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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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Birgit Schmauser| June 20102 |
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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Birgit Schmauser| June 20103 |
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
Dossier maintenance including variationsDossier maintenance including variations
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Birgit Schmauser| June 20104 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 20105 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 20106 |
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?
Dossier maintenance including variationsDossier maintenance including variations
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Birgit Schmauser| June 20107 |
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
Dossier maintenance including variationsDossier maintenance including variations
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Birgit Schmauser| June 20108 |
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
Dossier maintenance including variationsDossier maintenance including variations
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Birgit Schmauser| June 20109 |
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
Dossier maintenance including variationsDossier maintenance including variations
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Birgit Schmauser| June 201010 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201011 |
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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Birgit Schmauser| June 201012 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201013 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201014 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201015 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201016 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201017 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201018 |
Dossier maintenance including variationsDossier maintenance including variations
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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Birgit Schmauser| June 201019 |
Dossier maintenance including variationsDossier maintenance including variations
ExamplesExamples
NotificationsNotifications
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Dossier maintenance including variationsDossier maintenance including variations
ConditionsConditions
-- 11 The manufacturing site remains the sameThe manufacturing site remains the same
DocumentationDocumentation
-- 11,, -- 22
NN1, 21, 211
DocumentationDocumentation
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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Dossier maintenance including variationsDossier maintenance including variations
ConditionsConditions
--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
DocumentationDocumentation
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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Dossier maintenance including variationsDossier maintenance including variations
ExamplesExamples
Minor changesMinor changes
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Dossier maintenance including variationsDossier maintenance including variations
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
DocumentationDocumentation
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
ConditionsConditions
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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Dossier maintenance including variationsDossier maintenance including variations
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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Dossier maintenance including variationsDossier maintenance including variations
ConditionsConditions
-- 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)
DocumentationDocumentation
to be suppliedto be supplied
Conditions to beConditions to be
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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Dossier maintenance including variationsDossier maintenance including variations
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)
DocumentationDocumentation
to be suppliedto be supplied
Conditions to beConditions to be
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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Appendix 2Appendix 2
Major changesMajor changes
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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Appendix 2Appendix 2
Major changesMajor changes
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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Appendix 3Appendix 3
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
D i i t i l di i tiD i i t i l di i ti
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Appendix 4Appendix 4
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
D i i t i l di i tiD i i t i l di i ti
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Appendix 4Appendix 4
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
Major changesMajor changes
Stability studies depending onStability studies depending on
thethe naturenature of theof the changechange
thethe characteristicscharacteristics of theof the API/FPPAPI/FPP
D i i t i l di i tiD i i t i l di i ti
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Appendix 4Appendix 4
Major changesMajor changes
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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Dossier maintenance including variationsDossier maintenance including variations
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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