fda inspections - lessons learnt

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FDA Inspections – Lessons Learnt www.visamed.com Arne Briest CEO

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FDA Inspections – Lessons Learnt

www.visamed.com

Arne BriestCEO

FDA Inspections – Lessons Learnt

How does FDA decide who to inspect?

• Registration database identifies who manufacturers devices for distribution in the U.S.

• Listing database identifies what devices they distribute

• FDA prioritizes inspections by risk and gives higher risk devices/situations a higher priority

FDA Inspections – Lessons Learnt

How does FDA choose ?

• Mandated by law, every 2 years for class II and class III device manufacturers

• Risk• Follow up inspections to a regulatory action• Complaints (public & industry) and Recalls

FDA Inspections – Lessons Learnt

Investigator Tools

• Federal Food, Drug, and Cosmetic Act• 21 Code of Federal Regulations (800-

1299)• Quality Systems Manual: A Small Entity

Compliance Guide on-line

FDA Inspections – Lessons Learnt

Investigator Tools

• Compliance Policy Guides• Quality System Inspection Techniques

(QSIT)• Compliance Program Guidance Manual• CP 7382.845 Inspection of Medical Device

Manufacturers available on-line

FDA Inspections – Lessons Learnt

Investigator Tools

• Investigations Operations Manual• 5.2.1.1 Preannouncements• 5.6.2 Medical Device Quality System/

GMP• 5.6.9 Device Inspection Reports• 5.10.4.3.9 Manufacturing/Design

Operations Specific Instructions for medical device EIRs

• 5.10.4.3.16 Additional information Specific Instructions for medical device EIRs

FDA Inspections – Lessons Learnt

Investigator Tools

• Previous Establishment Inspections Reports

• Training Courses• Other investigators or FDA Labs• DSMICA

FDA Inspections – Lessons Learnt

Investigator Tools

• Guidance Documents (can be accessed from www.FDA.gov website under Medical devices CDRH Device Advice)

• Internet • Other Federal, State and Local agencies• FDA Recognized Consensus Standards

FDA Inspections – Lessons Learnt

What is high priority for an inspection?

• Make Class III or Class II devices • Make implantable devices and life

supporting and life sustaining devices• Recently introduced a new device to the

market• Have had significant violations and

complaints in the past• Have had a recall

FDA Inspections – Lessons Learnt

Does FDA notify the manufacturer of an upcoming inspection?

• FDA calls domestic manufacturers up to 5 calendar days before the inspection

• FDA contacts foreign manufacturers 2 - 3 months in advance to schedule inspection

• Manufacturer may be requested to send Quality System Manual or equivalent for pre-inspection review

FDA Inspections – Lessons Learnt

Does FDA notify the manufacturer of an upcoming inspection?

• FDA calls domestic manufacturers up to 5 calendar days before the inspection

• FDA contacts foreign manufacturers 2 - 3 months in advance to schedule inspection

• Manufacturer may be requested to send Quality System Manual or equivalent for pre-inspection review

FDA Inspections – Lessons Learnt

WhathappenswhentheFDAinvestigatorarrivesatthesite?

• Asktoseethetopmanagement(”mostresponsibleperson”atthefirm.

• Presentcredentials(identificationasanauthorizedFDAinvestigator)

• IssueFDA-482“NoticeofInspection”(explainsFDA’slegalauthoritytoinspect)

FDA Inspections – Lessons Learnt

ThisisanexampleofFormFDA482,NoticeofInspection

FDA Inspections – Lessons Learnt

Can you refuse an inspection?

• Under section 704 of the FD&C Act, FDA is authorized to enter establishments.

• They are further authorized to inspect “at reasonable times and within reasonable limits and in a reasonable manner”.

• FDA can also seek an Administrative Inspection Warrant from a United States District Court.

FDA Inspections – Lessons Learnt

Whathappensnext?

• Gatherinformationaboutsizeandstructureofcompany,whoaretheresponsibleofficials,whatproductsaremanufacturedthere.

• Evaluatethemanufacturer’sQualitySystemusingtheQualitySystemInspectionTechnique(QSIT)

FDA Inspections – Lessons Learnt

What happens during the inspection?

• Investigator may tour the facility to get an idea of layout, workflow, and areas that may need closer inspection. (Start Big, Get Small)

• This helps the investigator decide how to organize the inspection

FDA Inspections – Lessons Learnt

Whathappensduringtheinspection?

• TheInvestigatormayrequesttointerviewemployees,takesamples(484ReceiptforSample)andmakecopiesofdocuments.

• TheInvestigatormayalsorequesttotakedocumentsandpicturesduringtheinspection

FDA Inspections – Lessons LearntWhatisQSIT?

• Identifies4majorsubsystemstoevaluateandstatesthepurposeandimportanceofeachsubsystem

• CAPA• DesignControls• Management• ProcessControl

• Providesflowchartsandinspectionalobjectivestocoverduringinspection

• Offersadviceoninspection• Providestablesforstatisticalsamplingofrecordsfor

review

FDA Inspections – Lessons Learnt

WhatisQSIT?

http://www.fda.gov/downloads/ICECI/Inspections/InspectionGuides/UCM085938.pdf

FDA Inspections – Lessons Learnt

SubsystemsoftheQualitySystem

http://www.fda.gov/ICECI/Inspections/Inspect ionGuides/ucm074883.htm

FDA Inspections – Lessons Learnt

DoesFDAconductdifferenttypesofinspections?

• Investigationmayconduct1of4typesofinspectionformedicaldevices:

• Level1– AbbreviatedQSIT• Level2– BaselineQSIT(Comprehensive)• Compliancefollow-up• ”Forcause”

FDA Inspections – Lessons Learnt

WhatisaLevel2baseline(comprehensive)inspection?

• Coversall4mainsubsystems• IsconductedwhenthefirmhasneverhadLevel

2inspectionandevery6yearsthereafter,resourcespermitting

• Providesanoverallevaluationofthefirm‘squalitymanagementsystem

FDA Inspections – Lessons Learnt

WhatisaLevel1abbreviatedinspection?

• IsconductedafterfirmhashadaLevel2inspection,andqualitysystemwasincompliancewithrequirements

• CoversCAPAplusoneothermajorsubsystem• Coversadifferentsubsystemeachtime

FDA Inspections – Lessons Learnt

Whatisa“ForCause”inspection?

• InitiatedattherequestofCDRH,ORAHeadquarters,RegionalorDistrictDirective

• DictatedbythesourceofinformationandmaydifferfromtypicalQSITapproach

• TheseinspectionsaregenerallymoreindepthinparticularareasthantypicalQSITinspections

• ConductedastheneedarisesImportantnoteinCP,iftheInvestigatorencountersaseriouspublichealthriskduringtheQSITinspectiontheinvestigatormayswitchtoaforcauseinspection

FDA Inspections – Lessons Learnt

Whatisacompliancefollow-upinspection?

• Isconductedtoverifyadequatecorrectionofpreviousviolationsordocumentcontinuingviolationstosupportpossibleregulatoryaction

• Isconductedtofollowuponinformationindicatingseriousproblemsatfirm

• MayincludeelementsofQSIT

FDA Inspections – Lessons Learnt

Whathappensattheendoftheinspection?

• Meetwithmanagementtodiscusstheinspection• PresenttheFDA483“ListofObservations”ofany

significantobservations• Discusstheobservations

FDA Inspections – Lessons Learnt

ThisisanexampleoftheFDAForm483,InspectionalObservations.Theheaderidentifies theFDAdistrictofficethatperformed theinspection,thedate(s)ofinspection,nameandaddressofthefacilitythatwasinspected,thenameandtitleoftheindividualtowhomthe483isissuedto(usuallythemostresponsibleindividualphysicallypresentinthefacility),abriefdescriptionofthetypeoffacility,andthefacility'sFEI(FDAEstablishmentIdentification)number.

FDA Inspections – Lessons Learnt

FDA– 483“InspectionalObservation”

• Thecontentofa483maybehandwritten,typed,completedinaPDFfileandprinted,orcompletedviatheFDA'scomputersystemcalledTurboEIR.

• Theobservations listedonthisformdonotrepresentafinalagencydeterminationregardingyourcompliance.Anadditionalstatementonlyincludedformedicaldevicesisthattheobservationsarenotanexhaustivelistingofobjectionableconditions.Underlawyourfirmisresponsible forconductinginternalself-audits toidentifyandcorrectanyandallviolationsofthequalitysystemrequirements.”

• Ifthefirmhaspromisedand/orcompletedacorrectiveactiontoanFDA483priortothecompletionoftheinspection,theFDA483shouldbeannotated.

FDA Inspections – Lessons Learnt

FDA-483“InspectionalObservations”TurboEIR(EstablishmentInspectionReport)?

• Linkscitationstounderlyingregulationsandstatutes

• ProvidesuniformFDA-483sandEIRs• Improvesdataanalysis

FDA Inspections – Lessons LearntWhatareannotationstothe483Asof1997,theFDAestablishedanannotationpolicyformedicaldeviceinspections.Theinvestigator(s)shouldoffertoannotatethe483withoneofthefollowing:

• Reportedcorrected,notverified• Correctedandverified• Promisedtocorrect(maybeappendedwith"byxxxdate"or"withinxxxx daysormonths")• Underconsideration• Noannotation

Theactualannotationofthe483occursduringthefinaldiscussionofthefirm’smanagement;ifthefirmprefersnoannotation,thenannotationwillnotbeperformed.Theannotationsmaybeaftereachobservation,attheendofeachpage,oratthebottomofthelastpagepriortotheinvestigator’ssignature(s).

Theterm„verified”means„toconfirm;toestablishthetruthoraccuracy”.Incase,theinvestigatormustdotheverification.Insomesituations,theywillnotbeabletoverifythecorrectiveactionunlessthereisfurtherdistrictorCenterrevieworuntilthereisanotherinspectionoftheestablishment.Ifthefirmhaspromisedcorrectionandfurnishesadateortimeframeforcompletion,thismaybeaddedtotheannotation.Iftheinvestigatorandfirmhave„agreedtodisagree”aboutthevalidityofanobservation,theobservationmaybeannotatedwith„underconsideration”ornoannotationisused,basedonthefirm’sdecision.

FDA Inspections – Lessons LearntTop10DevicesObservationsUsedinTurboEIR- 2015http://www.fda.gov/ICECI/Inspections/ucm481432.htm#Devices

FDA Inspections – Lessons LearntTop10DevicesObservationsUsedinTurboEIR-2014

FDA Inspections – Lessons Learnt

Whatshouldthemanufacturerdoaftertheinspection?

• SendalettertoFDAidentifyinghowtheyhavecorrectedobservationsorwillcorrectthem

• Providedocumentationofanycorrectionsthathavebeencompleted

• Provideatimetableorestimatedcompletiondateforfuturecorrections

FDA Inspections – Lessons Learnt

Whathappensnext?

• Investigatorreturnstoofficetowritean“EstablishmentInspectionReport”orEIR

• Inspectionisclassifiedbasedoninspectionalfindings

• Complianceofficerdecideswhethertorecommendregulatoryaction

FDA Inspections – Lessons Learnt

HowdoesFDAclassifyinspectionreports?• NAI– Noactionindicated• VAI– Voluntaryactionindicated– somedeficiencies

butnotserious• OAI– Officialactionindicated– seriousdeficiencies

identified,andFDAmusttakeactiontoassurecorrection

FDA Inspections – Lessons Learnt

WhatactionscanFDAtaketoaddressOAIinspections?

• WarningLetter• Seizure(Importrestrictions)• Injunction• Civilpenalties• Criminal

FDA Inspections – Lessons Learnt

WarningLetter

• FDAsends“WarningLetter”describingmanufacturer’sviolationsofFDAregulationsandrequestingareplywithin15days

• FDAinspectsthemanufacturer6- 12monthsaftersendingtheWarningLettertoconfirmcorrectionofdeficiencies

FDA Inspections – Lessons Learnt

Preparation

• ConfirmInspectionDatewithFDAprovidetravelandhotelsuggestion

• ReviewpreviousFDAinspectiondocumentation483

• IdentifycompanyprimarycontactandSubjectMatterExperts

• PrepareListofProductsShippedtoUSA• ReviewEstablishmentListing• ReviewUSclearanceandapprovalstatus

FDA Inspections – Lessons Learnt

Preparation

• PerformGapAnalysistoQSR• Focus

• CAPA• DesignChangesandDesignControl• ComplaintsMDRs• Recalls• ProcessValidation• LabelingversusClearance• Audits• Purshasing

FDA Inspections – Lessons Learnt

Preparation

• EstablishrealisticCorrectionPlan• TrainEmployeesonQSRandGeneralBehavior

duringInspection• PrepareListofContacts/SME’sanddeputies• SetUpFrontandBackOffice• PerformSimulatedInspectiontoVerifyWorkFlow

duringInspection• PreparealistofknowGapsnotCorrectedpriorto

Inspection• DiscussopenRisksandGapstoagreeonStrategy

FDA Inspections – Lessons Learnt

DuringInspection

• AskforAgendatoplanfacilitytoursandSME’s• DocumentRequestsfromInspectorandStatus,

informinspectorondelaysinprovidingdocumentation

• TrackDocumentsRequested• TrackInteractionwithEmployees• Incasetheinspectorrequestsdocumentationtobe

sendtoFDAdocumentdocumentstransferred