004-dossier maintenance variations

7/30/2019 004-Dossier Maintenance Variations

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Birgit Schmauser| June 20101 |

Training workshop:Training workshop:

Pharmaceutical development with focus on paediatricPharmaceutical development with focus on paediatric

formulationsformulations

Presenter: BirgitPresenter: Birgit SchmauserSchmauser, PhD, PhD

Contact details:Contact details: Federal Institute for Drugs and MedicalFederal Institute for Drugs and Medical

Devices (Devices (BfArMBfArM), Germany), Germany

[email protected]@bfarm.de

Beijing, 21 to 24 June 2010Beijing, 21 to 24 June 2010

Dossier maintenance including variationsDossier maintenance including variations


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Dossier maintenanceDossier maintenance Changes to a dossierChanges to a dossier

Classification of ChangesClassification of Changes

Dossier requirementsDossier requirements ExamplesExamples

Future perspectivesFuture perspectives

RequalificationRequalification of a dossierof a dossier

In this presentationIn this presentation


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Changes made to a dossierChanges made to a dossier areare additional dataadditional data

before prequalificationbefore prequalification of the dossierof the dossier

are variationsare variations

after prequalificationafter prequalification of the dossierof the dossier

Changes made to a dossierChanges made to a dossier

may have an impact on the quality, safety and efficacy of a FFPmay have an impact on the quality, safety and efficacy of a FFP

Changes made to a dossier need to be regulatedChanges made to a dossier need to be regulated to ensure that they do not negatively impact the FPPto ensure that they do not negatively impact the FPP



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Variations to a melodyVariations to a melodyMozart, Sonata, KV 331, IMozart, Sonata, KV 331, I

........What are more striking than theWhat are more striking than the

differences, however, are thedifferences, however, are the

similarities.similarities.

So similar, indeed, are the aboveSo similar, indeed, are the above

variations to the original themevariations to the original theme

that they give the impression ofthat they give the impression of

being ornamentationsbeing ornamentations

not just of the theme itself but of annot just of the theme itself but of an

even simpler melodic outline, of whicheven simpler melodic outline, of which

MozartMozart ss original theme is perhapsoriginal theme is perhaps

itself an ornamentationitself an ornamentation........

From: Piston,From: Piston, DeVotoDeVoto, HARMONY,, HARMONY,

4th edition, W. W. Norton and Company4th edition, W. W. Norton and Company


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Variation No. 2Variation No. 2 Variation No. 1Variation No. 1

ToTo whichwhich extentextent areare VariationsVariations No. 1 and No. 2No. 1 and No. 2 supportingsupporting thethe

Original?Original?

[[BothBoth provideprovide a differenta different viewview ofofthethe samesame original]original]

OriginalOriginal


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Agencies and regulatory bodies encounter theAgencies and regulatory bodies encounter thesame challenges worldwidesame challenges worldwide

How to handle theHow to handle the huge number of changeshuge number of changes to a FPP afterto a FPP after

marketingmarketing authorisationauthorisation / registration / approval?/ registration / approval?

Industry complains if (necessary) changes to theirIndustry complains if (necessary) changes to theirFPPsFPPs arearedelayeddelayed

Patients complain if the FPP is not the same as it used toPatients complain if the FPP is not the same as it used to

bebe

How to beHow to be efficientefficient andand ensure thoroughnessensure thoroughness at the sameat the sametime?time?



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Possible solutionsPossible solutions Encourage Companies to develop and establish design spacesEncourage Companies to develop and establish design spaces

within the manufacturing procedurewithin the manufacturing procedure

Changes within the design spaceChanges within the design space arenarentt consideredconsidered

changeschanges

Establishing design spaces isEstablishing design spaces is very complexvery complex andand demandingdemanding

Classify changes according to a risk assessment?Classify changes according to a risk assessment?

Reporting (some) changes within the Annual product reviewReporting (some) changes within the Annual product review

oror

Evaluate changes according to risk categoriesEvaluate changes according to risk categories

With adapted procedural timelines/gatesWith adapted procedural timelines/gates



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Guide on Variations to aGuide on Variations to a prequalifiedprequalified product dossierproduct dossier((http://apps.who.int/prequal/info_general/documents/TRS943/TRS943http://apps.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=121.pdf#page=121))

[Variation Guide][Variation Guide]

Variations are classifiedVariations are classified according to theiraccording to their

potential impactpotential impact on pharmaceutical qualityon pharmaceutical quality The Variation guide is derived from EUThe Variation guide is derived from EU--RegulationRegulation

(EC) No 1084/2003 and associated Guidelines(EC) No 1084/2003 and associated Guidelines



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Notification (Notification (NN))

((low potential risklow potential risk to impact quality)to impact quality)

Acceptance by default (3 months)Acceptance by default (3 months)

Minor changeMinor change ((minor potential riskminor potential risk to impact quality)to impact quality)

AcceptanceAcceptance according to the Variation Guideaccording to the Variation Guide by approval onlyby approval only

Major changeMajor change ((major potential riskmajor potential risk to impact quality)to impact quality)

AcceptanceAcceptance according to the Variation Guide andaccording to the Variation Guide and further supporting documentationfurther supporting documentation

by approval onlyby approval only

Line extension/new applicationLine extension/new application (potential impact on quality considered(potential impact on quality considered too majortoo major

a new application is necessarya new application is necessary



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Variation GuideVariation Guide

Underlying principle of (risk) classification of changes:Underlying principle of (risk) classification of changes:

ConditionsConditions around the changearound the change

Potential impact of a change on quality isPotential impact of a change on quality is lowered /lowered /reducedreduced by a number ofby a number ofconditions to be fulfilledconditions to be fulfilled

If the conditions are not fulfilled the change must beIf the conditions are not fulfilled the change must be

considered to haveconsidered to have a potentially higher risk ona potentially higher risk on

qualityquality The change isThe change is automatically classified majorautomatically classified major


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Variation GuideVariation Guide

FOCUSFOCUS onon minor variationsminor variations

Lists types of variations that are subject toLists types of variations that are subject to notificationnotification ororapprovalapproval

Appendix 1Appendix 1

Gives assistance in classifying the intended changeGives assistance in classifying the intended change

Particular conditionsParticular conditions to be fulfilledto be fulfilled

Gives assistance in documentation to be providedGives assistance in documentation to be provided

SCOPESCOPE of major changes and line extensionsof major changes and line extensions Appendix 2, Appendix 3Appendix 2, Appendix 3

GENERAL ASSISTANCEGENERAL ASSISTANCE inin (additional)(additional) stability requirementsstability requirementsfor all changes (N, minor, major)for all changes (N, minor, major) Appendix 4Appendix 4



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ExceptionException

The Variation Guide isThe Variation Guide is not applicable tonot applicable to FPPsFPPs that arethat are

prequalifiedprequalified based on the assessment of a DRA of thebased on the assessment of a DRA of the

ICHICH--region and associated countriesregion and associated countries

(Innovator Guideline)(Innovator Guideline)((http://apps.who.int/prequal/info_applicants/Guidelines/GuideSubmhttp://apps.who.int/prequal/info_applicants/Guidelines/GuideSubmittingDocFPPs_DRA_ICH_08_2005.pdfittingDocFPPs_DRA_ICH_08_2005.pdf))

Variations on these types ofVariations on these types ofFPPsFPPs are approved by theare approved by the

respectiverespective DRAsDRAs of the ICH region and associated countriesof the ICH region and associated countries

and WHO is notified subsequentlyand WHO is notified subsequently


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GeneralGeneral considerationsconsiderations forforvariationvariation applicationsapplications (I)(I)

JustificationJustification//backgroundbackground whywhy changeschanges needneed toto bebe

introducedintroduced

ComparisonComparison ofofpresentpresent//prequalifiedprequalified andand proposedproposed

statestate inin tabulartabularformatformat ((transparencytransparency))

ReplacementReplacement of the relevant pages of the dossierof the relevant pages of the dossier

according to the structure listed in the PQIFaccording to the structure listed in the PQIF

Parts of the dossier that are affectedParts of the dossier that are affected by the variationby the variation need to beneed to beresubmitted according to the structure of the pharmaceutical quaresubmitted according to the structure of the pharmaceutical qualitylity

information form (PQIF)information form (PQIF)


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ExampleExample forforJustificationJustification/Background/Background

ReplacementReplacement of anof an excipientexcipient withwith aa comparablecomparable

excipientexcipient

In order toIn order to avoidavoid incompatibilitiesincompatibilities ofofmagnesiummagnesium stearatestearatewithwith ethambutolethambutol--HClHCl wewe intendintend toto exchangeexchange magnesiummagnesium

stearatestearate withwith stearicstearic acidacid


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ExampleExample forforaa ComparativeComparative TableTable ((replacementreplacement of Mgof Mg stearatestearate))

-- ComparabilityComparability ofofthethe replacedreplaced excipientexcipient isis

demonstrateddemonstrated

-- ComparativeComparative dissolutiondissolution profilesprofiles ofofbatchesbatches withwith oldold

andand newnew excipientexcipient presentedpresented

-- JustificationJustification forfornotnot submittingsubmitting aa newnew bioequivalencebioequivalence

studystudy providedprovided-- NoNo interferenceinterference withwith finishedfinished productproduct testtest methodmethod

observedobserved

-- TheThe newnew compositioncomposition isis presentedpresented

-- CoACoA ofofstearicstearic acidacid attachedattached togethertogetherwithwith aa copycopy ofof

thethe monographmonograph andand datadata onon TSETSE--safetysafety

-- CoAsCoAs ofofthreethree batchesbatches areare presentedpresented

-- StabilityStability studiesstudies withwith threethree productionproduction scalescale batchesbatches

werewere startedstarted

3.2.P.23.2.P.2 PharmaceuticalPharmaceutical developmentdevelopment

asas isis

3.2.P.3.23.2.P.3.2 BatchBatch formulaformula

asas isis

3.2.P.43.2.P.4 ControlControl ofofExcipientsExcipients

asas isis

3.2.P.53.2.P.5 ControlControl of FPPof FPPasas isis

3.2.P.83.2.P.8 StabilityStability

asas isis

ProposedProposedPresentPresent


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GeneralGeneral considerationsconsiderations forforvariationvariation applicationsapplications (II)(II)

ConsequentialityConsequentiality

SmPCSmPC consequentiallyconsequentially needsneeds toto bebe changedchanged,, ififaffectedaffected byby

thethe changechange

e.ge.g.. changechange inin pharmaceuticalpharmaceutical attributesattributes listedlisted inin thethe SmPCSmPC//containercontainer

labellabel ((manufacturingmanufacturing sitesite,, containercontainermaterial,material, excipientsexcipients etc.)etc.)

AdditionalAdditional variationvariation applicationsapplications toto bebe filedfiled ififeffectedeffected byby thethe

originaloriginal variationvariation applicationapplication

e.ge.g.. changechange inin manufacturingmanufacturing sitesite maymay necessitatenecessitate adaptationadaptation ofofbatchbatch

sizesize duedue toto equipmentequipment needsneeds


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GeneralGeneral considerationsconsiderations forforvariationvariation applicationsapplications (III)(III)

ConditionsConditions

reducereduce thethe riskrisk ofofimpactimpact onon qualityquality

OnlyOnly if all conditions are metif all conditions are met the variation is consideredthe variation is considered minorminor In caseIn case one of all conditions is not metone of all conditions is not met the variation isthe variation is

consideredconsidered majormajor

Documentation requirementsDocumentation requirements beyond those of Variation Guidebeyond those of Variation Guide

Essential toEssential to clarifyclarify whetherwhetherthethe conditionsconditions areare metmet


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Condition No. 1:Condition No. 1: You must proceed at a minimum velocity of 30 miles/hourYou must proceed at a minimum velocity of 30 miles/hour

It is essential to clarify whether the conditions are metIt is essential to clarify whether the conditions are met


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ExamplesExamples

NotificationsNotifications


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-- 11 The manufacturing site remains the sameThe manufacturing site remains the same

DocumentationDocumentation

-- 11,, -- 22

NN1, 21, 211


to be suppliedto be suppliedConditions to beConditions to be

fulfilledfulfilled44 Change in the name and/or address of theChange in the name and/or address of the

manufacturer of the finished pharmaceutical productmanufacturer of the finished pharmaceutical product


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--11 No changes to the manufacturing methods other than those necessiNo changes to the manufacturing methods other than those necessitated bytated byscalescale--up, e.g. use of different sized equipmentup, e.g. use of different sized equipment

--22 Test results of at least two batches according to the specificatTest results of at least two batches according to the specifications should beions should beavailable for the proposed batch sizeavailable for the proposed batch size

--33 The change does not affect the reproducibility of the processThe change does not affect the reproducibility of the process

--44 The change should not be the result of unexpected events arisingThe change should not be the result of unexpected events arising duringduringmanufacture or because of stability concernsmanufacture or because of stability concerns

DocumentationDocumentation ((--11,, --22,, --33,, --44))

1, 3, 41, 3, 41, 2, 31, 2, 3c)c) More than 10More than 10--fold increase compared to thefold increase compared to the

prequalifiedprequalified batch sizebatch size

NN1, 21, 21, 2, 3,1, 2, 3, 44b)b) DownscalingDownscaling

NN1, 21, 21, 2, 31, 2, 3a)a) Up to 10Up to 10--fold increase compared to thefold increase compared to the

prequalifiedprequalified batch sizebatch size


to be suppliedto be supplied

Conditions to beConditions to be

fulfilledfulfilled99 Change in batch size of API or intermediateChange in batch size of API or intermediate


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ExamplesExamples

Minor changesMinor changes


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1, 2, 3, 4, 51, 2, 3, 4, 51, 3, 41, 3, 4

NN1, 4, 51, 4, 51,1, 22, 3, 4, 3, 4b)b) All other pharmaceutical formsAll other pharmaceutical forms

1, 2, 3, 4, 51, 2, 3, 4, 51,1, 22, 3, 4, 3, 4a)a) Semisolid and liquid pharmaceutical formsSemisolid and liquid pharmaceutical forms


to be suppliedto be suppliedConditionsConditions

to be fulfilledto be fulfilled

2626 Change in the qualitative and/or quantitativeChange in the qualitative and/or quantitative

composition of the immediate packagingcomposition of the immediate packagingmaterialmaterial


11-- The product concerned is not a sterile productThe product concerned is not a sterile product

22-- The packaging type and material remainThe packaging type and material remain the samethe same (e.g. a different blister, but same type)(e.g. a different blister, but same type)

33-- TheThe relevant propertiesrelevant properties of the proposed packaging material must be at leastof the proposed packaging material must be at least equivalentequivalent toto

those of thethose of the prequalifiedprequalified materialmaterial

44-- Relevant stability studiesRelevant stability studies with the relevant guidelines have been started with at leastwith the relevant guidelines have been started with at least two pilottwo pilot--

scale or production scale batchesscale or production scale batches, and at least, and at least three monthsthree months stability data are at thestability data are at the

disposal of the applicantdisposal of the applicant. Assurance is given that these studies will be. Assurance is given that these studies will be finalisedfinalised and that theand that thedata will be provided immediately to WHO if outside specifidata will be provided immediately to WHO if outside specifications or potentially outsidecations or potentially outside

specifications at the end of thespecifications at the end of the prequalifiedprequalified shelf life (with proposed action)shelf life (with proposed action)

Documentation (Documentation (--11,, --22,, --33,, --44,, --55))


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1, 2, 3, 4, 51, 2, 3, 4, 51, 3, 41, 3, 4

NN1, 4, 51, 4, 51,1, 22, 3, 4, 3, 4b)b) All other pharmaceutical formsAll other pharmaceutical forms

1, 2, 3, 4, 51, 2, 3, 4, 51,1, 22, 3, 4, 3, 4a)a) Semisolid and liquid pharmaceutical formsSemisolid and liquid pharmaceutical forms

DocumentationDocumentationto be suppliedto be supplied

ConditionsConditionsto be fulfilledto be fulfilled

2626 Change in the qualitative and/or quantitativeChange in the qualitative and/or quantitative

composition of the immediate packagingcomposition of the immediate packaging

materialmaterial

All dosage formsAll dosage forms

SterileSterile FPPsFPPs are handled as major variationsare handled as major variations

Semisolid and liquid preparationsSemisolid and liquid preparations

Change in type/materialChange in type/material of packaging material:of packaging material: major variationmajor variation

All other dosage formsAll other dosage forms Change type/material of packaging material:Change type/material of packaging material: minor variationminor variation but extendedbut extended

documentation requirements (1documentation requirements (1 5)5)


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-- 11 The specifications (including inThe specifications (including in--process controls, methods of analysis of allprocess controls, methods of analysis of allmaterials), method of preparation (including batch size) and detmaterials), method of preparation (including batch size) and detailed route ofailed route ofsynthesis are identical to those alreadysynthesis are identical to those already prequalifiedprequalified

-- 22 Where materials of human or animal origin are used in the procesWhere materials of human or animal origin are used in the process, the manufacturers, the manufacturerdoes not usedoes not use any new supplier for which assessment is required of viral safeany new supplier for which assessment is required of viral safety or ofty or ofcompliance with the currentcompliance with the current ......WHO or EU or ICH Guidelines on TSEWHO or EU or ICH Guidelines on TSE......

Documentation (Documentation (--11,, --22,, --33,, --44,, --55))

-- 22 A declarationA declaration from the supplier of thefrom the supplier of the prequalifiedprequalified FPPFPP that the route of synthesis,that the route of synthesis,quality control procedures and specifications of the API and keyquality control procedures and specifications of the API and key (ultimate) intermediate in(ultimate) intermediate inthe manufacturing process of the API (if applicable) are the samthe manufacturing process of the API (if applicable) are the same as those alreadye as those alreadyprequalifiedprequalified..

1, 2, 3, 4, 51, 2, 3, 4, 51, 21, 2b)b) New manufacturer (relacement or addition)New manufacturer (relacement or addition)

1, 2, 3, 4, 51, 2, 3, 4, 51, 21, 2a)a) Change in site of the already prequalifiedChange in site of the already prequalified

manufacturer (replacement or addition)manufacturer (replacement or addition)




fulfilledfulfilled

1212 Change in theChange in the manufacturer of the API ormanufacturer of the API or

final (ultimate) key intermediatefinal (ultimate) key intermediate in thein themanufacturing process of the APImanufacturing process of the API


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How to verify that the specifications/method of preparation/detaHow to verify that the specifications/method of preparation/detailediled

route of synthesis are the same as those alreadyroute of synthesis are the same as those already prequalifiedprequalified??

Comparison of APIComparison of API--datadata ofofprequalifiedprequalified and proposed APIand proposed API--manufacturer by themanufacturer by the

FPPFPP--manufacturermanufacturer

Available from the APIAvailable from the API--part of the dossier/OP ofpart of the dossier/OP ofAPIMFs/DMFsAPIMFs/DMFs

Tabular presentation of data (documented evidence)Tabular presentation of data (documented evidence)

1, 2, 3, 4, 51, 2, 3, 4, 51, 21, 2b)b) New manufacturer (relacement or addition)New manufacturer (relacement or addition)

1, 2, 3, 4, 51, 2, 3, 4, 51, 21, 2a)a) Change in site of the already prequalifiedChange in site of the already prequalified

manufacturer (replacement or addition)manufacturer (replacement or addition)




fulfilledfulfilled

1212 Change in the manufacturer of the API orChange in the manufacturer of the API or

final (ultimate) key intermediate in thefinal (ultimate) key intermediate in themanufacturing process of the APImanufacturing process of the API


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ExamplesExamples

Major changesMajor changes


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Exceed the scope of minor changesExceed the scope of minor changes

Do not yet reach the scope of line extensionsDo not yet reach the scope of line extensions

Most likely the following cases occur:Most likely the following cases occur:

Change in theChange in the manufacturing processmanufacturing process of theof the APIAPI

Change in theChange in the compositioncomposition of theof the FPPFPP

Change to theChange to the immediate primary packagingimmediate primary packaging of theof the FPPFPP

D i i t i l di i ti


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Documentation requirementsDocumentation requirements

Replacement of particular sections affected by the changeReplacement of particular sections affected by the change

According to the structure as listed in the PQIFAccording to the structure as listed in the PQIF

Potential implications of the change on the FFPPotential implications of the change on the FFP

IndividualIndividual documentation and justificationdocumentation and justification

D i i t i l di i tiD i i t i l di i ti


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Changes that afford a new application / line extensionChanges that afford a new application / line extension

Changes to the APIChanges to the API

Replacement, addition, removal, change of doseReplacement, addition, removal, change of dose

Changes to the pharmaceutical form / dosage formChanges to the pharmaceutical form / dosage form

From immediate release to delayed or modified release and vice vFrom immediate release to delayed or modified release and vice versaersa

From liquid to powder for reconstitution and vice versaFrom liquid to powder for reconstitution and vice versa



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Stability requirements for changes toStability requirements for changes to prequalifiedprequalifiedFFPsFFPs Scope and design of stability studies for variations basedScope and design of stability studies for variations based

onon

knowledge and experience acquired on APIs andknowledge and experience acquired on APIs and

FPPsFPPs

Stability profile, supportive data, data on primary batchesStability profile, supportive data, data on primary batches

InvestigationsInvestigations on potential impact of changes on stabilityon potential impact of changes on stabilityof API/FPP are at theof API/FPP are at the responsibility of Applicantsresponsibility of Applicants

Stability studies required due to changes are to beStability studies required due to changes are to becontinued up to the proposed shelf lifecontinued up to the proposed shelf life

WHOWHO to beto be informedinformed onon deviationsdeviations immediatelyimmediately



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Minor changesMinor changes

ComparisonComparison of stability data of theof stability data of the changedchanged product toproduct to

stability data ofstability data ofunchangedunchanged productproduct

Evidence ofEvidence ofunchanged quality characteristicsunchanged quality characteristics


Stability studies depending onStability studies depending on

thethe naturenature of theof the changechange

thethe characteristicscharacteristics of theof the API/FPPAPI/FPP



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Changed manufacturing process of APIChanged manufacturing process of API

Changed quality characteristics of API?Changed quality characteristics of API?

Changed stability profile of API?Changed stability profile of API?

Impacted stability profile of FPPImpacted stability profile of FPP??

Changed composition/container of FPPChanged composition/container of FPP

Critical dosage form or unstable API?Critical dosage form or unstable API?

Changed container of FPPChanged container of FPP Risk of interaction/less protection by packaging?Risk of interaction/less protection by packaging?

D i i t i l di i tiDossier maintenance including variations


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Variation GuideVariation Guide ForecastForecast ReRe--Evaluation of the suitabilityEvaluation of the suitability of Variation Guideof Variation Guide

for PQ initiatedfor PQ initiated

Suitability of the new EUSuitability of the new EU--Variation RegulationVariation Regulation forfor

PQ under discussionPQ under discussion

WHAT ARE THE MAIN DIFFERENCESWHAT ARE THE MAIN DIFFERENCES BETWEENBETWEEN

THE PREVIOUS AND THE NEW VERSION?THE PREVIOUS AND THE NEW VERSION?

(EC) No 1084/2003 versus (EC) No 1234/2008(EC) No 1084/2003 versus (EC) No 1234/2008



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New Variation Regulation (EC) No 1234/2008New Variation Regulation (EC) No 1234/2008

FOCUSFOCUS on notifications (type IA; exhaustive list)on notifications (type IA; exhaustive list)

Definition of major changes and line extensionsDefinition of major changes and line extensions

All remaining changes are automatically type IBAll remaining changes are automatically type IB

NotificationsNotifications may bemay be immediately implemented by manufacturersimmediately implemented by manufacturers

HOWEVERHOWEVER, within a year (in certain cases immediately) they must be, within a year (in certain cases immediately) they must benotifiednotified andand may be rejectedmay be rejected

Type IA changes (Notifications) are regulated byType IA changes (Notifications) are regulated by conditionsconditions andand

documentationdocumentation requirementsrequirements

Type IB changes are regulated byType IB changes are regulated by documentation requirementsdocumentation requirements onlyonly

Variation applications may beVariation applications may be groupedgrouped



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New EUNew EU--guidance versus PQ Variation Guideguidance versus PQ Variation Guide Grouping has always been allowed in PQGrouping has always been allowed in PQ

Grouping of dossiers affected by a changeGrouping of dossiers affected by a change

Grouping of variations affecting a dossierGrouping of variations affecting a dossier

So far fees have not been charged in PQSo far fees have not been charged in PQ

PQPQ cannot use the same timelinescannot use the same timelines as compared to EUas compared to EU

agenciesagencies

manman,, temporary scheduletemporary schedule



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RequalificationRequalification Guideline on theGuideline on the RequalifiationRequalifiation ofofprequalifiedprequalified dossiersdossiers

[[http://apps.who.int/prequal/info_applicants/Guidelines/RequalDoshttp://apps.who.int/prequal/info_applicants/Guidelines/RequalDossiers_Guideline.pdfsiers_Guideline.pdf]]

PurposePurpose

Verification of the acceptability of the product meeting currentVerification of the acceptability of the product meeting current

norms and standardsnorms and standards

Verification of the consistency of the quality of theVerification of the consistency of the quality of the prequalifiedprequalified

product including its manufacturing processproduct including its manufacturing process

Over the identified periodOver the identified period



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RequalificationRequalification Data requirementData requirement

Summary of key product information (Appendix 1)Summary of key product information (Appendix 1)

Summary of variations to the product (Appendix 2)Summary of variations to the product (Appendix 2)

Pharmaceutical Quality Information Form (PQIF)Pharmaceutical Quality Information Form (PQIF)

Specifications of API and FPP (history and current)Specifications of API and FPP (history and current)

Product quality review, if applicableProduct quality review, if applicable

Summary / ConclusionSummary / Conclusion


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Variations to aVariations to a prequalifiedprequalified product dossier need to beproduct dossier need to be

approved by WHO because they may impact the quality of theapproved by WHO because they may impact the quality of theFPPFPP

Most variations occurring in PQ are reflected in Appendix 1 ofMost variations occurring in PQ are reflected in Appendix 1 ofthe Variation Guide (minor changes)the Variation Guide (minor changes)

Major changes afford a more thorough documentationMajor changes afford a more thorough documentationapproach and evaluation procedure to ensure unchangedapproach and evaluation procedure to ensure unchangedquality characteristicsquality characteristics

The concept of the Variation Guide reflects a riskThe concept of the Variation Guide reflects a risk--basedbased--approachapproach

RequalificationRequalification aims at verification of continuous acceptabilityaims at verification of continuous acceptabilityand consistency of the quality ofand consistency of the quality ofprequalifiedprequalified FPPsFPPs

Summary / ConclusionSummary / Conclusion



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TT HH AA NN KK YY OO UU

004-dossier maintenance variations

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