircumstances,forinstanceifanissuearisesleadingtoaconfict
ofinterestduringthecourseoftheirworkfortheprocurementagency.
Job descriptions
Tereshouldbewrittenjobdescriptions,withdefnitionsofresponsibilities,forall
personnel.
Organizational structure
Teprocurementagencyshouldhaveanorganizationchartindicatingthepositions,
namesofresponsiblepersonsandreportinglines.
Te organization chart should refect the responsibilities and reporting lines in
accordancewiththejobdescriptions.
I.2 Documentation of policies and standards
Documentation is a critical part of a quality assurance system. Te procurement
agencyshouldhaveacomprehensivedocumentationinfrastructure,whichshould
include policies, guidelines, norms, standards, manuals, procedures, records and
relateddocuments.
Allactivitiesofeachsectionordepartmentshouldbeperformedanddocumented
inastandardizedmanner,followingapprovedwrittenprocedures.
Te main elements of the documentation system of this Model are described
below.
Module 1
20
I.2.1 Quality manual
Te procurement agency should have a quality manual. Te purpose of such a
manualistodocumentthequalitypolicyasdefnedbymanagementinrelationto
thevariousactivitiesundertakenbytheprocurementagency.Tereshouldbepolicy
statements and a quality policy in terms of the agencys activities and objectives,
as well as documents describing the policy of each section or department with
regard to all activities in prequalifcation and subsequent purchasing, storage and
distribution.
Oncethisqualitypolicyisdefned,itshouldbeimplemented,maintained,reviewed
andamendedasnecessaryatregularintervalsbytheprocurementagency.
I.2.2 Standard operating procedures
Teprocurementagencyshouldhavewritten,clearanddetailedstandardoperating
procedures(SOPs)foralltheactivitiestobeperformedintheprocurementagency.
TecontentofeachSOP,particularlythestep-by-stepdescriptionsofactivitiesand
approvedrecordingorreportingformatsattachedas addenda(see below), should
refecttheoperationsoftheparticularprocurementagency.
SOPsshouldbedraftedbythepersonresponsiblefortheprocedure.AnSOPfor
writing an SOP should be followed to ensure consistency of design, format and
layout.AnSOPonhowtowriteanSOPisattachedasAppendix4.
Style and layout
SOPs should be written in the procurement agencys approved format, and be
formallyapproved(signedanddated)bytheauthorizedperson(s).
SOPsshouldbewritteninclear,unambiguouslanguage.
Tenameand/orlogooftheprocurementagencyshouldbeincludedonthefront
pageofeachSOP.
Elements of standard operating procedures
TeSOPshouldcontainatleastthefollowingelements.
Title and number
EachSOPshouldhaveatitle.Tetitleshouldgiveaclearindicationoftheactivity
which it describes. A numbering system is useful to identify to which activity or
departmenttheSOPrefers.
Objective
Tissectionshoulddescribewhatistobeaccomplishedand/orachievedwiththe
SOP.
Scope
Tis section should describe to what level or depth, or how widely, the SOP is
applicable.
21
Policy
Tissectionshouldrefecttheprocurementagencyspolicyregardingthisparticular
activity.
Responsibility
Tissectionshouldlisttheperson(s)responsibleforperformingtheactivitieslisted
intheprocedure.Itmaybeusefultorefertothepositionratherthanthenameof
theperson.
Action
Tissectionshoulddescribethesequenceofactionstepstobefollowed,fromthe
beginningtotheendoftheprocess,toperformtheactivity.
Teactionstepsshouldbewrittenintheimperativeandshouldbenumbered.Itis
advisabletoindicatewhoisresponsibleforeachstep.Tiscouldbedonebyputting
theposition(jobtitle)oftheresponsiblepersoninbracketsnexttoeachstep,orby
indicatingthenumbersoftherelevantstepsnexttothepositionslistedunderthe
headingResponsibility.
Whereastepleadstoanotherproceduretobefollowed,theapplicableSOPshould
bereferredtointhatparticularstep.
Distribution and retrieval
Documentationshouldbedistributedwithcare.NosupersededorobsoleteSOPs
shouldbeavailableatuserpoints.Tesectionsand/orresponsiblepersons(positions)
towhomtheSOPwasdistributedshouldbelisted.EachtimetheSOPisreviewed
and amended, superseded versions of the SOPs should be removed from all the
user points listed and replaced with the updated version; the retrieval should be
documented.
Revisions
InasectionwhichcouldbeheadedHistory,thedateofeachchangetotheSOP,
thepersonresponsibleforthereview,thechangeitselfandthereasonforthechange
should be recorded. Tis section will provide the procurement agency with the
historyoftheamendmentstotheSOP.
Addenda
Any records to be completed or maintained as part of the activity should have a
standardized format. It is useful to defne and approve these formats in advance.
TeapprovedstandardformatshouldbepartoftheSOPandcanbeattachedasan
addendumtotheSOP.
Activities to be covered by standard operating procedures
TefollowinglistgivesexamplesofactivitieswhichcouldbecoveredbySOPs:
howtowriteastandardoperatingprocedure(seeAppendix4);
draftingacontractoragreement;
amendmentstocontractoragreement;
identifyingandreportingcounterfeitproducts;
reportingofdeviations;
appointingevaluatorsofproductinformation;
Module 1
22
appointingcontractinspectors;
maintainingamasterdocumentationlist;
receivingandscreeningofanoferreceived;
evaluatingofersreceived;
orderingproduct(s)fromsupplierormanufacturer;
publishingspecifcationsofproductsforprocurement;
sendingout,receivingandevaluatingsupplierquestionnaires;
handlingrecalls;
policyforregularre-inspection;
routinefollow-upofinspections;
inspectionfaultcorrection;and
standardformatsforinspectionreporting.
I.2.3 Change control policy
Teprocurementagencyshouldhaveapolicyforchangecontrol.Tispolicyshould
bedesignedtomanagechangesintheagencysownproceduresanddocumentation,as
wellaschangesindataandinformationonthepharmaceuticalstobeprequalifed.
AprocedureforcontrollingchangesthatafectAPIs,formulation,manufacturing
processes,analyticaltestingmethodsorpackagingofprequalifedproductsisessential.
Te procedure should ensure that these changes are reported to the procurement
agency before new batches are manufactured or before they are delivered and
releasedfordistribution.Detailsofmanagingchangesinproductinformationare
giveninModuleVI.
I.2.4 Code of conduct
Teprocurementagencyshoulddesign,authorizeandimplementawrittencodeof
conduct.
Te code of conduct should describe the policy of the procurement agency
regardingtheconductofstafinrespecttotheiractivities.Itshouldbefollowedby
allpersonnel.
Tecodeofconductshouldgiveguidancetostafmembersonappropriateconduct
invarioussituations.Tefollowingtopicscouldbecoveredinthecode:
introductionandobjectives;
keyresponsibilities;
personalresponsibilities;
safety;
professionalcompetence;
qualifcationsandexperience;
conduct;
integrityandattitude;
attire,healthandhygiene;
managementrelationship;
SOPs;
23
travelandaccommodation;
confdentialityandconfictofinterest;
documentationandrecords;
contractsandtermsofreference(TOR);
productfles,evaluationandinspection;
samples;
evaluationandinspectionreports;and
provisionofinformationandadvice.
I.2.5 Guidelines on confict of interest
Te procurement agency should have a policy on confict of interest which all
personnelshouldobserve.Anexampleofaguidelineonconfictofinterestisshown
inAppendix3.
Tedocumentshouldaddressatleastthefollowingpoints:
introductionandobjectives;
defnitionsandprinciples;
responsibilities;
confdentiality;and
impartiality.
I.2.6 List of prequalifed products and manufacturers
Teprocurementagencyshouldhaveaprocedurefordraftingandmaintainingalist
ofprequalifedproductsandmanufacturers,basedontheoutcomeoftheevaluation
ofproductdataandinformationandmanufacturingsiteinspections.Telistshould
be product- and manufacturing site-specifc, i.e. sites are prequalifed for one or
morespecifedproducts,andproductsareprequalifedasmanufacturedatspecifed
sites.
Tekeypersonresponsibleforprequalifcationshouldberesponsibleforaddition
toand/ordeletionsfromthelist.
Once the evaluation of a product dossier is complete, and the inspection has
been performed to assess compliance with good manufacturing practices, good
storage practices and good distribution practices as appropriate, the procurement
agency should prepare a list refecting the status of the prequalifed products and
manufacturers.
Telistshouldcontainatleastthefollowinginformation:
nameoftheprocurementagency;
authorizationsignatures;
referencenumberandversionofthelist;
dateofpreparationofthelist;
nameandphysicaladdressofmanufacturer,includingtheapprovedsite(s)of
manufacturelinkedtoeachproduct;
contact details, including postal address, telephone, fax number and e-mail
addressofthemanufacturerandsupplier;
Module 1
24
productdetails,includingthebrandname,INN,dosageform,strengthper
doseandpacksize;
dateoforiginalprequalifcation;
dateofexpiryoftheprequalifcation;and
dateuntilwhichthelistisvalid.
I.2.7 Maintenance of records
Records of all operations should be maintained and kept in a suitably organized
manner.
Sufcient areas for the storage of records, including product information,
manufacturersinformationandinspectionreports,shouldbeavailable.
Access to these areas should be restricted to authorized personnel only, as
confdential information may be fled (including records of manufacture, testing
and/orstorage).
Records should be maintained for a defned period of time, in accordance with
nationallegislation.Generallytheyshouldberetainedforatleastoneyearbeyond
theexpirydateofthefnishedproduct.
Module II. Further guidance on record-keeping in quality assurance systems is
providedintheWHOpublicationQuality assurance of pharmaceuticals (2, 3).
25
Module II
Prequalifcation
Introduction
Prequalifcation is one of the key elements in ensuring purchase and supply of
pharmaceuticalproductsofacceptablequality.Teprequalifcationprocesscanbe
subdividedintotwomajorparts,i.e.product-relatedassessmentandmanufacturer-
relatedassessment.
Product-related assessmentshouldensurethatthecorrectproductisspecifedby
theprocurementagency.Teprocurementagencyshouldthenassesswhether
themanufacturerisoferingaproductthatmeetsthepredeterminednorms
andstandardsintermsofsafety,qualityandefcacy.
Manufacturer-related assessmentshouldensurethatthemanufacturerisableto
manufacturetheproductasspecifedintheproductinformationpackageand
in accordance with good manufacturing practices (GMP) as recommended
byWHO.Temanufacturermustbecapableofroutinelycarryingoutthe
activities to the specifed standards to ensure batch-to-batch consistency of
theproduct.
Assessment of contracted-out services, e.g. by storage and distribution agents,
contract research organizations (CROs) and quality control laboratories for
compliancewithGMP,goodclinicalpractices(GCP)andgoodlaboratorypractices
(GLP),arefurtherelementsthatmaysupplementtheprequalifcationprocess.
Teprocurementagencyisresponsibleforensuringthatallstepsintheprequalifcation
processarecarriedoutinaccordancewiththisModel.Tisshouldensurethatthe
manufacturerswillbeprovidingproductsasspecifedthatmeetallpredetermined
normsandstandards.Itwillassistprocurementagenciesinmaximizingtheuseof
resources and will avoid duplication of prequalifcation by diferent procurement
agencies.Itshouldalsominimizetheriskofprocurementagenciespurchasingand
supplyingsubstandardproducts.
Tis module sets out recommendations which procurement agencies should
implementwhenevaluatingtheirproductneedsandwhenassessingtheproducts
andthemanufacturingandsupplyarrangementsoferedbythemanufacturers.
II.1 Principles for prequalifcation
Prequalifcationproceduresshouldbebasedonthefollowingprinciples:
reliance on the information supplied by the national drug regulatory
authority;
evaluation of product data and information submitted by manufacturers,
includingproductformulation,manufactureandtestdataandresults;
a general understanding of the production and quality control activities of
themanufacturersandsuppliersandoftheircommitmenttotheprinciplesof
GMP;
Module II
26
assessment of consistency in production and quality control through
compliancewithGMPasdescribedintheWHOpublicationQuality assurance
of pharmaceuticals,Volumes1and2(2,3)andsupplementaryWHOGMP
guidelines;
availabilityofappropriatequalitysystemsandSOPs;
randomsamplingandtestingofpharmaceuticalproductssupplied;
adequatepurchasingmechanisms(seeModuleIII);
goodstoragepractices(seeModuleIV);
gooddistributionpractices(seeModuleV);
monitoringofcomplaintsfromprocurementagenciesandcountries;
adequatehandlingofcomplaintsandrecalls;and
continuousmonitoringandrequalifcation.
Te procurement agency should have a document describing the policy and
procedures for prequalifcation, including the assessment of product information
andofmanufacturersforcompliancewithstandards.
II.1.1 WHO Model List of Essential Medicines
Procurement agencies may fnd that many of the products they require are on
WHOs Model List of Essential Medicines, which contains medicines of proven
safety and efcacy and is updated periodically (4). Procurement agencies should
focusonprocurementofmedicinesrefectedintheModelList.Teywillfndthis
list a useful reference for establishing specifcations for the medicines needed for
theirpurposes.
II.2 Standards for prequalifcation
TeprequalifcationprocedureshouldbebasedontheProcedureforassessingthe
acceptability,inprinciple,ofpharmaceuticalproductsforpurchasebyUnitedNations
Agencies (5). In principle, products should meet at least the recommendations
madebyWHOinMarketing 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 prequalifcation
Tepersonresponsibleforprequalifcationshouldbeindependentfromtheperson
responsibleforpurchasing.
Te key responsibilities of the person responsible for prequalifcation activities
shouldincludethefollowing:
establishingspecifcationsforproducts;
publicationofinvitationsforexpressionsofinterest(EOI);
preparation of a questionnaire for collecting product data and information
and/orguidelinesforthecompilationofproductinformation;
27
assessmentofproductdataandinformationforcompliancewithnormsand
standards;
assessmentofmanufacturingsites,throughinspection,forcompliancewith
WHOGMP;and
preparationofthelistofprequalifedproductsandmanufacturers.
II.3.2 Staff responsible for evaluation of product information
Tepersonresponsibleforevaluationofproductinformationshouldbeindependent
from the person evaluating the manufacturing site. Neither should report to the
otherintermsofdecision-making.
Tekeyresponsibilitiesofthepersonresponsibleforevaluatingproductinformation
shouldinclude:
preparingandimplementingSOPsandguidelinesforevaluationofproduct
information;
receiptofproductinformation;
screeningofproductinformation;
evaluationofproductinformation;
informing manufacturers of the outcome of the evaluation of the product
information;and
communicatingwiththepersonresponsibleforinspectionsofmanufacturing
sites.
Tepersonresponsiblefortheevaluationofproductinformationmaybeamember
oftheexistingstaforappointedforthistask.
Te people assigned to evaluate product information should have relevant
qualifcations and experience, including a background in pharmaceuticals,
pharmaceutical chemistry and pharmacology. Ideally they should be from a
regulatorybackground,orhaveregulatoryexperience.
II.3.3 Staff responsible for inspection of manufacturing sites
Tekeyresponsibilitiesofthepersonresponsibleforinspectionofmanufacturing
sitesshouldincludethefollowing:
preparationandimplementationofguidelinesandSOPs;
coordinationofinspectionstobeperformed;
recruiting or appointing inspectors with appropriate qualifcations and
experiencewhennecessary;
trainingofinspectors;
organizationofinspections;
fnalizinginspectionreports;and
informingmanufacturersoftheoutcomeoftheinspection.
Asaminimum,thepersonnelresponsibleforinspectingmanufacturingsitesshould
have relevant qualifcations and experience in pharmaceutical manufacturing,
qualityassurance,GMP,performinginspectionsandaudits,chemistryandquality
control. Ideally they should have an inspection background from working with a
regulatoryauthority.
Module II
28
Althoughdecision-makingshouldbeindependent,thereshouldbecommunication
between the person responsible for evaluation of product information and the
personresponsibleforinspectionofmanufacturingsites,assomeinformationon
theproductmayhavetobeverifedduringthesiteinspection.
II.4 Key steps in prequalifcation
TekeystepsinprequalifcationaresummarizedinFig.1.Detaileddescriptionsof
thediferentstepsaregivenbelow.Tepreparatorystepsofdraftingadocumentation
system, including confdentiality agreements, declaration of confict of interest,
SOPsandguidelines,aredescribedinModuleI.
II.4.1 Step 1: solicit and receive expressions of interest
Draft product specifcations for prequalifcation
Specifcationsfortheproduct(s)tobeprequalifedshouldbedraftedwithinputfrom
thepersonresponsibleforpurchasing,sothattheproductmeetstherequirements
fortheintendedpurpose.
Tespecifcationsshouldbedetailed,clearandunambiguoustoavoidunnecessary
submission and processing of documentation not relevant to the product to be
sourced.
Tespecifcationshouldstateatleast:
thenameoftheactivepharmaceuticalingredient(s);
pharmacopoeia reference (if any), e.g. European Pharmacopoeia,
Japanese Pharmacopoeia, United States Pharmacopeia and International
Pharmacopoeia;
strengthperdoseanddosageform;
dosageform(routeofadministration);
packsize;
packingmaterial;and
labellingrequirements.
TespecifcationcouldbepublishedaspartoftheinvitationforEOIs.
Draft and publish invitation for expressions of interest
Oncethespecifcationisfnalized,aninvitationforEOIsshouldbepublishedwidely
to reach any manufacturers that may be interested in supplying the product(s).
29
233
Figure 1
Key steps in prequalication
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
Module II
30
Te process of inviting all interested manufacturers to submit their EOI for the
pharmaceutical products listed should be open and transparent. Invitations for
EOIsmaybepublishedforgroupsofproducts,andmayberepeatedasnecessary.
TeinvitationforEOIsshouldbedetailedandshouldstateatleast:
thepurposeoftheinvitationforEOIs;
theobjectiveoftheinvitationforEOIs;
thelistofproducts,includingspecifcationsforeachproduct;
informationonquantitiesrequired(ifavailable);
detailsoftheinformationtobesubmitted;
guidelinesforsubmission,includinginformationondetailstobesubmitted
aspartoftheEOI,onthefocalpointforthesubmissionandontheformat
forthesubmission;
contact details (name, address, telephone number, fax, e-mail and postal
address)forsubmissionoftheEOI;and
theclosingdateforreceiptoftheEOIbytheprocurementagency.
AnexampleofaninvitationforEOIsisshowninAppendix5.
Manufacturers should submit their EOI with the requested information about
theproduct(s)andmanufacturer(s),beforethedatespecifedbytheprocurement
agency.
Receive expressions of interest
Teprocurementagencyshouldensurethattherelevantinfrastructureexistsforthe
receiptandprocessingoftheEOIsthroughthesubsequentprequalifcationsteps.
Te procurement agency should have a clear policy regarding the acceptance of
EOIs after the specifed closing date. Processing of late submissions should not
normallybeallowed.OnlyinexceptionalinstancesshouldlateEOIsbeconsidered,
e.g.whenamanufactureristheonlyonetoexpressaninterestinsupplyingaspecifc
product.
It would be appropriate to express concern at the late arrival of the EOI, and
manufacturersshouldgivereasonsforlatesubmission.
ArecordofalltheEOIsreceivedfromeachmanufacturershouldbemaintained.
Send guidelines for submitting product information to manufacturers
Manufacturers who have submitted an EOI before the closing date specifed in
the invitation should be given guidelines for the compilation and submission of
information on products and manufacturers. Te guidelines should be publicly
available and accessible. In cases where this is not done, reasons for the decision
shouldbegivenanddocumented.
Teguidelinesshouldbewritteninclear,unambiguouslanguage.Guidelinesshould
containinformationincludingatleast:
the content and format of submission, including the type and format of
31
information required (e.g. the procedure for submission of information
foraproductregisteredinacountryrecognizedashavinganefectivedrug
regulatory agency, and instructions for cross-referencing an existing dossier
withtheprescribedsubmissionformat);and
theprocessofsubmission,includingtheaddresstowhichthedocumentation
shouldbesentandastatementofanyfeespayableforcostrecovery.
Content and format of submission
For each product to be prequalifed, interested manufacturers should be asked to
submitproductinformation,togetherwithasampleofsufcientquantitytoallow
analyses of the product against its fnished product specifcation as stated in the
productinformation,acoveringletter(asrecommendedontheEOI)andachecklist
fortheproductinformation.
Depending on the active ingredients, country of manufacture and registration of
productstobeprequalifed,diferentformatsforsubmissionwillberequired.
Detailedinformationshouldbesubmittedforproductsforwhichbioavailabilitymay
bealteredbychirality,isomerism,controlledreleaseformulation,polymorphismor
otherpropertieswhichmayafectthetherapeuticoutcome.
In this document, the term product information refers to any of the following
fourformats,inwhichsubmissionsshouldbemade:
1. A product dossier, which should be submitted for multisource (generic)
products,forinnovatorproductswhichhavebeenonthemarketforlessthan
fveyears,andforproductscontainingsubstancesthathavespecifcproperties
thatmayhaveexplicitimpactonthesafety,efcacyorqualityoftheproduct.
TeModel application form for new marketing authorizations, periodic reviews
and variations, with notes to the applicant (7) may also provide a helpful
exampleofguidelinesforthistypeofsubmission.
2. Astandardproductdossieraspreparedforanationaldrugregulatoryauthority
canbesubmitted,provideditcontainstheappropriateinformationasrequired
intheseguidelines.Insuchcases,thesuppliershouldprovideacoveringletter
whichindicateswheretherequiredinformationcanbefoundinthestandard
productdossier.
3. For products manufactured and registered in countries where regulatory
requirementsareinlinewithinternationalregulationsforassessmentofsafety,
efcacyandquality,thefollowinginformationshouldbesubmitted:
aWHO-typecertifcateofapharmaceuticalproduct(CPP)(8)issuedbyone
oftheregulatoryauthoritiesofanInternationalConferenceonHarmonisation
(ICH)region(EuropeanUnion,JapanortheUSA),togetherwithasummary
ofproductcharacteristics(SmPC);
anassessmentreportissuedbytheregulatoryauthority;
aWHO-typebatchcertifcatefromthemanufacturer.
Ifthepackagingoftheproductisdiferentfromthatapprovedbyaregulatory
authorityofanICHregion,stabilitytestingdatashouldbesubmitted.Ifthe
Module II
32
formulation,strengthorotherspecifcationsarediferentfromtheproductfor
whichtheWHO-typeproductcertifcate(CPP)wasissued,argumentsand/
or data to support the applicability of the certifcate despite the diferences
shouldbesubmitted.
4. Acompletedquestionnairewithlimitedinformationontheproductshould
besubmittedforproductscontainingonlysubstancesthatdonothavespecifc
propertiesthatmayhaveexplicitimpactonthesafety,efcacyorqualityof
theproduct.Anexampleofapharmaceuticalproductquestionnaireisshown
inAppendix6.
Informationaboutthesite(s)whereeachproductismanufacturedwillalsoberequired
atalaterstage.Forguidelinesonsubmissionofinformationonmanufacturingsites,
seePlanningandpreparationofinspections.
Tesameprocessasoutlinedaboveshouldbefollowedforsupplierswhoperform
onlypartofthesupplyprocess.Tisisparticularlyrelevantwhereaproductfroma
prequalifedmanufactureristobesuppliedthroughanewdistributionchannel.For
example,aprocurementagencymightwishtoshipanalreadyprequalifedproduct
to a new country using new traders, brokers or distributors. Te organizations
involvedinthenewdistributionchannelwillneedtobeappropriatelyprequalifed.
Dependinguponthenatureofthesupplyarrangement,therequirementsforproduct
informationandtheGMPinspectionprocessmaybemodifed.
Process of submission
Suppliersshouldbeallowedatleast60daysforthecompilationandsubmissionof
productinformation.
Suppliersshouldberequestedtosubmitacoveringletter,containingaclearstatement
bytheresponsiblepersonthattheinformationsubmittedistrueandcorrect.
Teprocurementagencyshouldreservetherighttoterminatetheprequalifcation
procedureofaproductandmanufacturerifthemanufacturerfailstoprovidethe
required information in a specifed time period, or if the information supplied is
inadequatetocompletetheprequalifcationefectively.
II.4.2 Step 2: receive product information
Te procurement agency should have the necessary infrastructure to receive and
process the product information submitted by manufacturers. It will require
personnel for processing the documentation; written procedures for receiving,
identifcation, marking fles, containers and samples, and sufcient space for
unpackingandstorage.
Containers with product information should be received at the specifed address
beforeaspecifeddateasdeterminedbytheprocurementagency.
Containersshouldbeopenedinthepresenceofatleasttwopeople.Arecordshould
bekeptofthenamesofthepeoplewhoopenedthecontainersandthecontentsof
thecontainers.
33
Eachproductshouldbeallocatedauniquereferencenumbertoensuretraceability
oftheproductinformation.
II.4.3 Step 3: screen product information
Each product information package submitted by the manufacturer should be
screenedforcompleteness.Tescreeningshouldbedoneinaccordancewithawritten
procedure.Iftheproductinformationsubmittedfailstomeettherequirements,it
shouldbeexcludedfromtheevaluationprocedureandinspectionprocess.
Ascreeningformshouldbeusedtoensureconsistencyofscreening.Tereshouldbe
awrittenrecordofthescreeningofeachproductinformationpackage.Information
toberecordedshouldinclude:
dateofreceipt;
nameoftheinterestedmanufacturer(s);
addressofthemanufacturer;
nameoftheproduct;
countryofmanufacture;
productnumber;and
outcomeofthescreening.
AnexampleofanSOPforscreeningandassessingproductinformation,including
asamplescreeningform,isshowninAppendix7.Incompleteinformationshould
not be kept for evaluation purposes. Te manufacturer should be informed that
an incomplete information package was received, and be requested to supply the
missinginformationwithinaspecifedperiod.Ifthisrequestisnotcompliedwith,
theapplicationshouldberejectedongroundsofincompleteness.
Product information packages which meet the requirements of the screening
procedureshouldberetainedforfullevaluation.
Asummaryshouldbemadeofeachproductinformationpackagereceived,stating
any reference number allocated to the product by the procurement agency, the
INN,strength,dosageformandpacksizeoftheproduct,thenameofthesupplier,
the name and address of the manufacturing site(s), whether a sample has been
submitted,andifso,thesamplesize.
II.4.4 Step 4: evaluate product information
Evaluators
Evaluatorswithsuitablequalifcationsandexperienceintheevaluationofproduct
dataandinformationshouldbeavailabletoconducttheassessment.Suitablyqualifed
externalevaluatorsmaybeappointed.Appointmentofexternalevaluatorsshouldbe
subjecttocompliancewiththepolicyoftheprocurementagency,regardingaspects
such as confdentiality, conficts of interest and fnancial resources. Examination
ofpotentialconfictsofinterestandconfdentialitymustgobeyondthepotential
evaluatorsigningadeclaration.Checksonreferencesshouldalsobemade.
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34
A formal agreement for the performance of work and terms of reference for
contractedevaluatorsshouldbeinplacebeforecommencementofwork.
A summary list of names, addresses, dates of appointment, qualifcations and
experienceofevaluatorsshouldbemaintained.Copiesofsignedagreementsshould
bekeptinacentralfle.
Evaluation
Timeframesshouldbesetforevaluationofproductinformation.Productinformation
shouldbeevaluatedwithin21daysaftertheclosingdateforsubmission.
Awrittenprocedureforevaluationshouldbefollowed.AnexampleofanSOPfor
screeningandassessingproductinformationisattachedasAppendix7.
Te person responsible for evaluation should monitor the process to ensure
that each product information package is evaluated in compliance with these
requirements.Informationontheproductspatentstatusshouldbeconsideredto
avoidinfringementofintellectualpropertyrights(seealsoSectionIII.7).
Contractresearchorganizationsshouldbeinspectedaspartoftheassessmentprocess
toensurethatbioequivalencestudieshavebeendoneinaccordancewithGCPand
GLP,andthattabulateddatasubmittedtoprovebioequivalenceaccuratelyrefect
thegeneratedrawdata.
Evaluation reports
Eachevaluatorshouldprepareaformalevaluationreportforeachproduct,including
a recommendation for acceptance or rejection. Te evaluation report should be
communicatedtothemanufacturerwithin14daysoftheevaluation.
A response should be invited from the manufacturer in cases where data and
informationarefoundtobeincompleteordonotmeettheguidelines.Aperiodofat
least60daysshouldbeallowedforsubmissionofadditionaldataandinformation.
Tis additional information should be assessed and the fnal outcome of the
evaluationshouldbecommunicatedtothemanufacturer.
Teevaluationreportshouldbefledwiththeproductevaluationdocumentation
forreferencepurposesandfollow-upwhererelevant.
Analysis of samples
Samplessubmittedtogetherwithproductinformationpackagesshouldbeanalysed
inaccordancewiththefnishedproductspecifcation.Certifcatesofanalysisoffnal
productsreleasedbythemanufacturershouldbemadeavailabletotheprocurement
agencyonrequest.
Te procurement agency should have access to a quality control laboratory to
perform the analyses. Te WHO Guide for a quality systems manual in a control
laboratory(9)seekstoestablishapracticalbasisforthequalitysystemsmanualofa
35
controllaboratorywhicheachcountrycanadoptandadapttoprepareitsownmore
detailedmanualtomeettherequiredlevelofspecifcityandcomplexity.
A laboratory may be contracted to perform the analyses. In that case, the
procurement agency should ensure that the laboratory complies with GMP and
goodpracticesforcontrollaboratories(10).Teuseofanaccreditedlaboratoryis
thereforerecommended.Teprocurementagencyshouldverifytheaccreditation.
Tereshouldbeawrittencontractoragreementbetweentheprocurementagency
and the contract laboratory. Te wording of the contract should be clear and it
shouldspecifytheresponsibilitiesofthecontract-giverandthecontract-acceptor.
Teprocurementagencyisresponsibleforensuringaccesstorawdata.
Teprocurementagencyshouldhaveaprocedureforinvestigating,handlingand
reportingout-of-specifcationresultswhentheseareobtainedfromlaboratories.If
asamplefailstomeetthespecifcations,theprocurementagencyshouldinvestigate
theproblemandcommunicatetheoutcometothemanufacturer.
II.4.5 Step 5: plan, prepare and perform inspections
Each batch of every product procured by a procurement agency should be
manufactured in compliance with GMP to ensure batch-to-batch consistency.
Teactualsiteofmanufactureoftheproductshouldbeknownandspecifed.In
somecases,acontractmanufacturermaymanufacturetheproductonbehalfofthe
supplier or agent. Each manufacturing site specifed in the product information
shouldbeinspectedtoassesscompliancewithWHOGMP.
Manufacturers of the active pharmaceutical ingredients (APIs) used should
be inspected as part of the assessment procedure to ensure that the APIs were
manufacturedinaccordancewithGMP.
Existing certifcates
ISO certifcation is not an assurance of compliance with GMP and is not a
replacementorsubstituteforverifcationofcompliancewithGMP.
Similarly, a CPP is not a guarantee of compliance with GMP. Participation in
theWHOCertifcationscheme(8)isavoluntaryprocess,andthereisnoformal
assessmentorevaluationofdrugregulatoryauthoritiesenteringthescheme.Insome
cases, reliance on the CPP alone is therefore not recommended. Te certifcation
scheme is an administrative tool and is reliable only where the relevant national
drug regulatory authority has an established system which is known to comply
withacceptablestandardsforevaluationandregistration/licensingofproductsand
manufacturers, including products for export markets. Information in addition
to the CPP, e.g. a copy of the inspection report and corrective action plan from
the manufacturer, may be requested. Tese documents, in addition to other
documentation, may be considered useful in the prequalifcation process and in
follow-upassessmentorevaluationatalaterstage.
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36
TeprocurementagencyshouldstillverifycompliancewithWHOGMPaspartof
theprequalifcationprocedure,andaninspectionofthemanufacturingsitemustbe
consideredineverycase.
Inspectors
Inspectionsshouldbeperformedbyasuitablyqualifed,experiencedinspectoror
teamofinspectorswithrelevantqualifcations,trainingandexperienceinperforming
inspectionsinforeigncountries.Inspectorsshouldhavesoundknowledgeofquality
assuranceandGMPinpharmaceuticalproductproductionandqualitycontrol.A
sufcientnumberofinspectorsshouldbeappointedtocarryoutinspectionswithin
predeterminedtimeframes.
Where possible, a representative from the procurement agency (the person
responsibleforprequalifcationwithaknowledgeofGMP)shouldbepartofthe
inspectionteam.
In exceptional cases, consultants from the private sector may be appointed to
perform inspections, provided that there is no confict of interests and that all
confdentiality undertakings are agreed upon and maintained. For these reasons,
persons working in a manufacturing company may not be considered suitable.
Interestedexternalinspectorsshouldsubmittheirlettersofinterestandcurriculum
vitae to the procurement agency. Te agency should review the documentation
beforedecidingtoappointanyinspectors.Aformalagreementfortheperformance
ofworkandtermsofreferenceshouldbeinplacebeforecommencementofwork
bycontractedinspectors.
A summary list of names, addresses, dates of appointment, qualifcations and
experienceofinspectorsshouldbemaintained.
Planning and preparation of inspections
Inpreparationfortheinspection,theprocurementagencyshouldensurethatthe
manufacturerswhohavesubmittedEOIstosupplyproductsarelistedinarecording
systemforinspectionplanningpurposes.
Tofacilitateplanningandtosavecosts,manufacturersshouldbegroupedtogether
bycountry.Insomecountries,onemanufacturermayhavediferentmanufacturing
sitesinadditiontothesubmittedaddressoftheheadquarters.
Manufacturers should be informed of tentative inspection dates, and should be
requestedtosubmitinformationabouteachmanufacturingsitetobeinspected.Tis
informationshouldnormallybeprovidedinasitemasterfle(SMF).Anexampleof
atechnicalquestionnaireforpharmaceuticalmanufacturersisattachedasAppendix
8. Tis information will be used during the preparation for the inspection and
duringtheinspectionitselftoverifyinformationsuppliedbythemanufacturerto
theprocurementagency.
37
Anexampleofastandardoperatingprocedureforplanninganinspectionisshown
inAppendix9.
As the manufacturer will be inspected as part of the prequalifcation process
for specifc products to the procurement agency, inspectors should prepare for
inspections by studying the product information submitted by the manufacturer.
Appendix10containsanexampleofanSOPforpreparingforaninspection.
AsitevisitbeforedecidingwhetheraGMPinspectionshouldbeperformedmayin
somecasesbeappropriate.Tisvisitisoptionalanddoesnotleadtotherequirement
fortheperformanceoftheinspectionbeingwaived.
Performing inspections
Inspections should be performed in accordance with a written procedure. Te
inspectionshouldcoverallaspectsofGMP.AnexampleofanSOPforperforming
aninspectionisshowninAppendix11.
Information submitted in relation to the supply of the API, formulation of the
product, manufacturing method and stability data should also be verifed during
theinspection.
Teinspectionshouldcovertheevaluationandassessmentofthedocumentation,
premises, equipment, utilities and materials. It should also cover verifcation of
dataanddocumentationsuchasresults,batchrecords,compliancewithSOPand
information submitted on the manufacturing method, equipment and aspects
including(butnotlimitedto)validationofthemanufacturingprocess,validation
ofutilitiesandsupportsystems,andvalidationofequipment.
If checklists are used, these should be drawn up and agreed upon for use by
collaborating procurement agencies implementing this Model. An example of a
GMPchecklistisshowninAppendix12.
Waiving of inspections
Teneedforaninspectionmaybewaivedwhereaninspectionreportisavailablefrom
inspectorsrepresentingnationaldrugregulatoryauthoritiesforthemanufacturing
site under consideration, covering activities for the product(s) being prequalifed,
providedthatthereportsatisfestheagencythat:
allaspectsofGMPfortherelativeproduct(s)havebeencovered;
theinspectionreportisnotolderthan24months;
thereisastatementfromthemanufacturerthatnomajorchangeshavebeen
madetopremises,equipmentandkeypersonnelsincetheinspectionbythe
medicinesregulatoryauthority;
the reports of the national drug regulatory authority demonstrate that the
manufacturerhasahistoryofcompliancewithGMP;and
theinspectionreporthasafavourableoutcome.
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Inspection report
Each inspector or inspection team (where inspection teams are performing
inspections)shouldprepareaformalinspectionreportforeachmanufacturingsite
inspected.
Teinspectororinspectionteamshouldmakearecommendationonthestatusof
themanufacturerinrelationtocompliancewithGMP.Accordingtothefndings,
the recommendation following the inspection may for example be one of the
following:
Te manufacturer is considered to be operating at a reasonable level of
compliance withWHO GMP and a follow-up inspection is recommended
to verify implementation and acceptability of corrective actions prior to
participationinanytender.
Te manufacturer is considered to be operating at an acceptable level of
compliancewithWHOGMP.
Temanufacturerisconsiderednottobeoperatingatanacceptablelevelof
compliancewithWHOGMP.
Te inspector or inspection team(s) will fnalize a report according to the
recommended format. Te WHO Guidance on Good Manufacturing Practices
(GMP): inspection report (11) (see Appendix 13) provides information on how to
writeaninspectionreport.
Acopyoftheinspectionreportshouldbefledinacentralmanufacturersflethat
isuniquetothatmanufacturer.
Teinspectionreportshouldbecommunicatedtothemanufacturer.Wherenon-
compliance was observed, corrective actions and time lines for completing them
shouldbesuggested.Aresponsewithsupportivedocumentationshouldbeinvited
fromthemanufacturer.
If any additional information is required, or if corrective action has to be taken,
a fnal recommendation as to the acceptability of the product and manufacturer
shouldbemadeonlyaftersuchinformationhasbeenevaluated,orthecorrective
actionhasbeenverifed.
Intheeventofanydispute,astandardprocedureshouldbefollowedfordiscussing
andresolvingtheissue.
Te ownership of the report should be with the procurement agency, as it is
responsiblefortheprequalifcation.
II.4.6 Step 6: fnalize assessment process and update prequalifcation list
Decision-making process for acceptance or rejection of a manufacturer
Teprocurementagencyshouldfollowawrittenproceduretocollatetheoutcomes
of the evaluation of product information, laboratory results for samples analysed
andinspectionreports.
39
TeSOPshouldalsoidentifythepeopleresponsiblefortakingthedecisiontoaccept
orrejectaproductand/ormanufacturer,includingthegroundsforthedecision.It
maybehelpfultorefertothepersonbyposition,ratherthanbyname.
Teprocurementagencyshouldinformthemanufacturerinwritingoftheoutcome
oftheprequalifcationofeachproductmanufacturedateachspecifedsite.
Recording of outcomes
Te person responsible for prequalifcation should record the outcome of the
prequalifcation process in a list of prequalifed products and manufacturers. Te
listshouldincludeonlythoseproductsevaluatedasindicatedbythemanufacturer
andlistedintheEOI.Itshouldbeproduct-andmanufacturingsite-specifc.
Telistshouldbepublishedinthepublicdomainandshouldincludeatleastthe
followinginformation.
General information
Normsandstandardsused;
referencetothegeneralprocedureforprequalifcation;
a statement to indicate that the list is not comprehensive for any disease
category, but includes only those products submitted by possible suppliers
andprequalifedbytheprocurementagency;
a statement to indicate that the purchaser of products from the list should
ensurethatonlyprequalifedproducts(i.e.thesameformula,manufacturing
methods,manufacturingsite,etc.asintheproductinformationsubmitted)
willbesuppliedbythesupplierthroughcontractualagreementbetweenthe
buyerandthesupplier;
astatementthatbeingonthelistdoesnotguaranteecontractsorsalestothe
suppliers;
astatementthatthelistshouldnotbeusedbysuppliersasamarketingtool
togeneratebusiness;
dateofpublication;and
periodofvalidity.
Product information
Products and their manufacturing sites where products and manufacturers
meet the standards set for the prequalifcation, including the following
specifcations:
INNofactiveingredient(s);
strength;
dosageform;
packsize;
shelf-life;
storageconditions;
nameofsupplier;
nameofmanufacturerandmanufacturingsite(s).
Te procurement agency should have a mechanism for sharing information with
otherprocurementagencies.
Module II
40
Te procurement agency should have an agreement with the supplier to ensure
compliancewiththeprequalifcationprinciplesandthattheproductssuppliedare
thesameproductsaswereprequalifed(e.g.theyaremanufacturedatthesamesite
and the same processes are adhered to). Te list should be reviewed and updated
at regular intervals, at least every year. Newly prequalifed manufacturers should
be added to the list as they become qualifed, and non-compliant manufacturers
shouldberemovedfromthelistassoonastheyarerecognizedassuch.
Where possible, more than one supplier of a product should be included on the
listtoensureopenandtransparentprocurementthroughcompetitiveprocurement
procedures(seeModuleIII).
II.5 Requalifcation and monitoring
Requalifcation should occur at regular intervals. Routine reinspection of
manufacturersshouldtakeplaceatleastonceeverythreeyears.Routinere-evaluation
ofproductinformationorquestionnairesshouldbedoneeverythreeyears.Non-
routinere-evaluationand/orinspectionshouldbedonewhennecessary,e.g.when
themanufacturerimplementsanychangetotheformula,manufacturingmethodor
manufacturingsite;ifanyproductsuppliedisconsiderednottobeincompliance
with the agreed specifcation of the product; or if a serious complaint has been
received.FormoredetailsonreassessmentseeModuleVI.
Randomsamplesofbatchesofpharmaceuticalproduct(s)suppliedbyprequalifed
manufacturers should be taken for independent testing for compliance with fnal
productspecifcationsaspartofthecontinuousmonitoringprogramme.
II.6 Monitoring of complaints
Complaintsshouldbehandledinaccordancewithawrittenprocedure.
Awrittenreportofthecomplaint,investigation,recommendationsforactionwhere
relevant,andoutcomeshouldbeavailabletotheprocurementagency.
Anycomplaintconcerningapharmaceuticalproductorbatchofproductssupplied
bythemanufacturershouldbethoroughlyinvestigated.Tenatureofthecomplaint
shouldbecommunicatedtothemanufacturer.
II.7 Cost recovery
It is recommended that the costs of prequalifcation should be covered by the
procurementagency.
If costs are to be recovered, defned transparent procedures should be established
andmanufacturersshouldbenotifedoftheseproceduresinadvance.Costrecovery
shouldbebasedonafee-for-servicesstructure.
41
Module III
Purchasing
Introduction
Pharmaceuticalproductsshouldbepurchasedwiththeaimofprocuringefective,
good-qualitymedicinesatthelowestpossiblecost.Prequalifcationofproductsand
manufacturers as described in Module II contributes to ensuring in advance that
manufacturersandsupplierscandeliverqualityproductsonasustainedbasis.
Tismodulegivesanoverviewofthestrategiesandmethodsusedinpharmaceutical
procurement. Te term procurement in this module relates specifcally to the
purchaseofhealthsectorgoodsfrommanufacturersorsuppliers.Temodulegoes
ontodescribethekeyactivitiesinpurchasingpharmaceuticalproducts,aswellas
therecommendedorganizationalstructureoftheprocurementagencieswhocarry
outthesekeyactivities.
III.1 Strategies for health systems
Although many health systems are decentralizing, some aspects of the health
system are often handled more efciently at a central level. Approval for a list of
essential pharmaceutical products and registration or licensing of pharmaceutical
productsarenormallytheresponsibilityofthecompetentauthorityatthenational
level. Centralized procurement of pharmaceutical products increases the quantity
obtainedundereachpurchasecontractandusuallyreducesthecostoftheproducts.
Programme ofcials should therefore consider consolidating quality assurance
proceduresatthenationallevelandpoolingdemandsforpharmaceuticalproducts
underacommoncontract.
Fourstrategicobjectivesforgoodpharmaceuticalprocurementarerelevanttoany
public sector drug supply system, whether it is managed using public or private
servicesoracombinationofboth.Teseareasfollows(12):
selectionofreliablesuppliersofqualityproducts;
procurementofthemostcost-efectivepharmaceuticalproductsintheright
quantities;
timelydelivery;and
achievementofthelowestpossibletotalcost.
Teseobjectivesshouldbeachievedthroughefcientandtransparentmanagement
refected in an adequate division of the diferent activities and responsibilities;
appropriate standardization, selection, specifcation and quantifcation of
pharmaceutical products; the use of good fnancial management procedures and
competitiveprocurementmethods;andaqualitysystemthatinvolvestheselection
andmonitoringofqualifedsuppliersandtheirproducts.
Itisrecommendedthatastandardprocedurebepreparedtoassistinthecalculation
ofthelowestpossibletotalcost.Tisapproachaimstoensurethatcostsarecalculated
42
inaconsistentmanner,withaconsistentweightgiventoeachofthefactorstaken
intoaccount.
Tobeefective,aprocurementofceshouldensurethatthefollowingprinciplesare
applied.
Prequalifedproductsarepurchasedfromapprovedmanufacturerswhenever
possible.
Procurementandpurchasingproceduresaretransparent.
Activitiesfollowformalwrittenproceduresthroughouttheprocess,including
explicitcriteriaforawardingcontracts.
Purchasing is based on competitive procurement methods, except for very
smalloremergencyorders.
Members of the purchasing groups purchase all contracted items from the
supplierswhoholdthecontract.
Purchasing and tender documents list all pharmaceutical products by their
INNornationalgenericnames.
Suppliersareselectedandmonitoredthroughaprocessthattakesintoaccount
productquality,servicereliability,deliverytimeandfnancialviability.
Intellectualpropertyrightsarerespectedinaccordancewithbestpracticeand
internationallaw.
Considerableeforthasbeenputintothedevelopmentofappropriatepoliciesand
proceduresfortheprocurementofhealthsectorgoods(pharmaceuticals,vaccines
and condoms) by the World Bank. Te reference documents are the standard
bidding documents (13) and the accompanying technical note (14). Although
thesedocumentsaredesignedtomeettheWorldBanksspecifcrequirements,they
includemuchsoundguidanceforusebyallinvolvedintheprocessesofprocuring
healthsectorgoods.
III.2 Procurement methods
Although there are diferent methods of procurement, they all involve a number
of common activities that must take place beforehand. Tese activities are the
establishmentoftechnicalspecifcations,quantifcationofrequirements,issuingof
some form of tender, and selection of product(s) and manufacturer(s) preferably
basedonprequalifcation.
Responsestotendersshouldbeexaminedtoensurethatofershavebeenreceived
frominvitedsuppliersandthattheofersaresubstantiallyresponsivetotheterms
andconditionsofthetender.Awardsshouldbemadetothemakerofthelowest
acceptablebidthatmeetsthetermsandconditionsofthetender.Disqualifcation
oflowbiddersshouldbedocumentedandformpartofthetenderrecord.Following
a review of the adjudication by an independent panel, the companies should be
informed of the outcome of the tender, and a contract should be awarded to the
successfulcompany.Tecontractmustsubstantiallyrefectthetermsandconditions
detailedinthetender.
Abriefdescriptionofdiferentprocurementmethodsisgivenbelow.
43
III.2.1 Restricted tender
In a restricted tender, also called a closed bid or selective tender, interested
suppliersareapprovedinadvancethroughaprequalifcationprocess.Tistypeof
procurement is often referred to as limited international bidding (LIB) which
is an invitation to competitive bids (ICB) conducted by direct invitation to all
prequalifedsuppliers.
Procurementagenciesshoulduserestrictedtenderstoinvitebidsfromprequalifed
suppliersforallhealthsectorgoodsandserviceswheneverpossible.
III.2.2 Competitive negotiation
Tismethodisalsoreferredtoasinternational/nationalshopping.Tebasisofthis
methodisthecomparisonofpricequotationsobtainedfromseverallocalorforeign
suppliers. Usually, quotations are solicited from a minimum of three suppliers to
ensurecompetitiveprices.
Tismethodisappropriateforprocuringsmallamountsofreadilyavailableproducts.
However, its use should be explicitly justifed, and approval should be obtained
fromseniormanagement.Onlyprequalifedsuppliersshouldbeused.
III.2.3 Direct procurement
Indirectprocurement,productsareobtaineddirectlyfromasinglesourcewithout
applyingtherequirementsofatenderprocessorcomparingpricequotations.
Normally direct procurement is not recommended, but it may be used when
thereisonlyoneprequalifedsourcefortheproducttobeprocured.Ahistoryof
reasonablepricesfortheproductinquestionshouldbeassessedtonegotiatethe
pricewiththesupplier.
III.2.4 Open tender
Open tender is the formal procedure by which all manufacturers, national and
international,areinvitedtobidforthesaleofgeneralgoods.Teterminternational
competitivebidding(ICB),whichisanopentendertoallmanufacturers,isoften
used.
Opentenderingisnotappropriateforhealthsectorgoods,becauseitmaybedifcult
toestablish,beforeacontractisawarded,whetherunknownbidderswillbeableto
supply products of the required quality in the required quantities on a sustained
basis.
III.3 Quality assurance in purchasing
Teprocurementagencyshouldhaveadocumentedinfrastructureforpurchaseand
procurementofhealthsectorgoodsandservices,whichshouldaimtoensurethat
pharmaceuticalproductsareofthequalityrequiredfortheirintendeduse.Quality
Module III
44
assurancethereforeincorporatesGMPandotherfactors,someofwhichareoutside
thescopeoftheseguidelines,suchasproductdesignanddevelopment.
III.4 Key activities in purchasing
III.4.1 Product selection and specifcation
Te selection of pharmaceutical products based on a national formulary or on
the essential medicines list is recommended. WHOs Model Formulary (15) and
Model Essential Medicines List (4) identify the most cost-efective and afordable
pharmaceutical products to treat prevailing health problems. Tey are updated
regularly and are made freely available for adaptation by countries. Te health
systems of many industrialized and developing countries have used the essential
medicinesconceptfordecadestouseexistingresourcesefectively.Becausetheuse
ofanationalformularyreducesthenumberofproductsused,supplymanagement
activitiesandinventorycarryingcostsareminimized.
Mechanismsforprocurementofnon-essentialpharmaceuticalproductsbypublic
andprivatehealthsystemsshouldbeavailable.Procurementofsuchproductsshould
beexplicitlyjustifedandsubjecttoapprovalbyauthorizedofcials.
Procurement and tender documents should list pharmaceutical products by their
INNornationalgenericnames.
Eachproductselectedshouldbeavailableinadosageformwhichofersacceptable
safety, efcacy and quality, including acceptable stability and shelf-life under the
recommendedstorageconditions.
If two or more pharmaceutical products appear to be similar according to these
criteria,thechoicebetweenthemshouldbemadeafteracarefulevaluationoftheir
relative efcacy, safety, quality, cost, lead-time and availability from prequalifed
manufacturing sites. When comparing costs of pharmaceutical products, the
cost of the whole course of treatment, not only the unit cost, should be taken
into consideration. Te choice may also be infuenced by other factors such as
transportationcharges,storagerequirementsandshelf-life.
III.4.2 Product quantifcation
All requests for products should include quantities and required delivery dates.
Accurate quantifcation of needs is essential to avoid shortages or excess stocks.
Shortages could lead to patients not being treated or being improperly treated.
Excessstockscouldleadtoadditionalstoragecostsandexpiryofproductsbefore
theyareused.
Tepossiblemethodsofproductquantifcationincludetheconsumptionmethod,
themorbiditymethod,andtheadjustedorextrapolatedconsumptionmethod.
Te consumption method uses records of past consumption of individual
pharmaceuticalproducts.
45
Te morbidity method estimates the need for specifc pharmaceutical products
accordingtotheincidenceofcommondiseases,thenumberofpatientsattending
healthcarefacilitiesandtreatmentpatternsforthediseasestreated.Adherenceto
standardtreatmentguidelineswillmaketreatmentpatternsmorepredictable.
Te adjusted or extrapolated consumption methodusesdataondiseaseincidenceand
drugconsumptionfromastandardsupplysystemandextrapolatestheutilization
ratetothesupplysystemunderconsideration.
Te consumption method is the most reliable method provided that the
consumption records are accurate, the supply pipeline has been consistently full
andnomajorchangesareanticipatedinthenearfuture.Otherwise,oneoftheother
methodsshouldbeusedtoenableamoreaccuratequantifcationofprocurement
requirementstobemade.
Ifsufcientdataareavailable,themorbiditymethodofquantifyingdrugrequirements
canbeusedtodetectdiscrepanciesinpastconsumptionpatterns,whichcouldbe
indicativeofirrationaldruguseortheftofpharmaceuticalproducts.
III.4.3 Selection of suppliers
Prequalifcationistheprocedurebywhichtheproducts,manufacturersandsuppliers
are assessed before bids are solicited for specifc products. Te prequalifcation
processforpharmaceuticalproductsdevelopedbyWHOisbasedontheprinciples
statedinModulesIandII.
Prequalifcation requires time. However, once a list of prequalifed products and
manufacturers has been prepared, adjudication and awarding of contracts can be
expedited.
Postqualifcationistheprocessbywhichproductsandmanufacturersareassessed
after bids have been received. Tis process may cause delays because, if there are
severalofersfromunknownsuppliers,itwillbenecessarytovalidatetheabilityof
thesesupplierstosupplyproductsoftherequiredqualityintherequiredquantities
beforeanycontractsareawarded.Postqualifcationisthereforenotrecommended
forpharmaceuticalproductprocurement.
Procurement agencies should restrict tenders to prequalifed products and
manufacturers, soliciting bids from those manufacturers and suppliers that have
been prequalifed as described in Module II, or by contracting the services of a
procurement agency which meets the recommended norms and standards for
carryingoutprequalifcation.
III.4.4 Adjudication of tenders
Teadjudicationoftendersisanimportantstepinprocurement.Teprocedure,
including the decision-making process, should be transparent and documented.
Decisions taken should ensure both appropriate quality and lowest cost to the
procurementagency.
Module III
46
Followingabidtheawardshouldbemadetothesuppliermakingthelowestofer
respondingfullytothebid.Whenconsideringinformationsubmittedonaspectsof
qualityassurance,theprocurementagencyshouldseekexpertadvicetodetermine
iftheoferisfullyresponsive.
When adjudicating tenders, the attention given to the fnancial stability of the
manufacturershouldnotoutweightheconsiderationofmeasurestakentoensure
qualityofproducts.
III.5 Organization and responsibilities
Te key activities of purchasing pharmaceutical products (product selection and
specifcation, quantifcation, prequalifcation and adjudication of tenders) should
be performed by diferent people, sections or departments with the appropriate
expertiseandresourcesforperformingthespecifcfunctions.
III.5.1 Procurement agency structure
Tesectionordepartmentresponsibleforpurchasingpharmaceuticalproductsin
theprocurementagencyshouldhaveanorganizationalchartindicatingthepositions
andnamesofthepersonnelresponsibleforthekeyactivities,aswellasthereporting
lines.
Purchasing offce
Tepurchasingofceshouldbeappropriatelystafedtoprepareandissuetenders,
andtoaward,administerandmonitorcontracts.Inaddition,itshouldbeableto
ensurethatinformationconcerningproductselection,specifcation,quantifcation,
supplierpreselectionandfundingishandledappropriately.Tisofceshouldfollow
transparent,writtenproceduresthroughouttheprocessofpurchasingandshould
useexplicitcriteriafordecidingtowhomtoawardcontracts.
All staf in the purchasing group must sign confdentiality agreements and
declarationsofconfictofinterest.
Product selection offce
Acommitteeshouldberesponsibleforidentifyingproductstobepurchasedfrom
theessentialmedicineslistorthenationalformulary.Ifsuchacommitteedoesnot
exist,anadhoccommitteemaybesetupforthispurpose.
Each selected product should have standard specifcations, including the dosage
form, pack size, acceptable shelf-life and any other information necessary (e.g.
storageconditions).
Quantifcation offce
Tisofceshouldberesponsibleforensuringthefollowing.
Tequantitiesorderedarebasedonareliableestimateofactualneed.
Procurement takes into consideration long-term contracts to achieve
47
economiesofscaleandreduceworkinprequalifcation.Tisapproachapplies
tobothcentralizedanddecentralizedsystems.
Procurementtakesintoaccountthepotentialbeneftsofjoiningwithother
procurementagenciesandpoolingrequirements.
Productsaredeliveredaccordingtorequesteddeliverydates.
Finance offce
Tereshouldbemechanismsinplacetoensurereliablefnancingforprocurement.
Goodfnancialmanagementproceduresshouldbefollowedtoensurethatfnancial
resourcesareusedwithmaximumefciency.
Funds should be allocated before the tender is issued, and should be released in
accordancewiththepurchasecontract.
Quality offce
Prequalifcation procedures should provide assurance that the pharmaceutical
products purchased are of acceptable quality and meet applicable international
standardsasdescribedinModuleII.
Adequate laboratory services should be available to test pharmaceutical products
independently according to specifcations and standards. Random sampling and
testingshouldbecarriedoutbeforeandafterpurchase.
Te procurement agency (contract-giver) may decide to contract the services of
an agency (contract-acceptor) with expertise in technical assessment of product
dataandinformationand/orinspectionofmanufacturingfacilities.However,the
contract-giverremainsresponsiblefortheimplementationandmonitoringofthese
activities.
Management oversight
Procurementshouldbeplannedproperly,andprocurementperformanceshouldbe
monitoredregularly.
Anindependentcommitteeshouldreviewadjudicatedtenders.Committeemembers
shouldhavefnancial,legalandprogrammeplanningexpertiseandexperience.
III.5.2 Responsibilities
Each staf member who undertakes procurement or provides support to
procurement should have a job description which clearly describes his or her
tasks and responsibilities. All staf must have signed confdentiality agreements
and declarations of confict of interest before they carry out any tasks related to
purchasingofpharmaceuticalproducts.
Teresponsibilityplaceduponanyindividualshouldnotbemorethanthatperson
canhandle.Tereshouldnotbeanygapsoroverlapsintheareasofresponsibility.
Module III
48
III.6 Monitoring of performance of prequalifed manufacturers
Tere should be a procedure for continuous monitoring of prequalifed products
andmanufacturers,whetherornotthemanufacturerissupplyingproduct(s).
Ifadecisionistakentoremoveaproductormanufacturerfromtheprequalifcation
list,themanufacturershouldbenotifed.Allrecipientsofthelistshouldbeinformed
accordingly.
Performance of manufacturers and product compliance should be monitored.
Monitoringshouldincludeatleastthefollowingaspects:
samplingandtestingofsamplesforqualitycontrol;
verifcation that the product batches supplied have been manufactured
in compliance with standards and specifcations accepted in the product
information;
pharmacovigilance;
monitoringofcomplaints;
reinspectionofmanufacturingsites;
reassessmentofproductinformation;
monitoringofdirectandindirectproductcosts;and
monitoringofadherencetodeliveryschedules.
Te monitoring process should include continuous commercial monitoring that
includes tracking of lead-time and monitoring for compliance with all of the
contracttermsandconditions.
Inaddition,thequalityofthepharmaceuticalproductssuppliedshouldbemonitored.
Tisincludessamplingandindependenttestingoforderedanddeliveredproducts.
Testsshouldincludeatleastvisualexamination;shelf-life;compliancewithlabelling,
packagingandshippinginstructions;andlaboratoryanalysiswhenappropriate(e.g.
identifcationorassay).
Tere should be an information system that keeps track of the value of contracts
awarded,thevalueoftotalpurchasesfromeachsupplierperyearandtheperformance
foreachtender(e.g.speedofdeliveryandcompliancewithspecifcations).
Tesectionordepartmentoftheprocurementagencyresponsibleforprequalifcation
of products and manufacturers should schedule routine requalifcation at
predeterminedintervalsasdescribedinModuleVI.
III.7 Patents
In evaluating product information during prequalifcation and during tendering,
information regarding the patent status should be requested. No infringement of
patentsbyanyUnitedNationsorotherprocurementagencyshouldoccur.
Apersonwithintheprocurementagencyshouldbeidentifedashavingresponsibility
for checking the patent status of a particular product or formulation and to
recommend actions to be taken regarding the protection of intellectual property
49
rightsfortheproduct.Tispersonwilloftenbeamemberofthelegaldepartment
oftheorganization.
Countriesrequestingproductsfromprocurementagenciesshouldberesponsiblefor
ensuringthattheproductssuppliedcomplywiththedestinationcountryslegislation
onregistration/licensingstatusandpatentregistrationorrestrictions.
III.8 Donations
Any procurement agency receiving donations should handle donated drugs in
accordance with a written procedure to ensure that patients receive products of
known,appropriatequality.
WHOs Guidelines for drug donations (16) outline the key issues. Te principles
establishedintheseguidelinesshouldbefollowed.
Module III
50
Module IV
Receipt and storage of purchased products
Introduction
Teprocurementagencyshouldensurethatthepharmaceuticalproductspurchased
arereceivedandstoredcorrectlyandincompliancewithapplicablelegislationand
regulations. Products should be received and stored in in such a way that their
qualityandintegrityispreserved,batchtraceabilityismaintainedandstockcanbe
rotated.Tismodulefocusesonqualityassuranceandqualitycontrolduringreceipt
andstorageofproducts.
Quality control is concerned with sampling, specifcations and testing as well as
withtheorganization,documentationandreleaseprocedureswhichensurethatthe
necessaryandrelevanttestsarecarriedout,andthatmaterialsorproductsarenot
released for use until their quality has been judged satisfactory for their intended
purpose.
Eachprocurementagencyshouldhaveaccesstoaqualitycontroldepartment,which
should meet the general requirements for facilities, policies and procedures, staf
expertise,experienceandtrainingasspecifedinModuleI,aswellastherequirements
outlinedinModuleIIunderAnalysisofsamples.Tequalitycontroldepartment
mustbecapableofundertakingthefullrangeoftestsrequired,orofmanagingany
subcontractingofsuchworktothirdpartiescorrectlywhileretainingresponsibility
forthequalityoftheworkdone.
TeprinciplesestablishedintheWHO guidelines for good storage practice (17)(see
Appendix14)shouldbefollowedthroughoutthestepsdescribedinthismodule.
IV.1 Pre-shipment quality control
Eachbatchoffnishedproductshouldbetestedinalaboratorytodeterminethatit
conformssatisfactorilytoitsfnishedproductspecifcation,priortosupply.
Inlieuoftestingbytheprocurementagency,acertifcateofanalysismaybeaccepted
fromthesupplier,providedthattheagencyestablishesthereliabilityofthesuppliers
analysis through appropriate periodic validation of the suppliers test results and
throughon-siteauditsofthesupplierscapabilities.
Productsfailingtomeettheestablishedspecifcationsoranyotherrelevantquality
criteriashouldberejected.
IV.2 Receipt of stock
Receivinganddispatchbaysshouldprotectmaterialsandproductsfromtheweather.
Receivingareasshouldbedesignedandequippedtoallowcontainersofincoming
materialstobecleanedifnecessarybeforestorage.
51
Allincomingmaterialsandfnishedproductsshouldbequarantinedimmediately
afterreceiptuntiltheyarereleasedforuseordistribution.Importedpharmaceutical
products should be quarantined until test results confrm that the products meet
all of the requirements, specifcations, terms and conditions of the purchase
order.Areviewofcertifcatesofanalysisshouldbemadetoconfrmthatwhathas
been delivered is what was ordered and is certifed by the manufacturer to meet
specifcations.
Uponreceipt,eachincomingdeliveryshouldbecheckedforcorrespondencebetween
the order, the delivery note and the suppliers labels. Te consignment should be
examinedforintegrityofpackagesandseals,andforuniformityofthecontainers.
Should the delivery comprise more than one batch, it should be subdivided
according to the suppliers batch number. Containers should be cleaned where
necessaryandlabelled,ifrequired,withtheprescribeddata,e.g.labeldescription,
batch number, type and quantity. Each container should be carefully inspected
forpossiblecontamination,tamperinganddamage,andanysuspectcontainersor
the entire delivery should be quarantined. Damage to containers and any other
problemthatmightadverselyafectthequalityofthematerialshouldberecorded
andinvestigated.
Tepersonresponsibleforreceivingthegoodsshouldbeindependentoftheperson
responsibleforpurchasingthegoods.
IV.3 Postprocurement quality control
IV.3.1 Sampling
Te procedures for receipt of supplies should include random sampling for
independent laboratory analysis to ensure that pharmaceutical products meet the
required standards. Sampling should be performed in accordance with a written
procedure.Productsmayalsoberandomlysampledattheendofthedistribution
chain and sent for independent analysis. Representative samples should be taken
fromcontainersintheconsignment.Tesamplesshouldbeanalysedforcompliance
withtheproductspecifcation.
Samplesshouldbetakenonlybyappropriatelytrainedandqualifedpersonneland
strictly in accordance with written sampling instructions. Containers from which
sampleshavebeentakenshouldbelabelledaccordingly.
Following sampling goods should be quarantined. Batch segregation should
be maintained during quarantine and all subsequent storage. Materials and
pharmaceutical products should remain in quarantine until an authorized release
orrejectionisobtained.
IV.3.2 Rejected materials
Stringent precautions should be taken to ensure that rejected materials and
pharmaceuticalproductscannotbeused.Rejectedgoodsshouldbeclearlymarked
assuchandstoredseparatelyfromothermaterialsandpharmaceuticalproductsina
Module IV
52
lockedcompoundaccessibleonlytoauthorizedandtrainedresponsiblepersonnel,
whilethematerialsawaitdestructionorreturntothesupplier.Whateveractionis
takenshouldbeapprovedbyauthorizedpersonnelandrecorded.Rejectedmaterials
shouldbehandledinaccordancewithawrittenprocedure.
IV.4 Storage of materials and products
IV.4.1 Staff
Allmembersofstafshouldbetrainedtoobservehighlevelsofpersonalhygieneand
sanitation.Tedutiesandresponsibilitiesofallmembersofstafshouldbeavailable
intheformofawrittenjobdescription.
Personnel employed in storage areas should wear protective or working garments
appropriatefortheactivitiestheyperform.
IV.4.2 Storage areas
Storageareasshouldbeofsufcientcapacitytoalloworderlystorageofthevarious
categories of materials and products, including segregation of rejected, expired,
recalledorreturnedstock.
Adequateventilationshouldbeinplacetocontroltemperatureandrelativehumidity.
Wherespecialstorageconditionsarerequired(e.g.temperatureandhumidity)these
shouldbeprovided,checkedandmonitored.
Precautionsshouldbetakentopreventunauthorizedentryintothestorageareas.
A written procedure for fre control measures should be in place, including
prevention of fre, fre detection measures and fre drills. Fire detection and fre-
fghtingequipmentshouldbeservicedregularly.Smokingshouldnotbepermitted
inthestorageareas.
IV.4.3 Storage conditions
All materials and products should be stored under the appropriate conditions
establishedbythemanufacturerandinanorderlyfashiontopermitbatchsegregation
andstockrotationaccordingtothefrst-in,frst-outrule.
Stock should be stored of the foor and suitably spaced to permit cleaning and
inspection.Palletsshouldbekeptinagoodstateofcleanlinessandrepair.
Storage areas should be kept clean and free of vermin and accumulated waste. A
writtensanitationprogrammeshouldbeavailableindicatingthecleaningandpest-
controlmethodsused,andtheirfrequencyofuse.Safepest-controlagentsshould
beusedwhichwillnotcontaminatematerialsandpharmaceuticalproducts.Tere
should be appropriate procedures for the cleaning up of any spillage to eliminate
anyriskofcontamination.
53
Storageconditionsusedforpharmaceuticalproductsandmaterialsshouldcomply
withtheinstructionsonthelabelwhicharebasedontheresultsofstabilitytesting.
Ingeneral,theinstructionsonthelabelhavethemeaningsgiveninTable1.
258
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 specied 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 dened 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 normal
storage conditions; to be provided to the patient in
a moisture-resistant container
Protect from light To be kept in a light-resistant container
Table 1
Meaning of storage instructions given on the labels of pharmaceutical products
Incertaincases,e.g.withfreeze-sensitivevaccines,productsthathavebeenstored
belowthetemperaturespecifedonthelabelshouldbedestroyed.Freeze-sensitive
productsshouldbeequippedwithafreeze-watchmonitoringdevice.
Teequipmentusedformonitoringshouldbecalibratedatsuitablepredetermined
intervals and the results should be recorded and retained. All monitoring 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 legislation. Temperature
mappingofthefacilityshouldbewelldesignedtosupportassuranceofuniformity
ofthetemperatureacrossthestoragefacility.Itisrecommendedthattemperature
monitorsshouldbeplacedintheworst-caseareasofthefacility.Recordedtemperature
monitoringdatashouldbeavailableforreview.
Equipmentusedformonitoringshouldbecalibratedatdefnedintervals.
IV.4.4 Labelling and containers
All materials and pharmaceutical products should be stored in containers which
do not adversely afect the quality of the material or products, and which ofer
adequateprotectionfromexternalinfuences,includingbacterialcontaminationin
somecircumstances.
Allcontainersshouldbeclearlylabelledwithatleastthenameofthematerialor
product, the batch number, the expiry date or retest date, the specifed storage
conditions and reference to the relevant pharmacopoeia where applicable. Only
authorizedabbreviations,namesorcodesshouldbeused.
Module IV
258
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 specied 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 dened 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 normal
storage conditions; to be provided to the patient in
a moisture-resistant container
Protect from light To be kept in a light-resistant container
Table 1
Meaning of storage instructions given on the labels of pharmaceutical products
54
IV.4.5 Miscellaneous and hazardous materials
Materialswhichmayafectothermaterialsstoredintheirvicinityshouldbehandled
in accordance with a written procedure. Rodenticides, insecticides, fumigating
agentsandsanitizingmaterialsshouldnotbepermittedtocontaminateequipment,
starting materials, packaging materials, in-process materials or fnished products.
Toxic substances and fammable materials should be clearly marked as such and
shouldbestoredinsuitablydesigned,separate,enclosedareasasrequiredbynational
legislation. Flammable substances should be kept away from corrosive or oxidant
substancesatalltimes.
IV.4.6 Stock control
Stock rotation and control is best maintained by the use of a proprietary stock
control system. Care must be taken to select a system that can manage the rigid
requirements for batch number control and expiry dating which are essential for
handling pharmaceutical products. Many commercial systems lack these features.
Incaseofdoubtadviceshouldbesoughtfromcompetentexperiencedpersonnel.
Periodicstockreconciliationshouldbeperformedcomparingactualandrecorded
stocklevels.
All signifcant stock discrepancies should be subjected to investigation as a check
againstinadvertentmix-upsand/orincorrectissue.
Inmanufacturingfacilities,partlyusedcontainersofmaterialsandpharmaceutical
products should be securely reclosed and resealed to prevent spoilage and/or
contaminationduringsubsequentstorage.Materialsandpharmaceuticalproducts
from containers which are open or partly used should be used up before a new
containerisopened.
Damaged containers should not be issued unless it is certain that the quality of
the material inside is unafected. Where possible, damaged containers should be
broughttotheattentionofthepersonresponsibleforqualitycontrol.Anyaction
takenshouldbedocumented.
Control of obsolete and outdated materials and products
All stock should be checked regularly for obsolete and outdated materials and
pharmaceuticalproducts.Alldueprecautionsshouldbeobservedtopreventissue
ofoutdatedmaterialsandpharmaceuticalproducts.Tehandlingofsuchmaterials
shouldbesubjecttoawrittenprocedure.
Recalled materials
Recalled materials should be handled in accordance with a written procedure.
Writtenrecordsofallmajoractionswiththesignaturesofthepersonresponsiblefor
carryingouteachactionshouldbemaintained.
Recalledproductsshouldbeidentifedandstoredseparatelyinasecureareauntil
55
a decision has been taken on their fate. Te decision should be made as soon
as possible. An assessment may be made only by an appropriately qualifed and
experiencedmemberofstaf.
Returned goods
Returnedgoodsshouldbehandledinaccordancewithawrittenprocedure.Tey
should be placed in quarantine until a decision has been taken on their fate.
Productsreturnedfromthemarketshouldbedestroyedunlessitiscertainthattheir
qualityissatisfactory.Inthatcase,theymaybeconsideredforresale.Tenatureof
the product, any special storage requirements, its condition and history, and the
timeelapsedsinceitwasissuedshouldallbetakenintoaccountinthisassessment.
Whereanydoubtarisesoverthequalityoftheproduct,itshouldnotbeconsidered
suitable for reissue or reuse, although basic chemical reprocessing to recover the
activeingredientmaybepossible.Anyactiontakenshouldberecorded.
Waste materials
Wastematerialsshouldbehandledinaccordancewithawrittenprocedure.Provision
shouldbemadefortheproperandsafestorageofwastematerialsawaitingdisposal.
Toxic substances and fammable materials should be stored in suitably designed,
separate,enclosedcupboards,asrequiredbynationallegislation.
Wastematerialshouldnotbeallowedtoaccumulate.Itshouldbecollectedinsuitable
receptaclesforremovaltocollectionpoints outsidethebuildings anddisposed of
safelyandinasanitarymanneratregularandfrequentintervals.
IV.4.7 Documentation: written instructions and records
Writteninstructionsandrecordsshouldbekeptwhichdescribethestorageprocedures
anddefnetheroutesofmaterials,pharmaceuticalproductsandinformationthrough
theprocurementagency,includinghandlingofexpiredstock.Batchtraceabilityis
essentialintheeventofaproductrecall.
Permanentinformation,writtenorelectronic,shouldexistforeachstoredmaterial
or product to indicate recommended storage conditions, any precautions to be
observedandretestdates.Pharmacopoeialrequirementsandothercurrentnational
regulationsconcerninglabelsandcontainersshouldberespectedatalltimes.
Recordsshouldberetainedforeachdelivery.Teyshouldincludethedescriptionof
thegoods,quality,quantity,supplier,suppliersbatchnumber,thedateofreceipt,
assigned batch number and the expiry date. National regulations which state a
periodforretentionofrecordsmustbeobserved.Wherenosuchregulationsexist,
recordsshouldberetainedforoneyearaftertheendoftheshelf-lifeofincoming
products.
Comprehensiverecordsshouldbemaintainedofallreceiptsandissuesofmaterials
and pharmaceutical products according to a specifed system, e.g. by batch
number.
Module IV
56
Module V
Distribution
Introduction
Awell-manageddistributionsystemshouldachievethefollowingobjectives(1).
Maintainaconstantsupplyofdrugs.
Keepdrugsingoodconditionthroughoutthedistributionprocess.
Minimizedruglossesduetospoilageandexpiry.
Maintainaccurateinventoryrecords.
Rationalizedrugstoragepoints.
Useavailabletransportationresourcesasefcientlyaspossible.
Reducetheftandfraud.
Provideinformationforforecastingdrugneeds.
Tismodulefocusesonmeasurestobetakentoensureproductintegrityandquality
during distribution, and outlines the main points. Te principles established in
theWHOguidelines for good trade and distribution practice(18)(seeAppendix15)
shouldbefollowed.
V.1 Transport conditions
Materialsandpharmaceuticalproductsshouldbetransportedinsuchawaythatthe
integrityofthematerialorpharmaceuticalproductisnotadverselyafectedandthat
appropriatestorageconditionsaremaintained.
Everyprecautionshouldbetakentominimizetheriskoftheftandfraud.
V.2 Cold chain
Specialcareshouldbeexercisedwhenusingdryiceincoldchains.Inadditionto
addressingsafetyconcerns,itisnecessarytoensurethatthematerialorproductdoes
notcomeincontactwiththedryice,asthismayadverselyafectthequalityofthe
product,e.g.asaresultoffreezing.
V.3 Temperature monitoring and records
Whereappropriate,theuseofdevicestomonitorconditionssuchastemperature
duringtransportationisrecommended.Recordsshouldbeavailableforreview.
V.4 Delivery order
Te dispatch and transport of materials and pharmaceutical products should be
carriedoutonlyafterreceiptofadeliveryorder,whichhastobedocumented.Tere
shouldbeaproceduretoensurethatproductsaresuppliedtoauthorizedrecipients
only.
57
V.5 Dispatch procedures and policies
Rules for dispatch procedures should be established according to the nature of
thematerialsandpharmaceuticalproductsbeingdispatchedandaftertakinginto
accountanyspecialprecautionstobeobserved.Anyspecialpackagingrequirements
formovementofgoodsmustbemet.Somegoodsmayrequirespecialprotection
beforetheycanbeshippedbyboatorbyair.Alllegislationthatmayafectthese
requirementsmustbefulflled.
V.6 Dispatch containers
Teoutsidecontainershouldoferadequateprotectionfromallexternalinfuences
andshouldbeindeliblyandclearlylabelled.
Productsshouldbepackedinsuchawayastominimizetheriskoftheft,e.g.by
usinglockedcontainersorbyshrink-wrappingentirepalletsinplastic.
V.7 Dispatch records
Recordsfordispatchshouldberetained,statingatleastthefollowing:
dateofdispatch;
customersnameandaddress;
product description, e.g. name, dosage form and strength (if appropriate),
batchnumberandquantity;and
transportandstorageconditions.
V.8 Traceability
Recordsofdistributionshouldcontainsufcientinformationtoenabletraceability
oftheproductfromthepointofsupplytotheenduser.
Traceabilityofgoodsiscrucialincaseoftheneedforproductrecalls.Itwillalsohelp
todetecttheftandfraud.Anydiscrepanciesshouldbeinvestigatedandfollowedup
byappropriatemeasurestotacklepossiblesecuritybreaches.
V.9 Port of entry
All conditions required for storage should be achievable at the port of entry of
goods.Tisisparticularlyimportantforalltemperature-sensitiveproductsshipped
toportswheretemperaturesmaybelesswellcontrolled.Specifcarrangementsmay
needtobemadewithlocalhandlingagentsandcustomstoensurespeedyhandling
andclearance.
Security measures to prevent theft, fraud and bribery should be in place during
storageattheportofentry.
V.10 Packaging of products and materials
If any packaging or repackaging is required because of breakages, all the policies
andproceduresdescribedinWHOGMPguidelines(3)shouldbefollowedintheir
entirety.
Module V
58
Module VI
Reassessment
Introduction
Te quality of all products and services procured in accordance with this Model
should be continuously monitored. Reassessment will be required to ensure that
the products procured continue to meet the norms and standards defned. Tis
module briefy outlines the principles of routine and non-routine assessment of
manufacturers,productsandcontracted-outservices.
VI.1 Re-evaluation of manufacturers
Re-inspectionofmanufacturersshouldtakeplaceatregularintervalsatleastevery
threeyears.
Manufacturers should inform the procurement agency immediately of any
changes to the manufacturing site or equipment that may have an impact on its
prequalifcation.
Non-routinerequalifcationmayberequiredinthefollowingsituations:
incaseofanyomissionofinformationintheinitialassessment;
if false or misleading information is suspected during the follow-up
assessment;
ifchangesareimplementedthatmayhaveanimpactontheprequalifcation
ofthemanufacturingsite,suchaschangestokeypersonnelororganizational
structure,changestoequipment,apparatusorthemanufacturingprocess,or
therenovationoradditionoffacilitiesthatneedvalidation,commissioningor
re-inspection;or
ifacomplaintconsideredtobeseriousinnaturehasbeenreceived.
Teprocurementagencyshould suspendor withdrawaprequalifedfacilityfrom
theprequalifcationlistifthereisevidenceofnon-compliancewiththerequirements
forprequalifcation.
VI.2 Re-evaluation of products
Productinformationshouldbereviewedeverythreeyears,orsoonerifmajorchanges
occurinthemeantime.
Underroutinecircumstancestherewillbenorequirementforthemanufacturerto
retesttheproductaspartofthere-evaluationprocess.However,circumstancesmay
ariseinwhichretestingisnecessary.
Manufacturersshouldinformtheprocurementagencyofanycontemplatedchanges
totheproductthatmayafectitssafety,performance,efcacyorquality.Withregard
totheproduct,manufacturersshouldforinstancereportthefollowingchanges:
changeofmanufacturingprocess,siteorequipmentrelatingtotheproduct;
59
changeofcontractmanufacturers;
changeofpharmaceuticalproductreleasecontrollaboratories;
changedsuppliersofstartingmaterialsorcontainerorclosure;
changestotheformulationorcompositionoftheproduct;
newanalyticalmethodinthetestingofstartingmaterial,intermediateorfnal
product;or
changeofspecifcations.
Sufcient time must be allowed for the necessary testing, e.g. stability testing or
bioequivalencetesting.Basedontheinformationsubmitted,thepersonresponsible
for prequalifcation should decide whether to approve the changes or whether to
request additional data which demonstrate the equivalence of the product to the
onethathasbeenprequalifed.
Te section or department responsible for prequalifcation of products and
manufacturersshouldinformthepurchasingofceaboutthechangesandtheresult
oftheevaluationofsuchchanges.
Non-routinere-evaluationofproductsshouldbedoneinthefollowingcases.
If any omission by the manufacturer in the initial evaluation procedure, or
during the follow-up activities, is evident in relation to the requirements,
including compliance with quality system standards and failure to notify
complaints.
If any batch or batches of supplied product(s) are documented by the
procurementagencynottobeincompliancewiththeagreedspecifcationsof
theproductortorevealfailure(s)regardingsafety,performanceorqualityof
thedevice.
Iftheinvestigationofacomplaintconsideredleadstotheconclusionthatthe
qualityand/orsafetyoftheproductisinquestion.
Ifanyfraudormisconductbythemanufacturerisevident.
Ifanybatchorbatchesofproduct(s)wassuppliedandisconsiderednottobe
incompliancewiththeagreedspecifcationoftheproduct.
If a complaint considered to be serious in nature had been received by the
organization.
Incasesofchangesorvariationstoproducts,theWHOguidelinesMarketing
authorization of pharmaceutical products with special reference to multisource
(generic) products: a manual for drug regulatory authorities(6)giveguidanceon
whentoproceedwithwhichtypeofre-evaluation.
If,intheopinionoftheorganization,changesmadeinthesourcingofthe
API,formulation,manufacturingmethod,facilityorotherproductionaspects
requirethatareassessmentbemade.
Ifsupplyhasbeensuspendedforoneyearorlonger.
VI.3 Monitoring of contracted-out services
VI.3.1 Storage and distribution
Monitoring of the performance of contractors and follow-up of non-compliance
Module VI
60
shouldbecarriedoutaccordingtoawrittenprocedure.Itshouldincludecontinuous
monitoring,aswellasperiodicreviewandrenewalofthecontract.
Continuousmonitoringshouldincludetrackingofcost,orderanddeliverystatus,
lead-time and compliance with contract terms and conditions. A management
informationsystemshouldbeinplaceforthispurpose.Tereshouldbecontinuous
qualitycontrolofpharmaceuticalproductssuppliedincludingrandomsamplingand
aprocedurefordealingwithcomplaints.Teprocurementagencyshoulddocument
any reported problems with quality control or service and inform the contractor
of each problem. Continuous monitoring should also include compliance of the
contract-giverwithcontractconditions,andcorrectionofanyfactorsthatprevent
thecontract-acceptorfromfulfllingthespecifedduties.
Periodicreviewofthecontractshouldbebasedonanassessmentofthecontractors
overallperformance.Tecriteriaoutlinedformonitoringofprequalifedproducts
andmanufacturers(seeSectionIII.6)alsoapplytomonitoringofcontract-acceptors
whostoreanddistributepharmaceuticalproducts.
VI.3.2 Quality control laboratories
Contracted laboratories should comply with the principles of good laboratory
practice(GLP)(19).Teaccreditationstatusalonedoesnotguaranteecompliance
with GLP. Te performance of contracted laboratories should be continuously
monitored.
VI.3.3 Contract research organizations
Contract research organizations (CROs) should be inspected as part of the
assessment process to verify that raw data correspond to submitted data, and to
assesscompliancewithstandardsduringtheconductofclinicalandbioequivalence
studies. Monitoring and requalifcation should ensure that the principles of good
clinical practices (GCP) (20), good practices for quality control laboratories (10)
andGLP(19)areadheredto.
Conclusion
A trend towards the introduction of quality systems principles in the internal
operations of organizations concerned with pharmaceutical quality assurance has
led to the publication of the WHO document Quality systems requirements for
national good manufacturing practice inspectorates (21), which outlines principles
for implementing a quality management system (see Appendix 16). Te quality
management principles described are valid for all key aspects of procurement
and have been considered in designing and testing the model quality assurance
systempresentedinthisdocument.Itisrecommendedthatprocurementagencies
implementthisModeltoensureaharmonizedapproachtoqualityassuranceinall
keyactivitiesofprocurement.
Teestablishmentandoperationofaqualitysystemisanessentialelementinthe
mutualrecognitionoftheoutcomesofprequalifcationactivities.Onceaharmonized
61
systemisinplace,agencieswillbeabletoexchangeinformationonassessmentof
productinformationandinspectionfndings.
Sharingthisinformationwilleliminatetheneedforduplicationofprequalifcation
procedures. Reliance on a harmonized system for the procurement of products
meeting predefned norms and standards will expedite procedures for obtaining
quality products at competitive prices. Te beneft will be greatest for those
medicinesforwhichdemandishigh,e.g.medicinesforprioritydiseasesafecting
alargepartoftheworldspopulationinareaswheredrugregulatorycapacitiesand
healthbudgetsarelimited.
Module VI
62
References
1. 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 and
inspection.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 pharmaceutical
productsforpurchasebyUnitedNationsagencies.In:WHO Expert Committee
on Specifcations for Pharmaceutical Preparations, Thirty-seventh report.Geneva,
WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.908),Annex
8(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,periodicreviewsand
variations,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, Annex
6 (WHO/DMP/RGS/98.5) (http://mednet3.who.int/prequal/documents/WHO_
DMP_RGS_98_5_R.pdf).
8. WHO Certifcation 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/certifcation/certifscheme.shtml).
9. Guide for a quality systems manual in a control laboratory.Geneva,WorldHealth
Organization,1998(WHO/VSQ/98.04)(http://www.who.int/vaccines-documents/
DocsPDF/www9840.pdf).
10. Goodpracticesfornationalpharmaceuticalcontrollaboratories.In:WHO Expert
Committee on Specifcations 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 Specifcations for Pharmaceutical Preparations, Thirty-
seventh report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReport
Series,No.908),Annex6.
12. Operational principles for good pharmaceutical procurement. Geneva, World
HealthOrganization,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, World
Bank,2000(http://siteresources.worldbank.org/INTPROCUREMENT/Resources/
health-tn-ev2-a4.doc).
63
15. Model formulary 2004. Geneva,World Health Organization, 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 Specifcations for Pharmaceutical Preparations, Thirty-seventh report.Geneva,
WorldHealthOrganization,2003(WHOTechnicalReportSeries,No.908).Annex
9(http://www.who.int/medicines/library/qsm/good_storage.pdf).
18. Good trade and distribution practices for pharmaceutical starting materials. In:
WHO Expert Committee on Specifcations for Pharmaceutical Preparations,
Thirty-eighth report. Geneva,World Health Organization, 2003 (WHOTechnical
Report 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 Special
ProgrammeforResearchandTraininginTropicalDiseases(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),Annex
3.
21. Quality systems requirements for national good manufacturing practice
inspectorates.In:WHO Expert Committee on Specifcations for Pharmaceutical
Preparations, Thirty-sixth report.Geneva,WorldHealthOrganization,2002(WHO
TechnicalReportSeries,No.902),Annex8.
References
65
Appendix1
Example of a Code of Conduct
1. Introduction
TisCodeofConductmustbefollowedbyappointedstafmembersaswellasall
otherstafinvolved.
Allmembersofstafincludingtemporaryadvisersandexpertsappointedtocarry
outevaluationsandinspectiononbehalfofWHOshouldkeepinmindatalltimes
theimageofWHO.
(InthecontextofthisCodeofConduct,stafandmembersofstafincludecontract
appointments,short-termstaf,advisersandexpertsappointedfortheperformance
ofwork.)
2. Key responsibilities
Eachmemberofstaf,expertandtemporaryadviserhaskeyresponsibilitiestofulfl.
Teoverallobjectiveistoperformthesekeyresponsibilitieswithintheframework
ofthisCodeofConduct.
AninternaloversightframeworkhasexistedwithinWHOsincetheearlydaysof
theOrganization.Itisnecessaryperiodicallytoensurethatallstafunderstandthis
function.TeWHOsummarystatementonWHOsOfceofInternalAuditand
Oversight(IAO)whichdescribesitspurpose,authorityandscopeofwork,should
bereadbyeachmemberofstaf.Tisdocumentsummarizestheexpectationsfor
IAOanditfurnishesdirectionforinternalauditatWHO.
By accepting appointment, staf members pledge themselves to discharge their
functionsandtoregulatetheirconducttoservethebestinterestsofWHO.
In the performance of their duties staf members shall neither seek nor accept
instructions from any government or from any other authority external to the
Organization.
Nostafmembershallaccept,holdorengageinanyofceoroccupation,whichis
incompatiblewiththeproperdischargeofhisdutieswithWHO.
Stafmembersshallconductthemselvesatalltimesinamannercompatiblewith
theirstatusasinternationalcivilservants.
Staf shall avoid any action and in particular any kind of public pronouncement
whichmayadverselyrefectontheirstatus.Whiletheyarenotexpectedtogiveup
their national sentiments or their political and religious convictions, they shall at
alltimesbearinmindthereserveandtactincumbentuponthembyreasonoftheir
internationalstatus.
Appendix 1
66
Stafmembersshallexercisetheutmostdiscretioninregardtoallmattersofofcial
business. Tey shall not communicate to any person any information known to
thembyreasonoftheirofcialposition,whichhasnotbeenmadepublic,except
in the course of their duties or by authorization of the Director-General. At no
timeshalltheyinanywayusetoprivateadvantageinformationknowntothemby
reasonoftheirofcialposition.Teseobligationsdonotceasewithseparationfrom
service.
Anystafmemberwhobecomesacandidateforapublicofceofapoliticalcharacter
shallresignfromtheSecretariat.
Te immunities and privileges attaching to WHO by virtue of Article 67 of the
ConstitutionareconferredintheinterestsoftheOrganization.Teseprivilegesand
immunitiesfurnishnoexcusetostafmembersfornon-performanceoftheirprivate
obligationsorfailuretoobservelawsandpoliceregulations.Tedecisionwhether
towaiveanyprivilegesorimmunitiesofthestafinanycasethatarisesshallrest
withtheDirector-General.
AllstafmembersshallsubscribetotheoathordeclarationassetoutinWHOStaf
Regulations.
Astafmembermaynotactasadelegateorobserverfor,oradviserto,hisorher
government.
A staf member may participate in international or national societies when such
participationisnotinconfictwiththestandardsreferredtoinWHOStafRules
and may represent such societies at an international meeting with the Director-
Generalsauthorization.
A staf member shall obtain the Director-Generals permission before publishing
articleswhosecontentsrefectworkperformedfortheOrganizationorinformation
obtainedarisingoutofsuchwork.
All rights, including title, copyright and patent rights, in any work or invention
producedordevelopedbyastafmemberaspartofhisofcialdutiesshallbevested
intheOrganization.
Misconductmeans:
anyimproperactionbyastafmemberinhisofcialcapacity;
anyconductbyastafmember,unconnectedwithhisofcialduties,tending
tobringtheOrganizationintopublicdiscredit;and
anyimproperuseorattempttomakeuseofhisorherpositionasanofcial
forhisorherpersonaladvantage.
Anyconductcontrarytothetermsofhisoathordeclaration.
2.1 Personal responsibilities
Stafmembersmustbecommittedtoastrongoversightenvironmentandmustgive
IAOtheirfullcooperation.
67
Stafmustobserve,implementandmaintaintheresponsibilitiesinrelationtothe
positioninwhichtheyhavebeenappointed.
Stafmustperformtheworktheyhavebeenallocatedtothebestoftheirabilityand
fnalizetasksinaccordancewiththetimeframessetbyWHO.
2.2 Safety
SafetyistheresponsibilityofWHOstaf,supervisorsandWHOmanagement.It
includesreportingofpossiblehazardsandsuspectedhazardsandtakingthenecessary
precautionsandimplementingsafeguardstominimizesafetyproblems.
Stafinvolvedinactivitieswheresafetyproblemsmayarise,e.g.theinspectionofa
manufacturingsite,shouldobservesafetyrulesandregulationsasrecommendedby
WHO,themanufacturerandnationallegislation.
Staf must wear protective devices such as protective clothing, shields, eye covers
(glasses),earplugs,whererelevant,toprotectthebody,organsandextremitiesfrom
possibleharm.Stafmustusetheirprofessionalknowledgetoensurethattheytake
appropriate care of their own safety. Tis means that should a manufacturer not
provide what is deemed to be adequate personal protection, then the inspectors
shouldrefusetoenteranareaonthegroundsoflackofsafety.
Stafmustobservenationalregulationswhendrivingvehicles.
Staf must be aware of, and take, the necessary precautions when collecting
samples.
Specialattentiontosafetyrequirementsisnecessarywhenperformingsiteinspections.
Tese include aspects in relation to the dosage form and activities observed (e.g.
radioactive pharmaceuticals, hazardous materials, laboratory reagents, equipment
and apparatus, explosions, personnel lifts, ladders, glassware, freezers, steam,
radiation, microbiological hazards, viral and biological products and waste, and
otherrelevantpossiblehazards).
3. Professional competence
3.1 Qualifcations and experience
Testafappointedmusthavetherequiredqualifcationsandexperiencetoperform
thetasksrequired.AnypersonappointedtoperformworkfororonbehalfofWHO
mustindicateifhe/sheisnotsuitablyqualifedtoperformthetask,ordoesnothave
therelevantexperience,beforetakingontheworkorbeingappointed.
WhenpeopleareapproachedtoperformworkonbehalfofWHO,theymustbe
truthfulinprovidingevidenceoftheirqualifcationsandexperience.
Staf must not mislead WHO or procurement agencies in relation to their
qualifcations and/or experience. Any case of misrepresentation of qualifcations
Appendix 1
68
orexperiencewillbetreatedasfraudandmayeventuallyleadtoprosecution.No
futureemploymentinanycapacitybyanyWHOorUnitedNationsorganization
willbepossibleatanytime.
4. Conduct
Duringdailyactivities,stafmustmaintainhighstandardsofethicalconduct.
StafmustobservetheWHOconstitutionandareresponsibleforcomplyingwith
theWHOregulationsandguidelines.
4.1 Integrity and attitude
ToensurethatthebusinessofWHOisconductedefectively,andwithoutimproper
infuence, all staf members must be persons of integrity and observe the highest
standardsofconduct.
WHOmustbeabletorelyuponstaftodotherightthings.
Stafmustbehonestanddependable.
Stafmustbedevotedtoaccuracy,truthfulness,objectivenessandfairness.
Stafmustnotuserestrictedinformationnotavailabletothegeneralpublic
forgainortoadvanceprivateinterests.
Staf must report fndings such as presentation of false, misleading and
fraudulentinformationprovidedtoWHO.
StafshouldmaintainapositiveattitudetowardsWHOanditspoliciesand
projects.
Stafmustbedignifed,diplomatic,tactfulandcourteous.Strong-armtactics
mustbeavoided.
Stafmustnotactwithanairofsuperiorityorspecialauthority.
Staf must use a frm approach when requesting necessary and authorized
information.
StafmembersarethecontactpersonsofWHOandtheiractionwillbethe
basisuponwhichthepublicwilljudge theorganization.Stafmust exhibit
exemplarybehaviouratalltimes.
Astafmemberwhohasanyfnancialinterestinanybusinessconcernwithwhich
he may be required, directly or indirectly, to have ofcial dealings on behalf of
the procurement agency shall report such interests to the Director-General, who
shalldecideontheapplicabilityofStafRegulations.Stafmaynothavefnancial
interestsincompaniestobeevaluatedorinspected.Shareholdingsthroughpension
schemesandothersucharmslengtharrangementswillnotnormallybetakenas
afnancialinterestinthiscontext.Anydoubtsonthismattershouldbereferredto
theWHOInternalAuditOfceforclarifcation.
4.2 Attire, health and hygiene
Good public relations require that all members of staf dress appropriately for
the activities to be performed. Staf should observe WHO guidelines regarding
appropriatedresscode.
69
Stafshouldnormallywearprotectiveclothingforinspections.Inspectorsmustwear
protectiveclothingatleastequivalenttothatwornbyemployeesofmanufacturing
sites (e.g. head covering or masks, when appropriate). Staf should conform to
companyproceduresatalltimes.However,ifcompanyproceduresareconsidered
inappropriatethenthisfactshouldberecorded.
Stafinvolvedininspectionsmustinformsupervisorsormanagersoftheirhealth
statuswhenthiscouldhaveimpactoninspections,aspersonswithcommunicable
diseases,woundsandopenlesionsmaynotbeallowedinareaswhereproductsand
materialareexposed.
Stafareresponsiblefortakingthenecessaryprecautionswhentravelling(e.g.having
theappropriateinoculations).
Stafmustpracticegoodhygieneatalltimes.
4.3 Gifts, meals and favours
Nostafmembershallacceptanyhonour,decoration,favour,giftorremuneration
from any government, or from any other source external to the Organization, if
suchacceptanceisincompatiblewithhisstatusasaninternationalcivilservant.
Astafmemberwhoisoferedanyhonour,decorationorgiftfromsourcesexternal
totheOrganizationshallreportthisofertotheDirector-Generalwhoshalldecide
ontheapplicabilityofStafRegulations.
Nomemberofstafshallreceiveoracceptanythingofvaluefromanymanufacturer
fororbecauseofanyofcialactthathasbeenperformedoristobeperformed.
Staf will not solicit or accept directly or indirectly any gift, gratuity, favour,
entertainmentloanoranyotheritemofmonetaryvaluefrommembersofthepublic
withwhomstafmembershaveofcialrelationships.
Whenperforminginspections,stafmustpayfortheirownmealswheneverpossible
and must make an efort to pay for their own meals even when invited by the
manufacturer,unlessthesituationissuchthatitwillprovokeasceneorcreatean
embarrassmenttoWHO.
4.4 Management relationship
Stafmustpromoteapositiverelationshipwithsupervisorsandmanagers.
4.5 Standard operating procedures
Staf must follow authorized standard operating procedures (SOPs) for the
performanceoftasks.
4.6 Travel and accommodation
Staf must observe WHO regulations, guidelines and SOPs when travelling. Te
relevant procedures shall be followed for planning of visits, meetings, inspections
andotheractivitiessuchasmakingreservationsandpayingforaccommodation.
Appendix 1
70
4.7 Confdentiality and confict of interest
StafmustobservetheWHOpolicy,countryrulesandregulations,andcompany
policywithrespecttoconfdentiality.
Staf must sign and abide by the confict of interest and confdentiality
undertaking.
4.8 Documentation and records
Staf shall follow SOPs and maintain appropriate records as required in the
procedures.
Allinformationprovidedbystafmembersmustbetruthfulandcorrect,including
reportsandrelateddocumentation.
4.9 Contracts and terms of reference
Stafshallperformactivitiesasstipulatedinthecontractoragreementforperformance
ofwork(APW)andtermsofreference(TOR).
4.10 Product fles, evaluation and inspection
Staf shall handle product fles with care and treat all information as confdential
relatingtothetasktobeperformed.
All data submitted initially and as a result of the evaluation, shall be dealt with
in accordance with SOPs and be considered as confdential information between
WHOandthemanufacturer.Allaspectsrelatingtotheinspectionperformedshall
beconsideredasconfdentialbetweenWHOandthemanufacturer.
Staf members shall observe the requirements and undertaking with regard to
confdentialityandconfictofinterest.
4.11 Samples
SamplestakenduringinspectionsshallbeinaccordancewithaWHOSOP,with
theapprovalofthemanufacturer.
4.12 Evaluation and inspection reports
Tereshallbewrittenevaluationandinspectionreportsforeveryproductevaluated,
andeverymanufacturingsiteinspected.
Te reports shall be a true refection of the fndings of the evaluation and
inspection.
4.13 Provision of information and advice
Staf shall not act as consultants to individual companies or manufacturers when
appointedforthepurposesofevaluationorinspectionforaparticularproject,where
thecompanycaninparticularbeneftfromsuchadvice,unlesstheinformationisin
thepublicdomainorgiventoallmanufacturers.
71
Appendix2
Example of a guideline on confdentiality
Te evaluators and inspectors will treat all information submitted and observed
during the inspections and otherwise in connection with the discharge of their
responsibilitieswithregardtotheabove-mentionedproject,asstrictlyconfdential
andproprietarytoWHOorpartiescollaboratingwithWHOinaccordancewith
thetermssetforthbelowandthosecontainedintheattachedprovisionsforteam
membersparticipatinginsitevisitswithinthescopeoftheprequalifcationprocedure
ofpharmaceuticalproducts.Anexampleofaconfdentialityundertakingisshown
attheendofAppendix3.
Evaluatorsandinspectorswilltakeallreasonablemeasurestoensure:
thattheconfdentialinformationisnotusedforanypurposeotherthanthe
evaluationactivitiesdescribedinthisdocument;and
thatconfdentialinformationisnotdisclosedorprovidedtoanypersonwhois
notboundbysimilarobligationsofconfdentialityandnon-useascontained
herein.
Evaluators and inspectors will not, however, be bound by any obligations of
confdentialityandnon-usetotheextenttheyareclearlyabletodemonstratethat
anypartoftheconfdentialinformation:
wasknowntothempriortoanydisclosurebyoronbehalfofWHO(including
bymanufacturers);or
wasinthepublicdomainatthetimeofdisclosurebyoronbehalfofWHO
(includingbymanufacturers);or
hasbecomepartofthepublicdomainthroughnofaultoftheirs;or
hasbecomeavailabletothemfromathirdpartynotinbreachofanylegal
obligationsofconfdentiality.
All personnel involved in prequalifcation and related matters, having access to
confdential information regarding products and manufacturers, should treat
all information submitted and observed during the inspections and otherwise in
connectionwiththedischargeoftheirresponsibilitieswithregardtotheseactivities,
as strictly confdential and proprietary to the procurement agency or the parties
collaboratingwiththeprocurementagency.
72
Appendix3
Example of a guideline on confict of interest
Introduction
Tis document presents policy on confict of interest as it applies to external
evaluatorsandmembersofadvisorycommittees.Tesetwocategoriesaretogether
referred to as consultants for the purposes of these guidelines. An example of a
signedstatementonconfictofinterestisshownattheendofthisAppendix.
Defnitions and principles
Tecommonmeaningofconfictofinterestisaconfictbetweenanindividuals
private or personal interest and his or her duty. However, it may also refer to a
situationwhereanindividualhasseveraldutieswhichconfictwithoutinvolvement
ofanyprivateorpersonalinterests.
A conficting private or personal interest may be fnancial or non-fnancial as
explainedbelow.
Whenadecision-makerorconsultanthasadirectfnancialinterest,howeverslight,
in the matter to be decided, there is a conclusive presumption of bias and the
decision-makerorconsultantwillthusbedisqualifedfromacting.
Where a decision-maker or consultant has a non-fnancial interest, which gives
rise to a reasonable presumption of bias, the decision-maker or consultant will
be disqualifed from acting. Te test here is whether a reasonable observer would
suspect that there is a possibility of bias, not whether that bias actually exists. A
relevant non-fnancial interest may arise, for example, out of personal or family
involvementbetweenadecision-makerorconsultantandapartywhoseinterestsare
afectedbythedecisionorrecommendations.Suchaninterestmayalsoarisewhere
adecision-makerorconsultantisseentohaveprejudgedtheissues,eitherthrough
preconceivedopinionsorpriorinvolvementwiththefactsofacaseonwhichheor
sheisrequiredtomakeadecisiononrecommendations.
Confict of interest in relation to consultants
Tere are a variety of situations in which consultants may fnd themselves in a
situationofconfictofinterestbetweentheirprofessionalactivities(e.g.preparation
ofobjectiveandindependentevaluationsormembershipofindependentcommittees)
andpersonalandprivateinterest(e.g.privateconsultancies,grantstocovertraveland
accommodationatcompany-sponsoredconferences,shareholdings,researchgrantsor
honoraria).Itisrecognizedthatalmostallconsultantshavesomepotentialconfictof
interestbecauseoftheirpresentorpastassociationwiththepharmaceuticalindustry.
73
Some situations of confict of interest are clear-cut and some are more difcult
to determine. If an individual is an employee of, or a retained consultant to, a
pharmaceutical company, there is a clear possibility of confict of interest. If an
individualisanemployeeofagovernmentorganization,doesnoworkonbehalfof
pharmaceuticalcompanies,andisnotinreceiptofgratuitiesorfunding,thereisa
minimalrisk.Betweenthesetwosituationsisaspectrumofpossibilitieswherethe
decisionastowhetherthereisaconfictofinterestmaybelessobvious.
Contractsareunlikelytobeoferedtoconsultantsinanyoneofcategories1to6
listedbelow.
1. Teconsultantworksinthepharmaceuticalindustry,eitherasanemployeeor
asanownerorpartowner(e.g.shareholderinthepharmaceuticalcompanyto
beassessed).
2. Teconsultantreceivesaretainer(fee)fromoneormoreofthepharmaceutical
companieswhoseproductssheorhehastoassessorwhichthenewproduct
islikelytoreplace.
3. Te consultants have a signifcant direct current relationship with one or
morecompanies.Tismaytaketheformof(a)fnancialsupportforacurrent
research project or projects; (b) sponsorship of graduate or postgraduate
students;or(c)companyemployeeswhoareunderthedirectresponsibility
oftheconsultant.
4. Heorshereceivessubstantialfnancialassistanceorexpensiveequipmentto
conductresearchonbehalfofthepharmaceuticalcompany.
5. Teconsultantactsorhasactedasaconsultantforapharmaceuticalcompany
on the product she or he has agreed to assess.Suchaconsultancymayinclude
sponsorship as a speaker, or appointment as chairperson at professional
meetingsconcerningtheproduct,orattendanceonbehalfofthesponsoring
company at national or international professional meetings concerning the
product.
6. Te consultant has provided signifcant input to the planning or conduct
of a clinical trial of the product to be assessed, for example as a principal
investigator, signatory to the study report, or author of any published or
unpublishedpaperorotherreportofthestudy.Participationlimitedtothe
inclusion of patients in a large-scale multicentre study is not considered a
signifcantconfictofinterest.
Aconfictofinterestislesslikelytobeseeninsituations7to10(seebelow).
7. Te consultant has occasional contracts with one or more companies for
particular projects, but does not have a signifcant relationship with any
onecompany.Sheorhehasnotbeendirectlyinvolvedwiththeproductin
question.
8. Teconsultantownsorworksforaconsultancy,whichdoesnotprovideadvice
to the pharmaceutical industry but may provide advice to other industries,
suchasthedevices,foodorpaintindustries.Howeveritisunlikelythatsuch
consultants will have the technical knowledge or experience to qualify as a
consultantinthepharmaceuticalsfeld.
9. Teconsultantoccasionallyprovidesadvicetooneormorecompaniesonthe
designofclinicaltrialstobeconductedpriortosubmissionofanapplicationfor
Appendix 3
74
marketingauthorization,butdoesnothaveasignifcantcurrentrelationship
withanyonecompany(e.g.points1to6above).
10. Te consultant has been invited to attend and contribute to national or
internationalmeetingsorganizedbyprofessionaloracademicassociations.
The responsibility of consultants
Adrugregulatoryauthoritycannotbeawareofalloftheconsultantsinvolvements
and their ramifcations when a contract is ofered. Te onus is therefore on the
consultant to declare in writing any potential confict or what may be seen as a
potentialconficttothestafmemberofthedrugregulatoryauthoritywhonegotiated
thecontractorcommitteemembership.Ifthereisanydoubt,thepotentialconfict
mustbedeclared.Teconsultantmayonlyproceedwiththeevaluationofthedata
ortakeupcommitteemembershipafteranypotentialconficthasbeendiscussed
withthedrugregulatoryauthorityandfoundnottobesignifcant.
Forthisreason,eachevaluationcontractrequirestheevaluatortosignastatement
totheefectthatsheorhehasnocurrentconfictofinterestandthat,iftheriskof
such a confict arises during the evaluation, the drug regulatory authority will be
notifedimmediatelyinwriting.
Te evaluator is expected to cease reading the application immediately she or he
becomes aware of a confict of interest,andreturnitpromptlytothedrugregulatory
authority.Tisclauseappliesalsotothoseinvolvedintheinspectionoffacilities.
Confdentiality
Anydataconcerningacompanysproductwhicharesuppliedbythedrugregulatory
authoritytoaconsultantforreviewarestrictlyconfdential.Asstatedinthecontract,
all materials related to or referred to in the contract must be accepted in strict
confdenceandheldinsafeandsecurecustodyatalltimes.Anapplicationmaybe
discussedonlywiththestafmembersofthedrugregulatoryauthority.
Consultants must be aware of and avoid the possibility of indirect breaches of
confdence. Tere is clearly a potential, consciously or subconsciously, to misuse
informationgainedfromaconsultancyinotherpapersorscientifcpresentationson
theproductinquestion.Suchacasewouldalsoconstituteaconfictofinterest.Te
consultantmustnotuseinformationgainedinthiswayinfuturescientifcpapersor
presentationswithouttheagreementofthecompanyorindividualthatsubmitted
thedata.
Impartiality
To protect impartiality, the company concerned is not informed by the drug
regulatoryauthorityoftheidentityoftheconsultanttowhomapplications,dataor
committeepapersareforwarded.Forthisreason,theconsultantshouldhavenodirect
communicationwiththecompanyconcerningtheproduct.Teconsultantmaynot
75
disclose his or her role to the company, even after a decision on the application
hasbeencompleted.Tisisclearlynotpossibleinthecaseofaninspectorofthe
manufacturingfacility.
Subcontracting the evaluation
A consultant is not allowed to subcontract part or all of an evaluation to any
second person without written permission from the drug regulatory authority. If
thedrugregulatoryauthorityagreestosuchanarrangement,theconsultantmust
ensurethatthesubcontractorisfullyawareoftheprovisionsonconfictofinterest,
confdentialityandimpartialitysetoutinthesenotes.
Ifanypartofanevaluationissubcontracted,thepersonwhoactuallyundertakesthe
workmustalsosignallthereportstowhichsheorhehascontributed.
Appendix 3
76
Example of a confdentiality undertaking
and declaration of Confict of Interest
PROVISIONS FOR EVALUATORS OF PRODUCT INFORMATION
AND FOR INSPECTORS (TEAM MEMBER PARTICIPATING IN
SITE VISITS) WITHIN THE SCOPE OF THE QUALITY
ASSESSMENT 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 confdential
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 confdentiality and non-use as contained herein.
However, you will not be bound by any obligations of confdentiality 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 confdentiality.
You also undertake not to communicate your deliberations and fndings 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 confrm that the information
disclosed by you in the declaration of interest is correct and that no situation of real, potential
or apparent Confict of interest is known to you, including that you have no fnancial 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
77
(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 this
document.
Signed
Name(typewritten)
Organization
Place Date
Appendix 3
78
Appendix4
Example of a standard operating procedure (SOP) for
writing an SOP
1. Title
Standardprocedureforwritingastandardoperatingprocedure(SOP)
285
Appendix 4
Example of a standard operating procedure (SOP)
for writing an SOP
1. Title
Standard procedure for writing a standard operating procedure (SOP)
2. Policy and objective
2.1 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 dene 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. Responsibility
All 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
2.1 TeprocurementagencyshouldhaveanSOPforeachactivityperformedby
theprocurementagency.AllSOPsshouldbeintherequiredformatanddistributed
with care to a predetermined list of personnel. SOPs should be authorized,
implementedandkeptuptodate.
2.2 AllSOPsshouldbewritteninEnglishifanyinternationaluseisexpected,or
inthelocallanguageifrequiredonlybylocalstaf.
2.3 Documentationisaprimenecessityinqualityassurance.Itspurposeistodefne
thesystemofcontrol,toreducetheriskoferrorinherentinoralcommunication,
toensurethatpersonnelareinstructedinthedetailsof,andfollowtheprocedures
concernedinalogical,reproduciblemanner.
2.4 Tere should be a written SOP for every critical or important activity in
the procurement agency. SOPs should be written in the standardized format as
attached.
2.5 AlistshouldbekeptofallSOPsrequiredbytheprocurementagency.
2.6 Management should authorize SOPs prior to their distribution and
implementation.
3. Responsibility
All members of staf should adhere to the SOP when drawing up the SOP. Te
projectmanagershouldsuperviseitsimplementation.
4. Action
4.1 AnypersonmayinitiatethefrstdraftofanSOP.Teheadings(listedbelow)
shouldconformtotheattachedformatandshouldbeusedwhenwritingtherelevant
sectionsoftheSOP.
79
4.2 TeSOPshouldincludeatleastthefollowingheadings:
A.Title
B.Policyandobjective
C. Responsibility
D.Action
E.Addenda
F. Distribution
G.Reviewdate
H.Revisionhistory
Tefollowinginformationshouldappearundereachheading.
A. Title
Write in clear language the title of the procedure to ensure understanding of the
processthattheSOPwillbedescribing.Teprocedureshouldalsocontainaclear
indicationofwhowasresponsibleforthepreparation,reviewandapprovalofthe
procedure.
B. Policy and objective
DescribetheWHOorprocurementagencypolicyregardingthemattertobedealt
withundertheSOP.DescribetheobjectivetobereachedinfollowingtheSOP.
C. Responsibility
Describeandlistthepeopleresponsibleforperformingtheactivitieslistedinthe
SOP.Whereverpossible,itispreferabletousejobdescriptionsorpositionnames
forthesepeopleratherthannamesofindividuals.Useofthepersonalnamesofstaf
membersmeanstheSOPhastobechangedeverytimepersonnelchangesoccur.
D. Action
4.1 Describethesequenceofactionsneededtoperformthetask.
4.2 Listtheactionsintheorderinwhichtheyneedtobeperformedandnumber
themfrom1totheend.
4.3 Explainallthestepsindetailinclear,unambiguous,language.
4.4 Puttheinitialsoftheresponsiblepersoninbracketsnexttotheactionstepif
aspecifcpersonisresponsiblefortheactionstep.
4.5 Read the completed SOP to determine whether it describes all the action
stepstobefollowedfromthestartoftheprocesstotheend.
4.6 IfastepleadstoanotherSOP,thenrefertotherelevantSOPinthatstep.
4.7 IftheSOPrequiresanyrecordstobekept,drafttherequiredformatofthe
documenttobecompletedandattachittotheSOPasanaddendum.
Appendix 4
80
4.8 ForwardtheSOPtothesupervisororpersonresponsiblefordocumentation
andqualityassurance.
4.9 ReadtheSOPandassessitssuitabilityandapplicability.
4.10 If any changes are to be made, make amendments to the SOP in ink and
returnittothepersonwhowrotetheSOPfortheircomments.
4.11 ReturntheSOPtothesupervisor.
4.12 SignanddatetheSOPifsatisfedwithitscontents.
4.13 Forward the SOP to the second person who is responsible for approving
documentation.
4.14 TeSOPshouldbesignedanddatedbythesecondpersonwhoisresponsible
forapprovingthedocumentationifheorsheisinagreementwiththecontents.
4.15 ReturntheSOPtothepersonresponsibleformaintainingthedocumentation
infrastructure.
4.16 If applicable, proceed with the steps for distribution and retrieval of the
previousversionoftheSOP.
4.17 FiletheoriginalSOPintheSOPfle.
E. Addenda
4.18 Drafteachaddenduminsuchamannerthatitleadsthepersonresponsible
forcompletingtheaddendumtodocumentalltherequiredinformation.
4.19 EachaddendumshallformpartoftheauthorizedSOPandshallbereviewed
whentheSOPisreviewed,orwhennecessary.
F. Distribution
4.20 Records shall be maintained of the distribution and retrieval of SOPs to
ensurethatsupersededSOPsarenotstillinuseanywhere.
4.21 Completethetable(seeAddendumA,point6)toindicatethenameofthe
persontowhomtheSOPwillbesent.
4.22 MakeacopyoftheoriginalSOPandstampitinredinkasofcialcopy.
4.23 OnlyofcialcopiesofSOPsshallbecontrolled.SOPsnothavingaredstamp
willbeconsiderednon-ofcialanduncontrolledSOPs.
4.24 Te person shall sign and date (in the appropriate space in the table (see
AddendumA,point6)ontheoriginalSOP),asproofofreceiptoftheSOP.
4.25 WhentheSOPisreviewedandamended,copiesofthesupersededSOPshould
beretrievedfromallthosewhoholdacopywhenthenewversionisdistributed.
4.26 When replacing the superseded SOP, the persons from whom it has been
retrievedshouldsign(anddate)theappropriatespaceonthedistributiontablein
theoriginalSOP.
4.27 MarktheoriginalSOPassupersededoneachpageandfleinthesuperseded
SOPfle.
81
4.28 DestroyallretrievedcopiesofsupersededSOPs.
G. Review date
AdateshouldbeassignedonwhichtheSOPwillbereviewedtodeterminewhether
anychangesarerequiredtokeepituptodate.
H. Revision history
4.29 TomaintainarecordofthehistoryoftheinformationontheSOP,complete
thetableregardingthehistoryofthechangestotheSOP(seeAddendumA,point
7).
4.30 Each SOP should have a time limit for validity and should be reviewed
beforetheendoftheperiodofvalidity.Tisisanopportunitytoconsiderwhether
theSOPstillmeetsallitsobjectivesandisappropriatefortheworktobedoneand
themethodsofworking.TeupdatedSOPshouldgothroughthesamewritingand
revisionprocess.
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
82
290
Addendum A: Format of a standard operating procedure
1. Title
(indicate title)
3. Responsibility
4. Action
4.1
4.2
4.3
5. Addenda
7. History
WHO Logo Document no.
Review date: 2006
Standard operating procedure
Signature Date
Authorized by
83
Appendix5
Example of an invitation for expression of interest
SIXTH INVITATION FOR EXPRESSION OF INTEREST (EOI)
Inthecontextofdramaticallyincreasingtheaccessto,andafordabilityof,HIV/
AIDS-related care and treatment, WHO, together with UNICEF, UNAIDS and
UNFPAareinvitingexpressionsofinterestfrommanufacturersofpharmaceutical
productsinrespecttotheprovisionofdrugsforthemanagementofHIV-related
diseases.TeWorldBankisinsupportofthisefort.
Tissixthinvitationispublishedinordertoincreasetherangeofpossibleproducts
andsourcesasafollowuptotheinterestthatwasexpressedasaresultofthefrst,
second,third,fourthandffthinvitationspublishedin2000,2001,2002,2003and
2004.
Manufacturersshouldbecommittedtoprovidingtheabove-mentionedproductsat
preferentialpricestodevelopingcountries.Interestedmanufacturersareencouraged
tosubmitdocumentationandsamplesasspecifedbelowforvariousdosageforms
andstrengthsoftheproductsinthefollowingcategories:
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
Nelfnavir
Ritonavir
Saquinavir
Applications are also encouraged for single-ingredient formulations suitable for
use in paedatric populations, that support existing international and or national
treatmentguidelinesforpaediatricantiretroviraltherapy(ART).
As solid dosage formulations are the preferred formulations for treating children
except for in the very young infant, manufacturers should also apply for reduced
and/orscoredsoliddosageformulationsof:
84
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 fxed-dose combinations (FDC):
Applicationsarealsoencouragedforfxed-dosecombinationsofanyfrstlineARV
regimensasdescribedintheWHO Guidelines for Scaling Up Antiretroviral Terapy
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
85
Protease.Inhibitors
Lopinavir+Ritonavir
Co-packaged. preparations. of the standard ARV combinations, for adult,
adolescent and paediatric use are also sought. for further information on
paediatric fxed-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
Cefxime
Ciprofoxacin
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
86
TemedicineslistedinthisInvitationforExpressionofInterestarethoseforwhich
aneedhasbeenidentifedbytheHIV/AIDSdepartment,WHO.Tesubmitted
productsshouldbeofassuredpharmaceuticalqualityandrelevantdatatosupport
efcacyshouldbeprovided.
ProcedureforsubmissionofEOI
1. Submitacoveringletterexpressingtheinterestinparticipatingintheproject,
confrmingthattheinformationsubmittedintheproductdossiersiscorrect.
2. Submit a product dossier in the recommended format* as specifed in the
Guidelineforsubmissionofaproductflewhichcanbeobtainedbyelectronic
mailfromoakesl@who.int,alsoavailableonthethewebpagehttp://mednet3.
who.int/prequal.Tedossiershouldbeaccompaniedbyasampleoftheproduct
toenableanalyses(e.g.1100tablets).
*Ifthedossieriscompiledinadiferentformat(e.g.EU),thensuchadossiercanbesubmittedwithacovering
lettercross-referencingthepageswheretherelevantdatacanbefoundinaccordancewiththeabove-mentioned
Guideline.
SubmitteddocumentationreachingUNICEFSupplyDivisionwillbeevaluated
duringMarch,May,July,SeptemberandNovember2005.Documentation
shouldbeprovidedinEnglish.Interestedmanufacturersshouldsubmitthe
above-mentionedinformationto:
. UNICEF.Supply.Division
. Reference:.Accelerated.Access.to.HIV/AIDS.Care
. SIXTH.EOI
. UNICEF.Plads.-.Freeport
. DK-2100.Copenhagen
. Denmark
. E-mail:.supply@unicef.org
. Tel:.(45).35.27.35.27.Fax:.(45).35.26.50.48
3. Submitasitemasterfleforeachmanufacturingsiteaslistedintheproduct
dossier,intherecommendedformat,alsoavailablebyelectronicmailandon
thewebpagehttp://mednet3.who.int/prequal/to
Te.Secretary
. WHO/HTP/PSM/QSM
. 20.Ave.Appia
. 1211.Geneva.27
. Switzerland
Productsandmanufacturingsitesassessedforacceptabilityandmeetingthe
specifedstandardswillbeaddedtothelistpublishedontheprojectwebpage
(http://mednet3.who.int/prequal/).Productsandmanufacturersincludedin
this list may be invited to bid for the supply of products, individually or
collectively,directlybymembergovernments,bytheaforesaidUnitedNations
agenciesand/orbyassociatedNGOs.
87
Tefollowingcriteriawillbetakenintoaccountinthequalityassessmentprocess.
Validmanufacturerslicenceforproduction.
Productregisteredorlicensedinaccordancewithnationalrequirements.
ProductsmanufacturedincompliancewithGMPascertifedbythenational
regulatoryauthorityand/orcertifedGMPinspectors.
ProductcertifcatesexistinaccordancewiththeWHOCertifcationschemeon
thequalityofpharmaceuticalproductsmovingininternationalcommerce.
Productdossiersofacceptablequalitysubmittedandoutcomeoftheassessment
inrespectoftheprequalifcationprocedure.
Outcomeoftheinspectionperformedbyoronbehalfoftheabovementioned
agencies.
Manufacturerdemonstratessoundfnancialstanding.
Only manufacturers THAT CAN SUPPLY APPROPRIATE PRODUCTS OF
ACCEPTABLEQUALITYCOMPLIANTWITHAPPLICABLEREGULATORY
REQUIREMENTS, WHO GUIDELINES AND LEGISLATION will be
considered.
Te United Nations procurement agencies reserve the right to determine specifc
conditions,asforexampletheexclusionofcompaniesusingchildlabour,orengaged
inthemanufactureoflandminesorpartsthereof.
Further references
Forbackgroundinformationondrugsforthetreatmentofopportunisticinfections
inHIV/AIDS,pleaserefertowww.aidsinfo.nih.gov/guidelines.
For background information on palliative care drugs, please refer to http://www.
who.int/3by5/publications/documents/en/genericpalliativecare082004.pdf
Appendix 5
88
Appendix6
Pharmaceuticalproductquestionnaire
I Product identifcation
Activepharmaceuticalingredient(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 product
Name,addressandactivitiesofthemanufacturer(s)(orcontractmanufacturer(s)):
296
Appendix 6
Pharmaceutical product questionnaire
I Product identication
Active 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 product
Name, 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 prequalied 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
IsthemanufacturingsiteforTHISproductprequalifedbytheprocurementagency?
q Yes q No
Has the manufacturing method for each standard batch size been validated?
q Yes q No
Listthestandardbatchsizequantities:
III Supplier identifcation
(to be flled in if not identical to that indicated in question II)
Name:
Address:
Telephonenumber:
Facsimilenumber:
E-mailcontactdetails:
89
Linkwiththeproduct:
q Marketinglicenceholder q Distributor q Manufacturer
q 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 Certifcate of Pharmaceutical Product according to the WHO Certifcation
scheme (WHO Technical Report Series, No. 863). Earlier version is not acceptable.
V Regulatory situation (licensing status) in other countries
Listothercountrieswheretheproductisregisteredandiscurrentlymarketed:
VI Finished product specifcations
q BritishPharmacopoeiaEdition(BP)
q UnitedStatesPharmacopeiaEdition(USP)
q InternationalPharmacopoeiaEdition
q Other:
Please attach a copy of the fnished product specifcation, if diferent from BP, USP or
International Pharmacopoeia specifcation.
Limitsin%fortheassayinactiveingredient(s):
q 95105% q 90110% q Other:
Additional specifcations to those in the pharmacopoeia (e.g. dissolution,
syringeability):
Please attach a copy of the model certifcate of analysis for batch release.
Areyouwillingtoprovidenecessaryinformation(analyticalmethod)fortheteststo
bereplicatedbyanothercontrollaboratory?
q Yes q No
Appendix 6
90
VII Stability
Stabilitytestingdataavailable:
q Yes q No
Ifyes,typeandconditionsoftesting:
q Acceleratedtesting q 40C/75%RH/6months q Other:
InthesamepackagingasspecifedunderpointI(page1): q Yes q No
Real-timetestingtemperature:
q ambient q 25C q 30C q Other:
Relativehumidity:
q non-controlled q 45% q 65% q Other:
Periodoftime:
q 1year q 2years q 3years q Other:
InthesamepackagingasspecifedunderpointI(page1): q Yes q No
Canastabilityreportbeforwardedwithinoneweekofbeingrequested?
q Yes q No
Wasthestabilitytestingdoneonaproductofthesameformula,manufacturedon
thesamesiteandpackedinthesamepackagingmaterialastheproductthatwillbe
supplied?
q Yes q No
VIII Label and insert information
Shelf-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 Samples
Can free non-returnable samples be obtained upon request within one week of
beingrequested? q Yes q No
X Therapeutic equivalence
q Demonstrated:
q byinvivobioequivalencestudies:Referenceproduct:
Numberofvolunteers: Countryofstudy:
91
Yearperformed:
q by another method claimed by the supplier/manufacturer (please describe
briefy):
q byinvitrodissolutiontests: Referenceproduct:
q notdemonstrated q notrelevant q unknown
Can a copy of the report be obtained upon request within one week of being
requested?
q Yes q No
Istheproductusedinthetrialortestessentiallythesameastheonethatwillbe
supplied(samematerialsfromthesamesuppliers,sameformula,samemanufacturing
method)?
q Yes q No
XI Active pharmaceutical ingredient(s) (APIs)
(In case more than one active ingredient is used, please replicate this question.)
DospecifcationsandstandardtestmethodsexistforeachAPIandexcipient?
q Yes q No
EachAPIused(inINNifany):
q hasaCertifcateofsuitabilitytotheEuropeanPharmacopoeia(CEP)
Certifcateno.:
q TeCEPisinourpossession(includingannexifany)
q TeCEPisinthepossessionofthefnishedproductmanufacturer(including
annexifany)
q hasadrugmasterfle(DMF)
registeredin:(country) registrationno.
q TefulloropenpartoftheDMFisinourpossession
q TefulloropenpartoftheDMFisinthepossessionofthefnishedproduct
manufacturer
Qualitystandard:
q BP q USP q EP q InternationalPharmacopoeia
q Other(e.g.in-house;specify):
q Nopharmacopoeiamonographexists*
*If there is no monograph in a recognized pharmacopoeia, then the following
informationshouldbeprovidedandevaluated:
chemicalstructure;
ifrelevant,theisomericnatureoftheactiveingredient,includingstereochemical
Appendix 6
92
confguration(e.g.racmate,pure(S)-isomer,50/50mixtureof(Z)-and(E)-
isomers;
thesolubilityoftheactiveingredientinwaterat25or35C;
thesolubilityoftheactiveingredientinothersolventssuchasether,ethanol,
acetone and bufers of diferent pH (if the active ingredient is acidic or
basic);
other relevant physicochemical characteristics of the active ingredient
such as partition coefcient (usually octanol/water) and the existence of
polymorphs;
copiesofinfrared,nuclearmagneticresonance(protonandC-13),ultraviolet
andmassspectra;
information on the chemical stability of the API, and on physicochemical
stability if relevant (e.g. formation of a hydrate, change of polymorphic
form).
Manufacturer(name,physicaladdress+country):
GMPcertifed:
q Yes(attach a copy of the GMP certifcate if any) q No q Unknown
Certifedby:
XII Commitment
I,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 andIcertifythattheproductoferedisidenticalinallaspectsofmanufacturing
andqualitytothatmarketedin:
(countryoforigin),includingformulation,methodandsiteofmanufacture,sources
ofactiveandexcipientstartingmaterials,qualitycontroloftheproductandstarting
material,packaging,shelf-lifeandproductinformation;
q andIcertifythattheproductoferedisidenticaltothatmarketedin:
(nameofcountry),except:
(e.g. formulation, method and site of manufacture, sources of active and excipient starting
materials, quality control of the fnished product and starting material, packaging, shelf-
life, indications, product information)
Date: Signature:
93
Appendix7
Example of a standard operating procedure for
screening and assessing product information
1. Title
Assessingproductfles
302
Appendix 7
screening and assessing product information
1. Title
Assessing product les
2.1 Each product le submitted by an interested manufacturer should be
assessed as part of the prequalication process.
2.2 Each product le should go through a screening procedure.
2.3 Product les found to comply with the screening requirements will
be retained for assessment.
2.4 The objective is to screen product les to determine whether these
comply with the requirements. This will prevent loss of valuable assessment
time, should the product les be incomplete when received.
2.5 The objective of the assessment process is to verify that the re-
quired information regarding safety, efcacy and quality of the product is
documented and submitted in the required format. Where possible during
inspections, and as a part of the verication process, the data and results
should be veried to ensure that correct, accurate and reliable data have
been submitted to the procurement agency.
3. Responsibility
Project Manager
Evaluators
Signature Date
Authorized by
2.1 Eachproductflesubmittedbyaninterestedmanufacturershouldbeassessed
aspartoftheprequalifcationprocess.
2.2 Eachproductfleshouldgothroughascreeningprocedure.
2.3 Product fles found to comply with the screening requirements will be
retainedforassessment.
2.4 Teobjectiveistoscreenproductflestodeterminewhetherthesecomply
withtherequirements.Tiswillpreventlossofvaluableassessmenttime,shouldthe
productflesbeincompletewhenreceived.
2.5 Te objective of the assessment process is to verify that the required
information regarding safety, efcacy and quality of the product is documented
andsubmittedintherequiredformat.Wherepossibleduringinspections,andasa
partoftheverifcationprocess,thedataandresultsshouldbeverifedtoensurethat
correct,accurateandreliabledatahavebeensubmittedtotheprocurementagency.
3. Responsibility
ProjectManager
Evaluators
4. Action
A. Screening
4.1 Unpackeachproductfleontotheworkingsurfaceinthepresenceofatleast
twootherpersons.Signasheetindicatingthenamesofthepersonsresponsiblefor
openingthecontainersonthatdate.
4.2 Completetherelevantdetailsintheproductreceivedregister.
4.3 Record details such as the product number, date, product detail (INN),
nameofsupplier,nameofmanufacturer(s),countryofmanufacturer(s),screening
outcome,datemanufacturerinformed(AddendumA).
4.4 Allocatetheproductnumberinnumericalorderstartingfrom001.
94
4.5 Tenumbershouldstartwiththeyear,e.g.01(for2001).
4.6 Identifytheprojectforwhichtheproductwassubmitted,e.g.HAforHIV/
AIDS.Tefrstproductfortheprojectwouldthusbenumbered01HA001.
4.7 OpenaWHOflefortheproduct.Writetheproductname,numberandthe
nameofthemanufacturerontheouterpage.
4.8 Write the product number on the product fle and screening form for the
product.
4.9 Screentheproductfletoassessitscompleteness.Confrmthatalltherequired
information,dataandformshavebeensubmittedbythemanufacturer/supplier.
4.10 Usetheattachedscreeningformforthispurpose(AddendumB).
4.11 Entertherelevantinformationintheappropriatecolumnofthescreening
formaspartofthescreeningprocess.
4.12 Oncethescreeningiscomplete,makeacopyofthescreeningform.
4.13 Filethecopyofthescreeningforminthescreeningformfle.
4.14 Placetheoriginalofthecompletedscreeningforminthefrontoftheproduct
fle.
4.15 Iftheproductfleiscomplete,placetheproductfleinnumericalorderin
thedesignatedareamarkedForevaluation.
4.16 Iftheproductfleisincomplete,placethefleinthedesignatedarea,marked
Incompletefles.
4.17 Entertheoutcomeintheproductreceivedregister.
4.18 Foreachproductflereceived,sendaletterofacknowledgementofreceiptto
themanufacturer.ForanIncompletefle,informthemanufacturerinwritingthat
theproductflesubmittedwasincompleteandcannotbeconsideredforevaluation
orassessment(seeAddendumCforamodelletter).
B. Assessing product fles
Note: Eachproductflemustbeassessedbyatleastthreeevaluators.
TreeevaluatorsshouldevaluatePartI(qualityaspects)andatleasttwoevaluators
shouldevaluatePartII(bioavailability,safetyandefcacyaspects).
Step 1 (Evaluator 1)
4.19 TakeaproductflefromthesectionmarkedForevaluation.
4.20 Usetheattachedproductassessmentreport(AddendumD)forthepurpose
ofevaluatingtheproductinformation.
4.21 Gothrougheachsectionandassesscompliancewiththerequiredstandards
forthesubmissionoftherelevantinformation.
4.22 Recordyourfndingsinthereportform.
4.23 Oncompletionoftheassessmentrecordyourname,signatureandthedate
onthereportform.
4.24 Recordanyspecifcproblemassociatedwiththeevaluationoftheproducton
aseparatereportform,entitledProduct-specifcproblemreport(AddendumE).
IfyouareevaluatingPart2,Bioequivalence(safetyandefcacy),andtheefcacy
95
partofthedossierisnotincludedforalloralpreparations,exceptaqueoussolutions,
atthetimeofadministration,informthemanufacturerinwritingthattheproduct
fle was submitted without bioavailability aspects and cannot be evaluated at
present.
4.25 Placethereportformsinthefrontoftheproductfle.
4.26 ReplacethefleinthesectionForevaluation.
Performstepsequivalenttosteps4.19to4.26above.
Performstepsequivalenttosteps4.19to4.26above.
Step 4
4.27 If a fle contains the evaluation reports signed by three evaluators (quality
aspects) and two evaluators (bioavailability), place the fle in the area marked
Evaluationcompleted.
4.28 Assesswhethertherelevantnumberofevaluators(threeforqualityaspects,
andtwoforbioavailability)haveevaluatedeachproductadequately.
4.29 Collatetheinformationinthereports.Ifadditionalinformationisrequired
fromthemanufacturerorsupplier,drafttheletteronthebasisoftheinformation
containedinthereports.
4.30 Request the additional information to be submitted within the specifed
period.Remindthemanufacturerthatfailuretosupplytherequestedinformation
withinthetimescalerequestedmayleadtoexclusionoftheproductfromfurther
consideration.
4.31 Recordtherecommendationofevaluatorsonthelistfortheinspectionofthe
manufacturingsite.
5. Addenda
AddendumA: Productdetails
AddendumB: ScreeningformtoassessthequalityofthesubmissionofEOI
AddendumC: Productinformationreceipt
AddendumD:Productassessmentreport
AddendumE:Product-specifcproblemreport
TerecordofdistributionandretrievaloftheSOPshouldbeenteredinatable;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-
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. Addenda
Addendum A: Product details
Addendum B: Screening form to assess the quality of the submission of EOI
Addendum C: Product information receipt
Addendum D: Product assessment report
Addendum E: Product-specic problem report
The record of distribution and retrieval of the SOP should be entered in a
table; see the model below.
7. History
The history of changes to the SOP should be recorded in a table; see the
model below.
Appendix 7
96
7. History
Te history of changes to the SOP should be recorded in a table; see the model
below.
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-
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. Addenda
Addendum B: Screening form to assess the quality of the submission of EOI
7. History
The history of changes to the SOP should be recorded in a table; see the
model below.
306
Addendum B: Screening form to assess the quality of
the submission of an expression of interest
Access to drugs and diagnostics of acceptable quality
Pilot 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 Japan
USA
EU*
YES
YES
YES
NO
NO
NO
If Yes, proceed to Appendix 1
If No, proceed to Appendix 2
* (EU countries: Austria, Belgium, Denmark, Finland, France, Germany, Greece,
Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, United Kingdom)
Product
Number
Date Product
details
(INN)
Name of
supplier
Name of
manufac-
turer(s)
Country
of manu-
facture
Screen-
ing
outcome
Date
manu-
facturer
informed
Inspec-
tion
planned
(Y/N)
Product submission number:
Addendum B: Screening form to assess the quality of the submission of an
expression of interest
Accesstodrugsanddiagnosticsofacceptablequality
Pilotprocurementqualityandsourcingproject
306
Product name
Strength
Dosage form
Pack size
Date of submission
Manufacturer: ______________________________
USA
EU*
YES
YES
YES
NO
NO
NO
Product
Number
Date Product
details
(INN)
Name of
supplier
Name of
manufac-
turer(s)
Country
of manu-
facture
Screen-
ing
outcome
Date
manu-
facturer
informed
Inspec-
tion
planned
(Y/N)
97
Appendix 1
Tefollowingisincludedinthesubmission:
306
Product name
Strength
Dosage form
Pack size
Date of submission
Manufacturer: ______________________________
USA
EU*
YES
YES
YES
NO
NO
NO
Product
Number
Date Product
details
(INN)
Name of
supplier
Name of
manufac-
turer(s)
Country
of manu-
facture
Screen-
ing
outcome
Date
manu-
facturer
informed
Inspec-
tion
planned
(Y/N)
307
Appendix 1
The following is included in the submission:
A WHO-type certicate 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 certicate 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 CPP
for at least:
________ ________
Formulation
2
Strength
2
Specications
2
1
Stability testing data are submitted
2
Arguments and/or data to support the applicability of the certicate(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,United
Kingdom).
98
Appendix 2
Check that the following has been submitted in the product documentation for
EOI:
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
Properties
Chemical structure; solubility in water, other solvents such as ether, ethanol, acetone and
buffers of different pH; its isomeric nature including stereochemical conguration; partition
coefcient 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 manufacture
Name and street address of each facility of manufacture (synthesis, production), including
any alternative manufacturers
GMP certicate attached (including for all alternative sites of manufacture being submitted)
Route(s) of synthesis
1. Including reagents and reaction conditions; specications for starting materials,
reagents, solvents, catalysts and intermediates in the synthesis; synthetic by-products
and degradation products
2. If a European certicate of suitability with any appendices is submitted, then an outline
of the route of synthesis is sufcient
3. The manufacturer of the 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
Specications
Pharmacopoeial requirements: copy of the monograph and tests, additional specica-
tions, certicates of analysis, two batches, including results for impurities
Non-pharmacopoeia: tests and limits, methods, results of validation
Stability testing
Results of stability, physical as well as chemical tests, methodology used (WHO guide-
lines or ICH guidelines), validation
Finished product
Formulation
Formulation and administration unit, excipients not present in nal formulation, the qualita-
tive and quantitative composition, overages, function(s) of each excipient, ranges in the
content of excipients justied and explained
Name and street address of each facility. Indicate the activity, alternative manufacturers,
major production step(s) certicate issued, product information approved, summary
basis of approval
)
99
309
YES NO
Manufacturing procedure
Outline of manufacturing and packaging
Copy of the master formula and a copy of a manufacturing record
Details of sterilization
Stages of sampling and in-process control tests
Specications for excipients
Pharmacopoeia: copy of the monograph, test methods referenced
Additional specications
Non-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
Specications for the nished product
Two specications: at release and end of shelf-life
List general characteristics, specic standards: tests and limits for results for the nished
product must be provided
Analytical 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 provided
Copy of pharmacopoeia monograph and verication data
Results of batch analysis (inc. date of manufacture, place of manufacture, batch size and
use of batch tested)
Container/closure system(s) and other packaging
Detailed description (inc. liner or wadding, details of composition); describe other
(e.g. outer) packaging; state materials and specications for part in contact with the
product, or if protective.
Parenteral: BP, EP, JP or USP
Stability testing
Results 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 labelling
Name, 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 information
Copy approved by competent authority
Patient information and package inserts
Copies of package inserts and information for distribution
Justication for any differences
Arguments provided and/or data to support, validation data. Only minor differences are
likely to be acceptable
Interchangeability
Multisource (generic): bioequivalence study. Bioequivalence of all oral preparations
except aqueous solutions. Orally or parenterally administered aqueous solutions:
chemicalpharmaceutical characteristics. Comparative clinical trial using clinical or
pharmacodynamic end-points can be presented. End-points justied and validated for the
compound and trial should be designed to show equivalence. Trial showing the absence
of signicant difference cannot be accepted
Bioequivalence study report included
Appendix 7
100
310
YES NO
Report
Study 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 efcacy of the product
New active ingredients and new combinations of active ingredients: full safety and
efcacy (EU, FDA, Japan)
Accept Reject Hold
Reasons for rejecting or holding an application: ____________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
101
Dear
Prequalifcationofmanufacturersandsuppliersofdrugproducts
Tankyouforsubmittingaproductfleafterhavingindicatedyourcompanysinterest
insupplyingdrugproductsaspartoftheprequalifcationprocessofdrugproducts
totheUnitedNationsorganizationsandinterestedprocurementagencies.
Weherewithacknowledgereceiptofyourproductinformationsenttothisofceas
partoftheprequalifcationprocess.
Te product information submitted has been screened to assess completeness
of the submission in accordance with the guidelines that were sent to you after
receivingyourExpressionofInterest(EOI)inparticipatingintheprequalifcation
programme.Kindlynotethatyoursubmissionisnowpendingthefullassessment.
Itispossiblethataninspectionofthemanufacturingsite(s)willbeperformedin
duecourse.Detailsofthiswillbeadvisedtoyouonceallthenecessaryarrangements
havebeencompleted.
OR
Kindlynotethatyoursubmissionwasfoundtobeincomplete.Wethereforeregret
toinformyouthatnofurtherevaluationwilltakeplacewithregardstoyourproduct
fle, and that the manufacturer will be not be included in the prequalifcation
process.Wouldyoukindlycontactthisofcewithin30daystoenableustomake
thenecessaryarrangementsforthereturnoftheinformationalreadysubmitted.
OR
Kindly note that your submission was found to be incomplete. It is missing the
followinginformation.
IfyouprovidethemissingdatawithinXdays,anditisofsatisfactoryquality,then
yoursubmissionwillgoforwardtofullassessment.
Yourcooperationisappreciated.
Appendix 7
102
312
Product number:
Product name (API):
Manufacturer:
Product manufactured and registered/licensed
in EU, Japan or USA
YES
1
NO
2
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 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 certicate 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:
Tisproductevaluationreportconsistsoftwoparts.Bothpartsshouldbecompleted
as part of the assessment. Te report should be written in clear unambiguous
language referring to shortcomings or lack of data submitted, as communication
withthemanufacturermayresultfromtheassessment.
PartOneshouldbecompletedbyatleastthreeevaluatorsfromdiferentcountries,
responsible for assessing product quality including pharmaceutical and analytical
aspects.(Tereportshouldbenolongerthansixpages.)
PartTwo should be completed by an evaluator responsible for the assessment for
bioavailability.(Tereportshouldbenolongerthantwopages.)
Te report should be signed of by the person responsible for the evaluation and
assessmentoftheproductfles.
1
Productlicensed/registeredintheEU,JapanortheUSA.Reviewthedatasubmitted
andcomment(seealsoguidelines):
312
Product number:
Product name (API):
Manufacturer:
Product manufactured and registered/licensed
in EU, Japan or USA
YES
1
NO
2
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 les.
1
Product licensed/registered in the EU, Japan or the USA. Review the data
submitted and comment (see also guidelines):
A WHO-type certicate 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:
103
313
Formulation
Strength
Specications
2
Product not licensed/registered in the EU, Japan or the USA. Review the
data submitted and comment:
Active pharmaceutical ingredient(s) (API)
Properties of the API(s)
Specications
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
Appendix 7
313
Formulation
Strength
Specications
2
Product not licensed/registered in the EU, Japan or the USA. Review the
data submitted and comment:
Active pharmaceutical ingredient(s) (API)
Properties of the API(s)
Specications
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
104
314
Specications for the nished product
Container/closure system(s) and other packaging
Stability testing
Container labelling
Product information
Patient information and package inserts
Justication for any differences of the product in the country or countries issuing
the submitted WHO-type certicate(s)
Evaluator (name): Signature: Date:
1
2
3
Part II: Bioavailability (safety and efcacy)
(See also guidelines)
Bioequivalence study report
Summary of pharmacology, toxicology and efcacy
Evaluator (name): Signature: Date:
1
2
3
105
Addendum E: Product-specifc problem report
315
API:
This product-specic problem report should highlight any specic prob-
lems identied during the evaluation of products. No mention should be
made of the specic manufacturers product. The objective is to identify
any problems associated with a specic product containing a specic API,
or specic to any dosage form.
Dosage form
Problems
General recommendations
Tis product-specifc problem report should highlight any specifc problems
identifed during the evaluation of products. No mention should be made of the
specifcmanufacturersproduct.Teobjectiveistoidentifyanyproblemsassociated
withaspecifcproductcontainingaspecifcAPI,orspecifctoanydosageform.
315
API:
This product-specic problem report should highlight any specic prob-
lems identied during the evaluation of products. No mention should be
made of the specic manufacturers product. The objective is to identify
any problems associated with a specic product containing a specic API,
or specic to any dosage form.
Dosage form
Problems
General recommendations
Appendix 7
106
Appendix8
Technical questionnaire for pharmaceutical
manufacturers
1. General information on the manufacturer
Name,address,telephone,telefax,Internetaddressofthecompany:
316
Appendix 8
Technical questionnaire for pharmaceutical
manufacturers
1. General information on the manufacturer
Name, address, telephone, telefax, Internet address of the company:
Name
Postal address
Physical address
Telephone
Fax number
Web site URL
Contact e-mail address
2. Afliates
If the company is owned by another company, or belongs to a group of
companies,
Please describe your position within the structure: __________________
__________________________________________________________
3. Regulatory issues
3.1 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 certicate 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. Affliates
If the company is owned by another company, or belongs to a group of
companies,
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 certicates for re-
view on a condential basis.
4. Manufacturing
4.1 Manufacturing site
Please state all the names and addresses at which manufacturing of pharma-
ceutical products to be prequalied 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, qualication and years of experience of the fol-
lowing key staff:
Position Name Qualication 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 the
companycomplies:
Provide a copy of the latest inspection report or certifcate whichever is appropriate.
3.2 Manufacturing licence for medicinal products
Pleaselistthepharmaceuticaldosageformsyouarelicensedtomanufacturebythe
nationalregulatoryauthorityandattachacopyofthemanufacturinglicence(s):
3.3 Inspection
Dateoflastinspectionbyanationalorothercompetentdrugregulatoryauthority:
107
Please attach a copy of the last inspection report(s) or certifcates for review on a
confdential basis.
4. Manufacturing

Pleasestateallthenamesandaddressesatwhichmanufacturingofpharmaceutical
productstobeprequalifedtakesplace,andindicateinwhichyearthefactorywas
built. Include dates of upgrading and adaptation, as well as a description of the
activity:
317
3.3 Inspection
authority:
4. Manufacturing
upgrades
Activity (e.g. all,
compression, pack-
aging, etc.)
4.2 Personnel
lowing key staff:
Managing Director
Technical Director
Production Manager
Quality Control
Manager
Quality Assurance
Manager
4.2 Personnel
Pleaseindicatethename,qualifcationandyearsofexperienceofthefollowingkey
staf:
317
3.3 Inspection
authority:
4. Manufacturing
upgrades
Activity (e.g. all,
compression, pack-
aging, etc.)
4.2 Personnel
lowing key staff:
Managing Director
Technical Director
Production Manager
Quality Control
Manager
Quality Assurance
Manager
Numberofpersonnelintotal:
Numberofpersonnelinproduction:
Numberofpersonnelinqualityassurance/control:
4.3 Ventilation system
Please indicate whether the manufacturing areas are equipped with controlled
ventilationsystems qYes qNo
If Yes, please give a brief description of the ventilation system. (A diagram
complementingthedescriptioncanbesubmitted.)
IfNo,explainreasons:
Appendix 8
108
4.4 Quality control
Instrumentation?
Chemicallaboratory in-houseq contractedoutq
Biologicallaboratory in-houseq contractedoutq
Microbiologicallaboratory in-houseq contractedoutq
4.5 Contract manufacture
Doyouundertakecontractmanufactureforothercompanies? qYesqNo
IfYes,pleaseindicatethetypeofproducts(e.g.pesticides,antibiotics,hormones,
cytotoxics,etc.)
Doyousubcontracttoothercompanies? qYesqNo
IfYes,pleaselistproductsand/orservicesthataresubcontracted:
4.6 Sterile products
Doyoumanufacturesterileproducts? qYesqNo
Giveabriefdescriptionofthemethodofsterilizationused:
4.7 Beta-lactam, highly sensitizing compounds, hormones, cytotoxic ..
products
Doyoumanufacturepenicillinsorotherbeta-lactam,highlysensitizingcompounds,
hormonesorcytotoxicproducts? qYesqNo
Ifyes,doesthisproductiontakeplaceinaseparatebuildingprovidedwithitsown
dedicatedair-handlingsystem? qYesqNo
4.8 Complaints and recalls
Do you have a recall procedure, which enables you to recall any product
efectively and promptly within 24 hours from the distribution points
ormarket? qYesqNo
Doyouhaveaprocedureforhandlingcomplaints? qYesqNo
Doesitcoveranalysisoftrends? qYesqNo
Please list signifcant product complaints and any recalls during the last three
years:
109
4.9 Research and development activities
Pleaseindicatethetypeofactivitiesandannualinvestment:.
4.10 Production capacity
319
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 signicant product complaints and any recalls during the last
three years:
Product List complaints
Year 1 Year 2 Year 3
Please indicate the type of activities and annual investment: . __________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
Product No. of units per year Last years
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
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 signicant product complaints and any recalls during the last
three years:
Product List complaints
Year 1 Year 2 Year 3
Please indicate the type of activities and annual investment: . __________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
Product No. of units per year Last years
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 fgures based on one or more shifts? (Tick appropriate
box)
qOne qTwo qTree
4.11 Stock
Doyoumaintainapermanentstock? qYesqNo
320
Penicillin, powder for injection
Other, specify
Are production capacity 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 specic
reference to aspects such as procurement agency, documentation infrastruc-
ture, validation, training, statistical analysis, and other related aspects: __
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
5. Products
5.1 Product licences
Please enclose a list of all products manufactured by your company for
which you seek prequalication 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
110
assurance)
Giveabriefdescriptionofthequalitymanagementsystem,withspecifcreference
to aspects such as procurement agency, documentation infrastructure, validation,
training,statisticalanalysis,andotherrelatedaspects:
5. Products
Pleaseenclosealistofallproductsmanufacturedbyyourcompanyforwhichyou
seekprequalifcationandwhichareauthorizedforsale.Foreachlicensedproduct,
pleasecompletethetablebelowandcategorizeasshown.
320
Penicillin, powder for injection
Other, specify
Are production capacity 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
assurance)
Give a brief description of the quality management system, with specic
reference to aspects such as procurement agency, documentation infrastruc-
ture, validation, training, statistical analysis, and other related aspects: __
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
5. Products
Please enclose a list of all products manufactured by your company for
which you seek prequalication 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
Te following product documentation must be made available upon request for
eachproductofered.PleaseindicateifthisdocumentationisNOTavailableforany
oftheproductsonthelistshownunderpoint5.1:
Productcompositionmasterformula
Startingmaterialsspecifcation
Manufacturingandpackagingspecifcation
In-processtestspecifcationsandmethods
Finishedproductspecifcation
Packagingandlabellingspecifcations
Analyticalprocedures
111
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
confdentialbasis)whenrequested? qYesqNo
5.4 Starting materials
Liststartingmaterialsmanufacturedbythecompanyorbyafliates,andindicate
in the table below whether approved drug master fles (DMF) or Certifcates of
suitabilityoftheMonographoftheEuropeanPharmacopoeia(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 specication __________________________________
Manufacturing and packaging specication ________________________
In-process test specications and methods _________________________
Finished product specication __________________________________
Packaging and labelling specications ____________________________
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
condential basis) when requested? Yes No
5.4 Starting materials
List starting materials manufactured by the company or by afliates, and
indicate in the table below whether approved drug master les (DMF) or
Certicates 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.IfNo,explain
reasons:
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 nished product
Active pharmaceutical
ingredients
Excipients
6. Audit
Can we or any other representative designated by us perform a GMP audit
of the manufacturing site? Yes No
Explainifnecessary:
Howdoyoudeterminetheshelf-lifeofyourproducts?
Appendix 8
112
5.6 Bioequivalence
Have you conducted in vivo bioequivalence studies for some of your products?
qYesqNo
Ifyes,listtheproductsstudiedandthereferenceproducts:
322
Temperature
(indicate)
Relative humidity
(indicate)
Accelerated studies
Real-time studies
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
5.6 Bioequivalence
products? Yes No
ingredients
Excipients
6. Audit
Doyoukeepretentionsamples? qYesqNo
322
Temperature
(indicate)
Relative humidity
(indicate)
Accelerated studies
Real-time studies
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
__________________________________________________________
5.6 Bioequivalence
products? Yes No
ingredients
Excipients
6. Audit
6. Audit
CanweoranyotherrepresentativedesignatedbyusperformaGMPauditofthe
manufacturingsite? qYesqNo
Can (a) representative(s) from the national regulatory authority participate as
observer(s)intheaudit? qYesqNo
Maywesharetheinspectionreportwiththeotherprocurementagenciessignatory
tothisquestionnaire? qYesqNo
Isasitemasterfle(PICorWHOformat)availableuponrequest?
qYesqNo
Will any required additional information be provided if we wish to perform an
auditofthecompany? qYesqNo
7. Other information
Contactperson(commercialissues):
323
Can (a) representative(s) from the national regulatory
authority participate as observer(s) in the audit? Yes No
May we share the inspection report with the other
procurement agencies signatory to this questionnaire? Yes No
Is a site master le (PIC or WHO format) available
upon request? Yes No
Will any required additional information be provided
if we wish to perform an audit of the company? Yes No
Contact 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
113
Anyadditionalinformation:
Iherebycertifythattheinformationgiveninthisquestionnaireandtheattachments
iscorrect.
Date.. . . . . Signature
Name Positionincompany
323
Can (a) representative(s) from the national regulatory
authority participate as observer(s) in the audit? Yes No
May we share the inspection report with the other
procurement agencies signatory to this questionnaire? Yes No
Is a site master le (PIC or WHO format) available
upon request? Yes No
Will any required additional information be provided
if we wish to perform an audit of the company? Yes No
Contact 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
114
Appendix9
Example of a standard operating procedure for planning
of inspections
1. Title
Inspection,planningofsiteinspections
324
Appendix 9
Example of a standard operating procedure
for planning of inspections
1. Title
Inspection, planning of site inspections
Signature Date
Prepared by 1 July 2006
Authorized by
2.1 Manufacturing sites should be inspected as part of the prequalica-
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.
nancial and human) through procurement agency planning.
3. Responsibility
Head of the Section or Department
Project Manager
Evaluator
4. Action
4.1 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 prequalication.
4.3 Dossiers lacking information, or of unacceptably low quality, may
lead to the manufacturing site failing to qualify for the inspection.
2.1 Manufacturing sites should be inspected as part of the prequalifcation
process.Toenabletheprocurementagencytoperformtheinspections,theyshould
beproperlyplanned.
2.2 Teobjectiveisproperplanningofsiteinspectionstoensurethatproducts
willbesourcedonlyfrommanufacturersthatcomplywithinternationalstandards.
2.3 Properplanningofinspectionsshouldsavetimeandresources(e.g.fnancial
andhuman)throughprocurementagencyplanning.
3. Responsibility
HeadoftheSectionorDepartment
ProjectManager
Evaluator
4. Action
4.1 Whenassessingproductinformation,makealistofalltheproductsreceived
(seeAddendumA).Completethetable.
4.2 Onthebasisoftheoutcomeoftheassessmentoftheproductinformation,
decidewhichmanufacturersshouldbeinspectedforprequalifcation.
4.3 Dossierslackinginformation,orofunacceptablylowquality,mayleadtothe
manufacturingsitefailingtoqualifyfortheinspection.
115
4.4 Groupallthemanufacturersinonecountrytogethertoensurethatwhena
tripisundertakentoonecountry,morethanonemanufacturercanbeincludedin
theinspectiontripwhererelevant.
4.5 Consultamaptoseewherethesitesarelocatedandplanthetripsoasto
preventunnecessarylossoftimethroughtravelling.
4.6 Plotthesitesonatable(calendar)andallocateatleast3daysforinspection
ofeachmanufacturingsite,dependingonthedosageformsmanufacturedandthe
sizeofthefacilities.
4.7 Writealettertothecompanyinformingthemofthetentativedateallocated
for the site inspection. Request the company to indicate whether the dates are
suitabletothem,andalsorequestthemtosubmitasitemasterfle.
4.8 Appoint inspectors for the inspection team. Tere should be at least two
inspectorsontheteam,includingtherepresentativefromWHO.
4.9 Sendalettertothenationalregulatoryauthorityinvitinganinspectorfrom
theinspectoratetoparticipateintheinspection.
4.10 Informtheinspectorsoftheproposeddatesfortheinspection.
4.11 Whenthemanufacturerconfrmsthedatesforinspectionconfrmthedate
withthecompanyandrequesttheinformationlistedinAddendumB.
4.12 Confrmthedateswiththeinspectors.
4.13 SendtheinspectorscopiesoftheSOPsneededtoperformtheinspections,
as well as the terms of reference, confdentiality clause, no confict of interest
declarationandagreementforperformanceofwork.
4.14 Make the relevant bookings (air travel, transport in the country where the
inspectionwillbeperformedandhotelaccommodation).
5. Addenda
AddendumA:Summarylistofdossiersreceived
AddendumB:Manufacturerinformation
Appendix 9
116
themodelbelow.
326
7. History
The history of changes to the SOP should be entered in a table; see the
model below.
7. History
Te history of changes to the SOP should be entered in a table; see the model
below:
326
7. History
model below.
117
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
118
Addendum B: Manufacturer information
1. General information
328
Addendum B:Manufacturer information
Name
Physical address
of head ofce
Postal address
Telephone number
Fax number
Contact person
E-mail address
2. Manufacturing licence
Please attach the manufacturing licence.
3. Product list
Please 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 list
Please attach a list of products manufactured at this particular manufacturing site.
328
Name
Physical address
of head ofce
Postal address
Telephone number
Fax number
Contact person
E-mail address
3. Product list
ing site.
authority (NRA)
Country Date
Telephone number
Fax number
Telephone number
Fax number
E-mail
328
Name
Physical address
of head ofce
Postal address
Telephone number
Fax number
Contact person
E-mail address
3. Product list
ing site.
authority (NRA)
Country Date
Telephone number
Fax number
Telephone number
Fax number
E-mail
119
6. Recalls
Please list the products and reasons for implementing a product recall in the last
5 years.
329
6. Recalls
Please list the products and reasons for implementing a product recall in
the last 5 years.
Product and batch number
(INN, strength and dosage
form)
Reason Date of recall
7. Complaints
If the company has had any product complaints in the last year, please com-
plete the table below.
Products and batch number
form)
Complaint and source Corrective action taken
8. Site master 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 specied previously.
9. Audit/inspection
We 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 prequalication of the manufacturing site and product.
I declare that the information given above is true and correct.
__________________________________ __________________
Signature: Date:
Name: _____________________________________________________
Position: ___________________________________________________
7. Complaints
If the company has had any product complaints in the last year, please complete the table
below.
329
6. Recalls
the last 5 years.
form)
7. Complaints
form)
Date submitted
SMF number
9. Audit/inspection
__________________________________ __________________
Signature: Date:
Name: _____________________________________________________
Position: ___________________________________________________
8. Site master fle (SMF)
329
6. Recalls
the last 5 years.
form)
7. Complaints
form)
Date submitted
SMF number
9. Audit/inspection
__________________________________ __________________
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 specifed previously.
9. Audit/inspection
WeherewithgrantWHOpermissiontoperformtheinspectionofthemanufacturing
sitetoassesscompliancewithgoodmanufacturingpractice,forthepurposeofthe
prequalifcationofthemanufacturingsiteandproduct.Ideclarethattheinformation
givenaboveistrueandcorrect.
Signature: Date:
Name:
Position:
Appendix 9
120
Appendix10
preparing for an inspection
1. Title
Preparationforaninspection
330
Appendix 10
for preparing for an inspection
1. Title
Preparation for an inspection
Signature Date
Authorized by
2.1 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. Responsibility
Project Manager
Inspectors
4. Action
All 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.
2.1 Eachmanufacturershouldbeinspectedbytheprocurementagencytoassess
compliancewithgoodmanufacturingpractices.
2.2 AllinspectorsshouldfollowtheSOPinpreparingfortheinspection(s).
2.3 Te objective is to ensure that a standardized procedure is followed by
all inspectors when preparing for the inspections to prevent inspections being
performedbydiferentinspectorsindiferentways.Tisshouldensureconsistency
inperformancebetweeninspectors.
3. Responsibility
ProjectManager
Inspectors
4. Action
All actions described here are taken from the details provided by the WHO
publicationQuality assurance of pharmaceuticals,Volume2,Chapter4:Inspectionof
pharmaceuticalmanufacturersandinspectionofdrugdistributionchannels.Tese
guidelines or other similar systems operated by national drug regulatory agencies
shouldbefollowedindetail.
4.1 Once the inspection has been allocated to the inspector, he or she should
planfortheperformanceoftheinspectionaccordingtothestepsoutlinedbelow.
4.2 Verifytheobjectiveoftheinspectionthatistobecarriedout.
121
4.3 Clarify which type of inspection will be performed, e.g. routine GMP or
follow-upinspection.
4.4 Decidewhethertheinspectionwillcovertheentirefactoryorjustpartofit.
4.5 Determinewhatthescopeanddepthoftheinspectionwillbetoenableyou
to prepare for it properly. (For a company producing sterile products, prepare by
reviewingtheguidelinesforsterileproductmanufactureinadditiontothegeneral
GMPguidelines.)
4.6 Scrutinizetheproductinformationfortheproductsintheprequalifcation
proceduremanufacturedatthismanufacturingsite.
4.7 Decidehowlongitwilltaketocarryouttheinspectionandplanthedate
whentheinspectionwilltakeplace.
4.8 Inform the manufacturer(s) in question of the proposed date for the
inspection.
4.9 Ensurethattheproposeddatefortheinspectionissuitableforallmembers
oftheinspectionteam.
4.10 Decideonachieforleadinspectortocoordinateandleadtheinspection.
4.11 Te lead inspector will be the main spokesperson during the closing or
exitmeetingattheendofaninspection,andhastheoverallresponsibilityforthe
inspectionreport.
4.12 Informotherinterestedpartiesoftheproposedorplannedinspection,e.g.
a regional ofce of the procurement agency or agency, or the national regulatory
authority.
4.13 Reviewdocumentationrelatingtothemanufacturertobeinspectedsuchas
acompletedquestionnaire.
4.14 In case of a follow-up inspection, and where the procurement agency or
agencyhasacompanyfleinwhichgeneralcorrespondenceandpreviousinspection
reportsarefled,reviewthecorrespondence.
4.15 Ifasitemasterfle(SMF)existsandisavailable,studytheSMFandmake
notestobefollowedupduringtheinspection(e.g.availableequipment,SOPsand
records).
4.16 Study the layout and design of the manufacturing facility, and some of
the systems the manufacturer has in place to ensure quality in manufacture of
products.
4.17 Lookattheinformationprovidedonthemanufacturinglicenceandproduct
licence.Makenotesoftheaspectsthatneedtobeinspectedtoconfrmcompliance
withlicenceconditions,andtoverifydataduringtheinspection.
Appendix 10
122
4.18Reviewthereportsofpreviousinspections,reportsofadversedrugexperiences
and complaints, if any exist, as investigations and corrective action taken by the
manufacturershouldbeverifedduringinspections.
4.19Foraspecialinspection,reviewrecordsofthecompanyinrelationtocomplaints
andrecalls,andregulatorytestresults(surveillance)whereavailable.
4.20Ifanannualreportisavailable,scrutinizethereportandnotetheinformation
in relation to fnancial aspects of the company, personnel issues and products
manufactured.
4.21 If any complaints had been received about the manufacturer or products
previouslysupplied,reviewthecontentsofthecomplaint,investigation,outcome
andcorrectiveaction.
4.22 Ifself-inspection/internalauditreportswererequestedfromthemanufacturer,
reviewthecontents.(Suchreportsarenormallynotrequestedassomemanufacturers
consider that the inspectors should assess GMP compliance themselves, and not
lookatthecompanysownfndingsofinspections.Requestingsuchreportswould
bedependentonthepolicyoftheprocurementagency.)
4.23 Studythediagramofthefacilitytogetabetterunderstandingofthefowof
material,personnelandprocessesinthefacility.
4.24 If any manuals and/or procedures were submitted by the manufacturer,
reviewtheseandpreparespecifcquestionsrelatingtothequalitypolicy,validation
policyandprocedureforperformingcertainactivities.
4.25 Draw up a checklist or aide-memoire of points to be verifed during the
inspection.
4.26 Drawupaprogrammefortheinspection.Produceanoutlineofwhatwillbe
coveredeachdayandclarifywhateachmemberoftheteamwillbedoingeveryday
orhalf-dayofthevisit.Indicateintheprogrammewhichsectionsordepartments
willbeinspected,andwhen(foranexample,seeAddendumA).
4.27 Distributetheprogrammetotheteammembers.Inthecaseofanannounced
inspection,formthecompanyoftheproposedinspectionprogramme.
5. Addenda
AddendumA:Exampleofaninspectionplan
123
themodelbelow.
333
7. History
model below.
7. History
below.
333
7. History
model below.
Appendix 10
124
Addendum A: Example of an inspection plan
334
Addendum A: Example of an inspection plan
Manufacturer
Address
Date
Inspectors
Day 1
Time Activity
08:30 Arrival
08:45 Opening meeting and company presentation
09:15 Receiving area and stores
10:15 Sampling
11:00 Tea
11:15 Weighing
12:00 Packaging components
13:00 Lunch
14:00 Manufacturing (organize time depending on the dosage form(s))
17:00 Summary of the days observations
Day 2
08:30 Manufacturing, continued
10:00 Tea
10:15 Quality control
12:00 Heating, ventilation and air-conditioning, water and other utilities
13:00 Lunch
14:00 Documentation
17:00 Summary
17:30 Closing meeting
125
Appendix11
performing an inspection
1. Title
Performanceofinspection
335
Appendix 11
for performing an inspection
1. Title
Performance of inspection
Signature Date
Prepared by 1 July 2006
Authorized by
2.1 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-
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 prequalication list as a manufacturer of pharmaceutical
products for possible supply of specied 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 les should be veried.
3. Responsibility
Project Manager
Inspectors
2.1 Eachmanufacturershouldbeinspectedbytheprocurementagencytoassess
compliancewithgoodmanufacturingpractices.
2.2 AllinspectorsshouldfollowtheSOPforperforminginspections.
2.3 Te objective is to ensure that a standardized procedure is followed by all
inspectorswhenperforminginspectionstopreventinspectionsbeingperformedby
diferentinspectorsindiferentways.Tisshouldensureconsistencyinperformance
betweeninspectors.
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 prequalifcation
procedure.
2.5 Troughsequentialexaminationofproductionandcontrolactivitiesofthe
manufacturer, the manufacturer of pharmaceutical products may be included on
theprequalifcationlistasamanufacturerofpharmaceuticalproductsforpossible
supplyofspecifedproductstoprocurementagenciesandotheragencies.
2.6 During inspections, the performance of manufacture of products and data
submittedintherelevantproductinformationflesshouldbeverifed.
3. Responsibility
ProjectManager
Inspectors
126
4. Action
All actions described here are taken from the details provided in the WHO
publicationQuality Assurance of Pharmaceuticals,Volume2,Chapter4:Inspectionof
pharmaceuticalmanufacturersandinspectionofdrugdistributionchannels.Tese
guidelinesorothersimilarsystemsoperatedbynationaldrugregulatoryauthorities
shouldbefollowedindetail.
4.1 Clarifcationanddefnitions
4.1.1 Diferent types of inspections are identifed in the WHO text referred to
above.Teseinclude:
routineinspection;
conciseinspection;
follow-upinspection;
specialinspection;and
qualitysystemsreview.
4.2 Teperformanceoftheinspectionisdependentonthetypeofinspection;
however, in principle, the basic aspects of this procedure can be followed for
performanceofaninspection.
4.3 AroutineinspectionisafullreviewofallaspectsandcomponentsofGMP
withinafacility.Itisappropriatetoperformaroutineinspectionunderthefollowing
circumstances:
Whenthereisanewexpressionofinterest(EOI)fromamanufacturerora
newlyestablishedmanufacturer.
Whenthelistingontheprequalifcationlistisdueforrenewal.
Iftherehavebeensignifcantchangessuchasnewproductsornewproduct
lines;modifcationtomanufacturingmethodsorprocesses;orchangesinkey
personnel,premisesand/orequipment.
Ifaninspectionhasnotbeencarriedoutwithinthepast35years.
4.4 A concise inspection is the evaluation of limited aspects relating to GMP
compliance within a facility. (It is known as an abbreviated inspection in some
countries.)AlimitednumberofGMPrequirementsareselectedbytheinspectorto
serveasindicatorsofoverallGMPcompliancebythemanufacturer.Teinspector
also has to identify and evaluate any signifcant changes that could have been
introducedbythemanufacturersincethelastinspection.
4.4.1 Collectively, the selected indicators and the changes identifed indicate the
manufacturersattitudetowardsGMP.
4.4.2 Aconciseinspectionisappropriateunderthefollowingcircumstances:
Where a manufacturer has a consistent record of compliance with GMP
throughroutineinspectionsinthepast.
Where a sample of aspects can be taken as a good indication of the overall
levelofcompliancewithGMP.
127
4.4.3 However,iftheconciseinspectionuncoversevidencethatthelevelofGMP
compliance has fallen, a more comprehensive or full GMP inspection should be
performedsoonaftertheconciseinspection.
4.5 Afollow-upinspectionisalsoreferredtoasare-inspectionorareassessment
ofthemanufacturer.
4.5.1 A follow-up inspection is performed specifcally to monitor the result of
correctiveactionsofthemanufacturerfollowingapreviousinspection.
4.5.2 Dependingonthenatureofthedefectsandtheworkrequired,thefollow-up
inspectioncouldbecarriedoutbetween6weeksand6monthsaftertheoriginal
inspectiontookplace.
4.5.3 Te follow-up inspection is limited to specifc GMP requirements that
have not been observed or that have been inadequately implemented by the
manufacturer.
4.6 Tereareanumberofcircumstancesinwhichspecialvisitsorinspectionsmay
benecessary.Aspecialinspectionisundertakentodospotchecks.Spotcheckscould
focusononeproduct,agroupofrelatedproducts,orspecifcoperationse.g.mixing,
or labelling. If there have been complaints about a specifc product that suggest
there may be defects, a special inspection could be performed to investigate the
qualitydefectsoftheproduct.Iftherehasbeenaproductrecall,thiscanalsotrigger
aninspection,aswouldadversedrugreactions.Intheabovecases,theinspection
wouldfocusonthespecifcproductoraspectofproductionthatissuspect.Aspecial
inspectioncouldalsobeperformedtogatherspecifcinformation,ortoinvestigate
specifcoperationsofthemanufacturer.
4.7 Tepurposeofaqualitysystemsreviewistoreviewthemanufacturersquality
systemandtoascertainwhetherithasbeenshowntooperatesatisfactorily.
4.8 Plantheinspectiontoensurethatallareasforassessmentarecoveredinthe
allocatedtimeframe.Telengthoftimeneededforaninspectionisdeterminedby
anumberoffactors,includingthetypeofinspectiontobeperformed,thenumber
ofinspectors,thesizeofthecompanyandthepurposeoftheinspectionorvisit.
4.9 An inspection can be performed over a period of a few days to several
weeks.
4.10 Tetimetakenwillalsodependonthesizeoftheinspectionteam.Oneor
moreinspectorscanperformtheinspectionaspartofaninspectionteam.
4.11 Ifnecessary,appointaspecialisttoaccompanytheteamduringtheinspection,
e.g.forparticulardosageforms,chemistryoranotheraspect,e.g.themanufacture
ofbiologicals.
Appendix 11
128
5. Addenda
AddendumA:Inspectionprogramme
AddendumB:Documentationrequiredforverifcationduringtheinspection
themodelbelow.
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. Addenda
Addendum A: Inspection programme
Addendum B: Documentation required for verication during the inspection
7. History
model below.
7. History
below.
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. Addenda
Addendum B: Documentation required for verication during the inspection
7. History
model below.
129
339
Manufacturer
Address
Date
Inspectors
Day 1
08:30 Arrival
08:35 Opening meeting
08:45 Company presentation
09:00 Receiving area and stores
10:30 Tea
10:45 Sampling and weighing areas
11:15 Packaging material stores and control
12:30 Lunch
13:15 Manufacturing areas
15:30 Tea
15:45 Manufacturing (cont.)
16:30 Summary of ndings, day 1
Day 2
08:30 Arrival
08:35 Manufacturing area (cont.)
10:30 Tea
10:45 Laboratories
12:30 Lunch
13:15 Laboratories (cont.)
15:30 Tea
15:45 Utilities
16:30 Summary of ndings, day 2
Day 3
08:30 Arrival
08:35 Utilities (cont.)
10:30 Tea
10:45 Documentation
12:30 Lunch
13:15 Documentation (cont.)
15:30 Tea
15:45 Preparation for closing meeting
16:00 Closing meeting
Appendix 11
130
Addendum B: Documentation required for verifcation during the
inspection
1. Organigram
2. Jobdescriptions
3. Qualitypolicy(e.g.qualitymanual)
4. Validationpolicy(e.g.validationmasterplanorprogramme)
5. Rawmaterialspecifcations(forspecifcproducts)
6. Packagingmaterialspecifcations
7. Manufacturingformulaandmethodmasters
8. Packinginstructionsmaster
9. Batchmanufacturingrecords(verifcationagainstmasterdocuments)
10. SOPindex
11. SOP:selfinspection
12. SOP:recalls
13. SOP:complaintsplusrecords
14. SOP:batchnumberallocation
15. SOP:plannedpreventivemaintenance
16. SOPandrecord:plannedpreventivemaintenanceofspecifcequipment
17. SOP:training(plusrecordofpersonnel)
18. SOP:environmentalmonitoringplusrecords
19. SOP:watersamplingandtestingplusrecords
20. Validationprotocolandreportforspecifcproducts
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
131
Appendix12
Example of a checklist for good manufacturing
practices
It is recommended that inspectors prepare an aide-memoire to remind them of
pointstobecheckedduringaninspection.
Aide-memoirescanbepreparedtocoveroneormoreaspects,e.g.
production
qualitycontrol
utilities
lyophilization
Teaide-memoireshouldcontainkeywordstoremindtheinspectorofaspectsto
beinspected.
Anexampleofanaide-memoireisshownbelow.
Example: Aide-memoire for inspection of the lyophilization process:
341
Appendix 12
Example 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
Dissolving
Filtration
Filling and stoppering
Transfer
Loading
Freezing
Vacuum
Heating
Stoppering
Capping
Validation:
Design qualication (DQ)
Installation qualication (IQ)
Operational qualication (OQ)
Commissioning
Process qualication (PQ)
Media lls
Air samples
Surface swabs
Operator swabs
Daily clothing
Simulate process with media (not freeze)
Smoke test (transport area)
Transport
Frequent ll volume
Pre-cooling of shelves (no ice)
132
342
Points to check Notes
Freezing
Cycle
Rate (slow = crystals, polymorphism)
Manner
Drying temp. < eutectic point
Determine eutectic point, consistent
Shelf loading variations
Validate:
shelf temperature
product temperature
condenser temperature
pressure (chamber)
pressure (condenser)
time, temperature, pressure
leakage in
contamination (thermal uid, oil)
cleaning
Cycle
Eutectic point determination
Scale up
Vial size
Batch size
Sterilization of lyophilizer
Moist heat used
Each cycle
Residue if applicable
Biological Indicators
Design: single door (double door, air class!)
133
Appendix13
Guidance on good manufacturing practices:
inspection report
GuidanceonGoodManufacturingPractices(GMP):inspectionreport.In:WHO
Expert Committee on Specifcations for Pharmaceutical Preparations, Tirty-seventh
report.Geneva,WorldHealthOrganization,2003(WHOTechnicalReportSeries
No.908),Annex6.
Availableat:
http://www.who.int/medicines/areas/quality_safety/quality_assurance/
inspections/en/
134
Appendix14
Good storage practices
For a guide to good storage practices for pharmaceuticals, see: WHO Expert
Committee on Specifcations for Pharmaceutical Preparations, Tirty-seventh report.
Geneva, World Health Organization, 2003 (WHO Technical Report Series No.
908),Annex9.
Availableat:
http//:www.who.int/medicines/areas/quality_safety/quality_assurance
distribution/en/
135
Appendix15
Good trade and distribution practices
For a guide to good trade and distribution practices for pharmaceutical starting
materials, see: WHO Expert Committee on Specifcations for Pharmaceutical
Preparations, Tirty-eighth report.Geneva,WorldHealthOrganization,2003(WHO
Availableat:
http://www.who.int/medicines/strategy/quality_safety/tr917ann2.pdf
136
Appendix16
Quality system recommendations for pharmaceutical
inspectorates
ForaguidetoQualitysystemsrequirementsfornationalgoodmanufacturingpractice
inspectorates, see: WHO Expert Committee on Specifcations for Pharmaceutical
Preparations, Tirty-sixth report.Geneva,WorldHealthOrganization,2002(WHO
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: prequalifcation,
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 defned
quality for supply to patients. The system should be based on a
mutually recognized process of prequalifcation of products and
manufacturers.
The publication is divided into six modules, with the frst 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 fnal 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 40
th
Report
of the WHO Expert Comittee on Specifcations for Pharmaceutical
Preparations (WHO Technical Report Series No. 937, Geneva, World
Health Organization, 2006).
agencies
World Bank
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