Session1:

IntroductiontoFDAAudits

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InthisSession

IntroductiontotheUSFDA
ReasonsforanFDAaudit
KindsofFDAaudits:GCP,GMP,GLP,etc
IntroductiontoFDAauditors
S i l
SpecialconsiderationsfornonUSauditsby
id ti
f
US dit b
FDA

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WhatisFDA?(1)

AUSfederalagency
Regulatesmanufactureandmarketingofdrugs,biologics,
medicaldevices,dietarysupplements,cosmetics,herbals,
combinationproducts,veterinarydrugs,tobaccoproducts
WorkswithUSDAtoregulatefoodandwater

FDA:agenciafederalenEEUUacargoderegularlamanufacturay
elmercadeodemedicamentos,productosbiolgicos,
dispositivosmdicos,suplementosdietticos,cosmticos,
productosabasedehierbas,productosdecombinacin,
medicamentosparausoveterinario,productosabasedetabaco,
etc.Regulalacalidaddelosalimentosyelaguajuntoconel
DepartamentodeAgricultura
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WhatisFDA?(2)

Morethan15,000employees
MostlyintheWashingtonDCarea
PhDs,MDs,Pharmacists,Lawyers,MBAs,andsimilardegrees
Mostdiverseintermsofbackgroundofemployees

HeadquarterinMaryland
OfficesinmostUSstates
Offices in most US states
6InternationalofficecoveringmostoftheWorld

LaFDAcuentaconmsde15.000empleadossituadosenEEUUy
alrededordelmundo.Cuentaconunadiversagamade
profesionales(cientficos,farmaceutas,abogados,etc.)
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FDAOrganization(1)

About10OfficesandCenters

CenterforDrugEvaluationandResearch (CDER)
CenterforBiologicsEvaluationandResearch (CBER)
CenterforDevicesandRadiologicalHealth(CDRH)
CenterforFoodSafetyandAppliedNutrition(CFSAN)
CenterforVeterinaryMedicine(CVM)
Center for Tobacco Products (CTP)
CenterforTobaccoProducts(CTP)

LaFDAsecomponede10oficinasycentros:
Centroparalaevaluacineinvestigacindemedicamentos
Centroparalaevaluacineinvestigacindeproductos
biolgicos
Otros
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FDAOrganization(2)

Twolevelorganizationstructure
Level1:Typeofproduct:drug,biologic,device,etc
Level2:Diseasepursued:cancer,cardiorenal,allergy,etc
Eachlevelsupportedbycommonoffices:Quality,Statistics,
pharmacology,advertisement,legal,audit(investigations)

Overallmorethan100Divisionsordepartments
EachapplicationhastoworkwithaspecificDivision
Each application has to work with a specific Division
Veryhierarchical;companiesneedtofollowtheprocess

LaFDAseorganizaen2nivelesdeacuerdoaltipodeproductoo
condicinatratar.Cadanivelcuentaconelapoyodedivisiones
comunes,talescomo:calidad,estadstica,farmacologa,etc.
Esteesunsistemaaltamentejerrquico
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USDrugMarket

About>50%ofglobalrevenues
Prescriptiondrugs:Innovatorandgeneric
Dietarysupplements,medicalfoods:risingsectors

Acceptabilityofproductsmanufacturedanywherein
theworld
About20%ofInnovatorand>80%ofgenericdrugsare
importedintotheUS

StrictcontrolbyFDAonimports

Extensivepaperwork:registrations
Audits:Pre andpostmarketapproval
Masdel50%delasgananciasglobalessegeneranenelmercado
deEEUU.Lamayorademedicinasgenricasproducidasen
otrospasessonaceptadasenEEUU.LaFDAmantieneun
estrictocontrolsobrematerialesimportados
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USRegulationsVersusROW

Increasedharmonizationofrules
ICHguidance
PIC/Ssignatory
Informationsharingwithotherregulators

GlobalstandardswithUScustomization
Applicationspecificselfreview
FrequentlycometodifferentconclusionsthanROW
Frequently come to different conclusions than ROW

Acomparacinconelrestodelmundo,elsistemaregulatorioen
EEUUseencuentraenmayorarmonaconotrasconvenciones
internacionales

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SoyouhaveaProductthatyouWantto
SellintheUS

Multidimensionalstrategy
Productclassification
Reviewofavailableinformation,e.g.,marketing
history,label,claims,etc
FDAconsultationandreviewofregulatoryoptions
Standardizationofmanufacturingprocesses
Testing clinical/nonclinical,ifrequired

ElpromoverunproductoenelmercadoAmericanorequiere
unaestrategiamultidimensional(clasificacin,evaluacin
delhistorial,comunicacinconlaFDA,planificacin,
normalizacindelprocesodemanufacturayevaluacin
clnicaopreclnica
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ManufacturersResponsibilities

Complywithapplicableregulations
ProvideFDAwithdocumentationtosupportclaims
LetFDAknowaboutallaccidents
BeavailabletobeauditedbyFDA
RespondtoallauditfindingsandFDAsactions

Esresponsabilidaddelproveedoracatarlasnormasde
manufactura,brindardocumentosrelevantesalaFDA,reportar
accidentes,estardispuestoarecibirauditoraydarrespuesta
apropiadaalosveredictosyaccionesdelaFDA

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WheretoFindFDAsRules?

CodeofFederalRegulations
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

Productspecificguidancedocuments
FDAswebsite

LosparmetrosquerigenlaFDAseencuentranenelcdigode
Los
parmetros que rigen la FDA se encuentran en el cdigo de
regulacinfederal,enguasespecificasparacadatipode
productoyenelsitiowebdelaFDA

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SpecialRulesfornonUSCompanies

NeedaAuthorizedUSagentforFDAcommunications
PrimarycontactforallapplicationswithFDA
Responsibleforcustomclearanceandapplicablepermits
LegalrepresentativetoFDAforalldecisions

CompliancewithlocalrulesadditionaltoFDArules

Mustbelegalentityinthecountryofoperation
ust be ega e t ty t e cou t y o ope at o
Mustfollowinternationalstandardsofqualityandtransparency
Lascompaasextranjerasrequierenunagenteautorizadoqueles
representeantelaFDA.Esteserelcontactoprimarioy
representantelegalantelaagencia.Lacompaadebeseruna
entidadlegalenelpasdondeoperaydebemantenerestndares
internacionalesdecalidadytransparencia
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SomeDefinitions(1)

Drug:Chemicalentity syntheticorpurified
Biologic:recombinantproteins,antibodies,cellcultureproducts
Device:Doesnotgetconsumedforbiologicalaction
Combinationproduct:twoormoreoftheabove
Cosmetic:Topicalnonpharmaceuticalapplication
Dietarysupplement:Generalhealthbenefit
MedicalFood:Specificdiseaserelateddietarysupplement
Medicamento:entidadqumica sintticaopurificada
Productobiolgico:protenasrecombinantes,anticuerpos,productosderivados
decultivocelular
Dispositivo:norequiereserconsumidoparaejecutaraccinbiolgica
Productodecombinacin:dosomsdelosyadescritos
Cosmtico:deusotpicoysinfinesfarmacuticos

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SomeDefinitions(2)

GCP:Rulesforconductofall clinicaltrials
GLP:Rulesforalltestinglabs
GMP:Rulesformanufactureofallproducts
GACP:GoodAgriculturalandCollectionPractices:Herbalproducts
GDP,GRP,GXP
(WhenFDAaudits,itwillcitethespecificrulesforfindings)
GCP:parmetrosquerigenlaconductadetodoensayoclnico
GLP:parmetrosparatodolaboratoriodepruebas
GMP:parmetrosparalamanufacturadetodoproducto
GACP:buenaspracticasdeagriculturayrecoleccin productosabasede
hierbas

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KindsofApplicationswithFDA

Drugs/CDER
IND:InvestigationNewDrugApplication
NDA:NewDrugApplication
ANDA:AbbreviatedNewDrugApplication
DMF:DrugMasterfile
BiologicalProducts/CBER
IND:InvestigationNewDrugApplication
BLA:BiologicsLicenseApplication
BMF:BiologicMasterFile
MedicalDevices/CDRH
IDE:InvestigationalDeviceExemption
PMA:PreMarketApplication
510(k):PreMarketNotification
DMF:DeviceMasterFile

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IntroductiontoFDAAudits

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AuditisanImportantFDAFunction

Beforemakingthefinaldecisionforallapplications,FDA
mustcertifyaccuracyofthecontentoftheapplication
Whenthereisanaccident(injury,qualityorfraud),FDA
mustinvestigatebeforeaction
FDAmakestherulessoitisbestpartytoverifythem

Antesdedarunveredicto,laFDAdebecerciorarsedelaveracidaddelcontenidode
cualquieraplicacin.Cuandoocurreunaccidente,laFDAdebeinvestigarantes
detomaraccin.LaFDAcrealasnormas;porende,aelloslescorresponde
verificardichasnormas

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ItstheLawforUSMarket

FDAisresponsibleforassuringthattheproductsit
approvesaresafeforpeople:developed,
manufactured,reportedanddistributedappropriately
FDAdecidesbasedoninternalcriteriawhotoaudit
FDAdecideswhentoauditandhow.

LaFDAesresponsableporcerciorarsedequelosproductosque
apruebasonsegurosparaelusohumano(desarrollados,
fabricados,verificadosydistribuidosdemaneraapropiada).La
FDAdecideaquinauditabasndoseencriteriosinternos.
Tambindecidecuandoycmoaudita.
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FDAInspection:AnIntimidatingThought
Are we in trouble?
What did we do?
Oops!

Are we ready?
How to prepare?

Dont Panic! Prepare.

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CommonCriteriatobeSelectedby
FDAtoAudit(1)

Priortofinaldecisiononamarketingapproval
applicationsuchasNDA/PMA
Clinicalsitesandvendors(randomorhighpriority)
Manufacturer(always)

Prior to grant of import license for DS or Food (!)

PriortograntofimportlicenseforDSorFood(!)

Hayauditorasantesdeunveredictorelacionadoaunaaplicacin
paramercadeo(NDA/PMA).Centrosclnicosyproveedoresse
auditanalazaroencasodealtaprioridad.Elfabricantese
auditasiempre.Tambinseauditaantesdeotorgaruna
licenciaparaimportarsubstanciasmedicinalesoalimentos.
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CommonCriteriatobeSelectedby
FDAtoAudit(2)

Iftheapplicationinvolvesahighriskproduct
Usedinvulnerablepopulation(verysick,children,pregnant)
Usedinlargepopulations
Newtechnology,unknownmechanism,etc.

Criteriosalserseleccionadoparaauditora:
Silaaplicacintienequeverconunproductoriesgoso(paraser
usadoenpacientesvulnerables,engranpartedelapoblacino
sisetratadeunanuevatecnologaounmecanismo
desconocido)
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CommonCriteriatobeSelectedby
FDAtoAudit(3)

Iftheapplicationahighriskprocess
Complaints,safetyconcerns,recalls
Specialtestingprocesses,e.g.,geneticdiagnostic
Inadequatedocumentation(SOPs,reports,records,etc)

Criteriosalserseleccionadoparaauditora:
Silaaplicacintienequeverconprocedimientodealtoriesgo
(quejas,riesgosdeseguridad,retirodeproductosdelmercado,
procesosespecialesdeevaluacin,malmanejodedocumentos)

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CanyouRefuseanFDAAudit?

No,youcannotrefuseanFDAaudit;refusalofanFDA
requestforauditisillegalintheUS

IndicatesnoncompliancewithUSregulations
Couldleadtosuspensionofimportlicense
Repeatedrefusalmayputthecompanyonimportblacklist
PunitiveactionsagainstthecompanysUSoperations

NoesposiblereusarunaauditoriadelaFDA;dichaaccinesilegal
enlosEEUUypuederesultarensuspensindelicenciapara
importacin;dereusarserepetidamente,lacompaapuede
servetadayrecibiraccinpenal

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CanyouAvoidanFDAAudit?

Yes,byeliminatingredflagissues
FDAcannotauditeverysinglefacilitysotheylookforissues
Evidenceofinadequatedocumentation
Evidenceofsloppiness,carelessness,trainingdeficiency
Complaints,recalls,adversepublicity

Esposibleevitarauditoriasaleliminarproblemaspotenciales.La
Es
posible evitar auditorias al eliminar problemas potenciales La
FDAejerceauditoriascuandoexistensospechasde
documentacininadecuada,mediocridad,descuido,faltade
entrenamiento,quejas,publicidadnegativa,etc.

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FDADoesNotAuditSeveralFacilities

Manyfacilities,particularlythoseinnonUSlocations
arenotauditedbyFDAifthey

Maintainhighlevelofcompliance
Keepuptodatewithdocumentation
AreproactivetoprovideFDAallrequestedinformation
MaintaingoodcommunicationwithFDA

ExistelatendenciaanoauditarfueradelosEEUUcuandose
mantieneunaltoniveldeconformidadconlasnormas,
documentacinactualizada,cuandosebrindaalaFDAtoda
informacinrequeridaycuandosemantieneunabuena
comunicacinconlaagencia
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HowFrequentareFDAAudits?
GMPauditsaremostfrequent:Atleastonceeverytwo
yearsforallmanufacturingfacilities

GCPinspectionswhenneeded,butnotmorethanonce
every3years

GLPandIRBinspections,lessthan5%oftotalaudits
LLasauditorasmsfrecuentesserelacionanconGMP(por
dit
f
t
l i
GMP (
lomenoscada2aosparatodoslosproveedores).
AuditoriasrelacionadasconGCPocurrenenpromedio
cada3aos.InspeccionesrelacionadasaGLPoIRB
constituyenmenosdel5%detodaslasauditoras

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WhoaretheFDAauditors?

EnforcementarmoftheFDA:
OfficeofCompliance,DivisionofScientificInvestigations
TheBioresearchMonitoring(BIMO)programforGCPaudits

About1000auditors(PhD,MS,Pharmacists)
EitherworkforFDAheadquarters(WashingtonDCarea)or
regionaloffices

T i d i FDA diti
TrainedinFDAauditingmanual
l

LaimposicindeauditoriasesresponsabilidaddelaOficinade
Conformidad,DivisindeInvestigacionesCientficas.LaFDA
cuentaconalrededorde1.000auditorestantoensusedeen
Washingtoncomoenoficinasregionales
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SelectionofFDAAuditorsForaSite

Locatedclosesttothesite

Regionalauditors(e.g.,theauditorsinArgentinamostly
comefromtheFDAOfficeslocatedinCostaRica,Chile,and
Mexico)
MayhaveinvitesfromtheHeadquarters(forhighrisksites)
Experiencedintheoperationsbeingreviewed
Nativelanguageconversants
Native language conversants
Seleccindeauditores:porlogeneral,seseleccionaunauditor
cercanoalsitiobajoauditora.Elauditortalvezsea
acompaadoporinvitadosdelasedeenWashingtonencasos
dealtoriesgo.Cadaauditortieneexperienciaenlas
operacionesrelevantesalaauditorayhablaellenguajedela
regin
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Session2:
ScopeofanFDAAudit:
WhatcanFDAsee?

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InthisSession
WhatcanFDAaudit?
DocumentationsrequiredforallFDAregulated
companies
PreparingforanFDAaudit
Mockaudits,interviewstrategies,andtrouble
shooting
h i
RequisitosparacompaasreguladasporlaFDA,preparacinpara
unaauditora,simulacrodeauditora,estrategiaspara
entrevistaysolucindeproblemas

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10

UnderstandingFDAsPerspectiveof
anAudit?

Anorganizationmustbeawareandcompliantofall
applicableregulations
Ignoranceisnotanacceptableexcuse
Thereisnoflexibilityonnoncompliance

Reviewofdocumentsshouldallowreconstructionof
Review
of documents should allow reconstruction of
tasksperformed

Cadaorganizacindebeestaraltantodelasnormasaplicables.La
ignorancianoesexcusable.Nohayflexibilidadencuantoala
faltadeconformidadnormativa.Losdocumentosdebenser
creadosdetalmaneraquetodoloquesellevaacaboenla
compaapuedasercorroboradoyreconstruido
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FDAPerspective

Lookatinterrelationship andinteractionbetweenthe:
Qualifications&Training
AdheringtoProtocolsandProcedures
AuthorityandReportingMechanisms
Communications

Desuperspectiva,laFDAsefijaenlarelacineinteraccinentre:
De
su perspectiva la FDA se fija en la relacin e interaccin entre
Credencialesyniveldeentrenamiento
Seguimientodeprotocolosyprocedimientos
Autoridadymecanismosdereporte
Comunicacin

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FDAsExpectationfromanAudit?

Responsiblepartystransparencytoreview
Completenessofresponses
Acceptanceoffindings:FDAhasthefinalsay
Timelyresponsetosuggestions

LaFDAestalaexpectativadetransparencia,respuestas
completas,aceptacindeveredictosyrespuestaoportunaasus
sugerencias

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11

KeyRegulations

GoodLaboratoryPractices:21CFR58
GoodClinicalPractices:21CFR312andICHE6
GoodManufacturingPractices:21CFR211,21CFR820
GoodmanufacturingPracticesforfoodanddietary
supplements:21CFR110and111
Compliance Program Guidance Manual
ComplianceProgramGuidanceManual
http://www.fda.gov/ora/ftparea/compliance/48_811.pdf

Aquaparecenlossitiosdondesepuedenencontrarlas
principalesnormasquerigenlaconductadelaFDA
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FDAEnforcementPolicy

Complianceiscustomizedbasedonscienceandlogic
Industryisconstantlymonitored
Industryisgivenopportunitytocorrectviolationsand
expectedtopreventfromrepeating
Enforcementresponseisproportionaltotheseverity
ofviolation
No tolerance for fraud, intentional violation or gross
Notoleranceforfraud,intentionalviolationorgross
negligence

Elniveldeconformidadsebasaencienciaylgica.Laindustriaes
monitoreadaconstantementeytienelaoportunidadde
corregirviolaciones;hayunaexpectativadeprevencinpara
evitarrepetirviolaciones.Laimposicindepenalidadeses
proporcionalalaseriedaddelaviolacin.Nohaytolerancia
algunaparaconelfraude,lasviolacionesintencionalesola
negligenciasevera
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WhatconstitutesMisconduct?

Falsificationofdataincludescreating,altering,
recording,oromittingdatainsuchawaythatthe
datadonotrepresentwhatactuallyoccurred.
Safetyrisk,reliabilityofdata

Lafalsificacindedatoscomprendecrear,alterar,registraru
p
,
, g
omitirinformacinalpuntodenorepresentar
propiamenteloocurrido.Losriesgosdeseguridadypoca
confiabilidadenlosdatosconstituyenmalaconducta

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12

WhatcouldbecomeMisconduct?

Baddocumentationpractices
Oversightsandignoranceofrulesduetolackof
training

If it is not written, it wasnt done.

If it is written and not done, it is fraud
Tantodocumentacininapropiadacomoinadvertencia
eignoranciaporfaltadeentrenamientopueden
resultarenmalaconducta
Sinoestescrito,nosehizo.Siestescritoynose
hizo,entoncesesfraude
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TheMisconductScale

InnocentIgnorance

Lackofknowledgeofregulations
IncompleteorincorrectCRF
Nonpreservingsourcedocuments

SurprisingSloppiness
Inattentiontodetail
Lackofsupervision
Protocol
Protocol shortcuts
shortcuts

MaliciousMalfeasance
Deliberatefalsificationofdata(Fraud)

Escalademalaconducta:
Ignoranciainocente< dejadezsorprendente< delincuenciamaliciosa
(faltadeconocimiento)(faltadeatencin)(falsificacindeliberada)

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AuditsareAlwaysApplicationSpecific

Auditsarealwaysbecauseofanapplicationorproduct
FDAoversightisoverproductsitapproves,processoversight
isindirect
Processesleadingtonoviableapplicationmightneverget
audited.,e.g.,R&Disnotdirectlyaudited

Allauditsfocusondocumentsandfacilitytours

Cadaauditoraesespecificaaunaaplicacinoproducto.LaFDA
vigilaproductosloscualeshaaprobado.Losprocesosson
vigiladosindirectamente.Unprocesoquenoresulteenuna
aplicacinviable,quiznuncaseaauditado

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DemonstrationofCompliance(1)

SiteOrganizationandPersonnel

Qualifiedpersonnel
Training,safety,management
QualityAssurance
Distributionofresponsibilities

Personalcalificado,entrenamientos,seguridad,administracin,
Personal
calificado entrenamientos seguridad administracin
controldecalidadydelegacinderesponsabilidadesson
parmetrosquedemuestranconformidadnormativa

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DemonstrationofCompliance(2)

AdequatelydesignedFacilities

Equipmentsandprocedures
Documentationandtraining(SOPs,manuals,etc)
Sitemanagement
Accesscontrol

Safetyprocedures:Personnelandenvironmental
Recordretentionandstoragepolicies

Otrosindiciosdeconformidadnormativason:
Diseoadecuado(equipos,procesos,documentacin,
administracin,controldeacceso),procedimientosde
seguridad(delpersonalydelambiente)yplizasparala
retencinderegistros
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WhatisSubjecttoFDAAudit?
Everythingrecordrelatedto:
Laboratoryprocesses(GLP)
Clinicalprocess(GCP)
Sites,investigators,vendors

Manufacturingprocesses(GMP)
SafetyReportingprocesses(GRP)

Todolorelacionadoaprocesosdelaboratorio,procesos
clnicos(centros,investigadores,proveedores),procesos
demanufacturayreportesdeseguridadestsujetoa
auditora
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14

CanFDASeeEverything??
NO!
Sales,pricingandotherfinancialdata
Internalauditresultsandsupplierauditreports
ManagementReviewmeetingminutes
Confidentialpersonnelinformation(otherthan
g)
training)
Todainformacinrelacionadaaventas,precios,finanzas,
auditoriasinternasydeproveedores,evaluaciones
administrativaseinformacinconfidencialdelpersonales
privadaynopuedeseraccedidaporlaFDA

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SponsorAudits(QA)VsFDAAudit

SponsorAudits:
Notrequiredunderthelaw.
Butessential.Withoutauditthereisnowayto
knowifthesystemisworking.
Sponsorsconductthesetotrainandpreparethe
sitesforfutureFDAaudits

Lasauditorasinternasnosonrequeridasporley.Sinembargo,son
esencialesparacorroborarqueelsistemadetrabajoesviable.
Dichasauditorassellevanacaboconfinesdeentrenamientoy
preparacin

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CommonProcessAcrossAllAudits
(GCP,GMP,GLP,GxP)(1)

Similarprocessandlogistics
Compliancewithcurrentregulations
Data/informationintegrity(documentation)
Personnelandfacilities

Independientementedeltipodeauditora,elprocesoesel
mismo:conformidadnormativa,integridaddedatos,personale
instalaciones

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15

CommonProcessAcrossAllAudits
(GCP,GMP,GLP,GxP)(2)

Similaractions
483s
Warningletterandotherpunitiveactions

Similarlytrainedinvestigators

Educationalbackgroundofinvestigators
Educational background of investigators
Experiencedinyourkindofoperations
Todotipodeauditoracomprendeaccionessimilares(forma483,
cartadeadvertenciayotrasaccionespenales)
Delmismomodo,todoauditorharecibidoelmismo
entrenamiento(antecedenteeducacionalyexperiencia)

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DocumentsRequiredforanAudit

SOPs:Number1reasonforauditfailure
Organizationalcharts
Personneltrainingfiles
Productspecificrecords:batchrecords,patientfiles,etc
CAPAreports,QAreports,andvalidationreports
Additi
Additionaldocumentsonanasneededbasis
ld
t
d db i

Deficienciasenprocedimientosoperativosestndar(SOPs)sonla
mayorrazndefallaenauditoras.Otrosdocumentosevaluados
duranteunaauditoraincluyen:tablasorganizacionales,archivos
deentrenamientodelpersonal,registrospertinentesalproducto,
reportes(CAPA,calidad,validacin),etc.
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PreAnnouncedFDAAudits
Atleast12weeksnotice,mostly4+weeksnoticefor

nonUS

Informaboutagenda
Usually13inspectors
Lowkeyaffairs

Avisodeauditora:12semanasdeavisoporlomenos;4semanaso
msacentrosfueradelosEEUU.Losauditores(13inspectores)
informarnlaagenda;asuntosdemenorimportanciaporlo
general

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SurpriseAudits
Forcauseaudits

Maybenonotice,inspectorsjustshowup
Causeforauditnotified,clearagendamayormaynot
Usually13inspectors,maybeaccompaniedbylaw
enforcement
Usuallyhighprofile,intrusiveandinconvenient
VeryrarefornonUSsites
Auditorasporcausaespecfica:talveznohayaaviso.Senotificade
A
di
fi
l
h
i S
ifi d
lacausadelaauditoraperoquiznoserevelalaagenda.1a3
inspectoresgeneralmente,talvezacompaadosporlas
autoridades.Estetipodeauditorausualmenteocurrepor
asuntosserios,esaltamenteinconvenienteyraravezocurreen
centrosfueradelosEEUU

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PreparingfortheInspection

FDAInspectionSOP

Developaproceduretoidentifyhowtohandlean
inspectionbefore FDAarrives
ReviewFDAstrainingmanual
TrainPersonnel
Rehearse
Esimportantedesarrollarunprocedimientoquedescribael
manejodeunainspeccinantes dequeocurra.Puntosa
seguir:repasarelmanualdeentrenamientodelaFDA,
entrenaralpersonalypracticar

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PreparingfortheInspection

FDAauditorscantakepictures,videos.
FDAauditorsareallowedtointerviewpersonnel
FDAauditorscantakesamplesofproducts,etc
FDAauditorscanstayaslongastheyneed

Losauditorespuedentomarfotosygrabarvideos,entrevistaral
Los
auditores pueden tomar fotos y grabar videos, entrevistar al
personal,tomarmuestrasdelosproductosyquedarseenlas
instalacionesporcuantotiempolesparezcanecesario

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17

PreparingfortheInspection

Identifyinspectionteammembers(andbackups)and
definetheirrolesandresponsibilities

Receptionist
Escorts/Coordinator
Scribes/Notetakers
SubjectMatterExperts
Employees at large
Employeesatlarge

Developastrategytomanagetheinspectionfromfirst
arrivaloftheinvestigatoruntilthecloseoutmeeting

Identifiquelosmiembrosdelequipo(yrelevos)acargodela
inspeccinydefinasustareasyresponsabilidades
(recepcionista,coordinador,escribas,expertosyempleadosen
general).Esnecesariodesarrollarunaestrategiaqueabarquela
inspeccindesdelallegadadelauditorhastalaltimareunin
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PreparingfortheInspection

Notifyallrelevantpartiesandpersonnelsubjectto
audit
Haveavailable
Anadequateworkroomreservedforthedurationofthe
inspection
person(s)knowledgeableaboutthestudy
Allstudydocumentsanddocumentationshowing
responsibilitiesandtrainingforallstudypersonnel

Tenerencuenta:notificaratodoelpersonalsujetoaauditoray
tenerdisponibleunasaladetrabajoapropiadadurantela
inspeccin,personasconconocimientossobreelestudioy
documentosquedescribanresponsabilidadesyentrenamiento
recibidoporelpersonal
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BeforeFDAvisits

MakeaPlan
Doathoroughselfcheckofdocumentation
Organizeandcleanup
Studydocumentandprocessreview
Allinternalauditfindings(QCandQAissues)

Antesdelainspeccin:disearunplanyrevisarmeticulosamente
todadocumentacin organizar,repasaryestaraltantode
asuntosinternos

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BeforeFDAvisits

Preparestaff
Mockinterviews
Twoquestionsandarequest:
Whatdoyoudo?
Howdoyoudothework?
Showme

Assignresponsibilitiesforinteracting

Troubleshoot
Identifiedissuesandtheirpotentialresolution

Prepareasupersonalsimulandoentrevistasyasignando
responsabilidades
Identifiqueproblemaspotencialesyposiblessoluciones
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Session3:
LogisticsofanFDAAudit
Planning What You Need
PlanningWhatYouNeed

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InthisSession
InitialcontactbyFDA:written,phone,fax,
email
SchedulingissuesforFDAaudits
ProcessofanFDAaudit
DosandDon
Dos and Don'ts
tsofanFDAaudit
of an FDA audit
ContactoinicialconlaFDA,conflictosalprogramarauditora,el
procesodeunaauditora,quehacer(yquenohacer)durante
unaauditora

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So,FDAcontactedyou

FDAauditorwillcontactthecontactpersononits
files
Thepersonwhosignsalldocuments
MostlyfirstcontacttheUSagentiftheagentislistedasthe
primarycontact
Mostlybyphoneandfollowupwithletter(faxormail)

ElauditordelaFDAcontactaralapersonaensusarchivos:
personaacargodefirmardocumentosoagenteenlosEEUU
siesteaparececomocontactoprimario.Porlogeneral,el
primercontactoocurreportelfonoyesseguidoporuna
cartaofax
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SchedulinganAudit

Forannouncedaudits,itisoktoaskforadifferent
date,ifreasonablereason
Keypeopleunavailableduetopreviousschedules
Companyclosedduetoholidayorotherreasons

Notunreasonabledelayindates

Afewdaysorweeks
Notmorethanonce
Espermisiblesolicitarunafechadiferenteparaunaauditora
avisada,siempreycuandoexistanrazonesvlidas(personal
importantenodisponibleocompaacerradaduranteunda
festivo).Esrazonableaplazarunaauditoraporunoscuantos
dasosemanasysolounavez
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ItsoktoPrep

FDAknowsyouaregoingtoprepare
Thoroughreviewofdocuments
Cleanupofdocuments
Notestofilesforchanges

Itsoktogethelp
Mockauditsbyexternalauditors

LaFDAsabequeustedsevaapreparar(revisinyorganizacin
dedocumentosynotasdearchivodebidoacambios)
Espermisiblebuscarayuda(simulacrosdeauditoraacargode
auditoresexternos)

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TheFDAInvestigatorishere!

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FDAInspection:Logistics
1.
2.
3.
4.
5.

Theinspectorannounceshimselftoreception
Introductionsandorientation
Openinginterview,PresentationofFDA482
Reviewofdocuments,interviews,touroffacility
Closinginterview,PresentationofFDA483
Elinspectorseanunciaenlarecepcin
Presentacionesyorientacin
Primeraentrevistaypresentacindeforma482
Revisindedocumentos,entrevistas,visitaalasinstalaciones
Entrevistadesalidaypresentacindeforma483

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FDAInspection:DosandDonts(1)

Accessshouldbecontrolled
1.
2.
3.
4.

Waitinreceptionarea
QA/Regulatorypersonnelescorttodesignatedarea
Checkcredentials,nevertrytocopy(itsillegal)
Alwaysescorttoalltheareasofthecompanythathe/she
wantstovisit/examine
5. Personnelaccesstobecontrolledandrecorded
Mantengacontrolsobreelacceso
Invitealauditoraesperarenelreadelarecepcin
Elpersonaldeasuntosregulatoriosdebeescoltaralreadesignada
Reviselascredenciales(notratedecopiarlas estoesilegal)
Siempreescoltealauditoratodaslasreasquedeseevisitar
Elaccesodelpersonaldebesercontroladoyregistrado

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FDAInspection:DosandDonts(2)

Makereadilyaccessible:Alldocumentsrequested

SOPs,manuals
Studydocumentation
Rawdataaccess(Labs)
Trainingfiles

Asegresedeteneraccesoatodoslosdocumentos
requeridos(procedimientos,manuales,estudios,datos,
archivosdeentrenamiento)

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FDAInspection:DosandDonts(3)

Makereadilyaccessible:Facilities

LabsandClinics
Manufacturingareas
Equipmentsuites

Beavailable,makeseniormanagementawareof
progress
p
g

Asegurese dequehayaaccesoalasinstalaciones(laboratorios,
centrosclnicos,reasdemanufactura,salasdeequipos)
Estadisposicinymantengaalosadministradoresaltantodel
progresodelaauditora

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FDAInspection:DosandDonts(4)
Takegoodnotes,everythingisbeingrecorded
Keepeveryonecalm

Peoplegetnervousanddefensive
Trainpeopletoonlysaywhattheyknow,notwhatthey
believe
Nevermakeunsubstantiatedcomments
If you donttknow,sayso,don
Ifyoudon
know, say so, donttmakeup!
make up!

Goodhospitalityandpersonablepeoplemakethe
processflowwell

Tomenotasymantengaregistros
Mantengalacalma
Elserhospitalarioyamableayudaaqueelprocesofluyabien
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DontsofanFDAAudit

GoonvacationwhenFDAcomes
Bedefensiveorargumentative

Ifyoudontagree,wewillgetachancetorebut

Dontofferfoodorgifts

Nosalgadevacacionesaltiempodelaauditora
No
salga de vacaciones al tiempo de la auditora
Nosemuestredefensivoniargumente(siustedesten
desacuerdo,tendrlaoportunidadderefutar)
Noofrezcaalimentosuobsequios

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FDAInspection:FinalMinutes

Exitinterview
Summarizefindings
Giveanopportunitytoclearanymisimpressions
Documentdiscussions

Seniormanagementmustbeavailableforthis
meeting
AuditorcanonlygivetheFDA483toseniormanagers
yg
g
Needpersonofauthoritytomakeagreements
Entrevistadesalida

Hagaunsumariodeconclusiones
Clarifiqueposiblesmisconcepciones
Documentediscusiones
Administradoresdebenestarpresentes(soloellosreciben483y
hacenacuerdos)

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InspectionCloseOut

FDAInspectorhastwooptions

Nofindings(Patyourselvesontheback!!)
Findings(FDA483)

Nobodysperfect,dontgetshocked
Dontargueorgetdefensive
Respondinwritingatalaterdate
y
p
p
FDA483andyourresponsebecomespublicinformation

Elauditortiene2opciones:

Nohallazgos

Hallazgos(forma483)
Nosesorprendadehaberhallazgos;nosemuestredefensivoni
argumente;respondaporescrito;surespuestajuntoconlaforma483
seharninformacinpblica

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Session4:
FollowUPtoanFDAAudit:
RespondingtoFindings

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FDA483:TheDreadedForm

Almost80%offirsttimeFDAauditsleadtoFDA483
FDA483isaformwhichlistsallthefindingsatthe
endofanaudit
Clarificationswerenotsatisfactory
Disputesbetweenauditorsandcompanypersonnel
Allfindings,major,moderateorminor

Casiel80%deauditorasrealizadasporprimeravezresultanen
hallazgos.Laforma483listadichoshallazgos,loscuales
incluyen:respuestasnosatisfactorias,disputasentre
auditoresypersonaldelacompaa,otroshallazgosdemayor
omenorimportancia

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NumberofFDA483Issued

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NumberofFDA483Issued

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TopAuditFindings:GMP
1.
2.
3.
4.
5.
6.
7
7.

InadequateSOPsforQCprocesses
ReleaseofOutofSpecificationproduct
InadequateSOPsforprocesscontrol
QCLabmethodsnotscientificallyvalidated
Inadequatecleaningandequipmentmaintenance
Contaminationcontrolineffective
I d
Inadequatereleasetesting
t
l
t ti
Procedimientosocontrolesinadecuados
Productosnoconformeaespecificaciones
Controlesymtodosnovalidadoscientficamente
Limpiezaymantenimientodeequiposinadecuados
Controldecontaminacinnoefectivo

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TopAuditFindings(GCP)
1.
2.
3.
4.
5.
6.

Documentationissues:InadequateSOPs,Poorrecords
SafetyReportingviolations
Inadequatetrainingrecords
Violationsofsiteprocedures(SOPs,training,etc)
Protocolviolations,e.g.,Inclusion/exclusioncriteriaviolations
Proceduralviolations:Studyprocessesinadequatelyfollowed
Problemasdedocumentacin:procedimientosyregistrosinadecuados
Violacionesenreportesdeseguridad
Registrosdeentrenamientoinadecuados
Violacionesdeprocedimientosencentros:SOPs,entrenamientos,etc.
Violacionesprotocolarias
Violacionesdeprocedimiento:seguimientoinadecuadodeestudios

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RespondingtoAuditFindings

Informalcommentsmadebyauditorduringaudit
offerperspectives
Allsuggestionsshouldberecorded
Followupdiscussionstoacknowledgeandaddress
Completedocumentationoffollowup

FDA483
ReceiveFDA483courteously;gettingangrywillnothelp
Receive FDA 483 courteously; getting angry will not help
Internaldiscussions/brainstormingforsolutions
Subjectmatterexpertadvise

Comentariosinformalesporpartedelauditorofrecenperspectivas(teneren
cuentasugerencias,discusionesaseguir,mantenerregistrosdetoda
comunicacin)
Recibalaforma483cordialmente;busquesolucionesyopinionesexpertas

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CorrectiveandPreventiveActions

Allfindingsandsuggestionsmustbeaddressed

Collectinterpretationsforcausalityandattribution
Listoptionsandriskbasedanalysis
Decideoncorrectiveandpreventiveactions
Implement,validateandperiodicreview

g y g
;
Todosloshallazgosysugerenciasdebensertomadosencuenta;
buscarinterpretacionesdecausayatributo;enumerar
opcionesyanalizarriesgos;decidircomocorregiryprevenir;
implementar,validaryrevisar

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RespondtoFDA

Within30daysorwhatevertimeframedirectedby
FDA
Completeresponseswithdocumentationsupport
Providefollowupresponsesorrebuttals,ifneeded
FollowupifnotheardfromFDAwithin6090days
fromresponse
Responderdentrodellapsode30dasoaltrmino
provistoporlaFDA
Darrespuestascompletascondocumentosquelas
corroboren
ContactaralaFDAsinohayrespuestaluegode6090das

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DisputeResolution

IfFDAauditingdivisiondoesnotagreewithsolutions
involvereviewersandSMEsforrebuttals
Mayneedtripartymeeting:sponsor,auditors,
reviewers
FollowFDAsformaldisputeresolutionprocess
RememberFDAhasthefinalsayafterfullreviewcycle
Siladivisindeauditorasnoapruebadelassoluciones
provistas,inviteaotrosrepresentantesyexpertosdelaFDA
aopinarensurefutacin
Sigaelprocesoformalderesolucindedisputas
RecuerdequelaFDAtienelaltimapalabraalfinaldelciclo

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WarningLettersandRecalls

UnresolvedissuesleadtoWarningLetter
Companygivenadditionaltimetorespondandresolve
FDAdecisionsarefinalandmustbefollowed
Affectedproducts(individuallotsorwholepipeline)
needtoberecalledandsalessuspended
Consentdecreeversusmandated(forced)actions

Losasuntossinresolverresultarnennotasdeadvertencia
Lacompaarecibirtiempoadicionalpararespondery
resolver
LasdecisionestomadasporlaFDAsonfinalesysedebenseguir
Productosafectadosdebenserretiradosysuventasuspendida
Decretoconconsentimientovs.Accionesobligatorias

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FDASanctions

Individuals,CompaniesandInstitutionsinvolvedin
FDAregulatedresearch

Manufacturers
ClinicalInvestigators
Sponsors,CROs,Monitors
Laboratories
InstitutionalReviewBoards(IRBs)

ApplicationsanddatasubmittedtoFDA

Individuos,compaaseinstitucionesinvolucradaseninvestigaciones
reguladasporlaFDA:fabricantes,investigadoresclnicos,patrocinadores,
monitores,laboratorios,juntasinstitucionales

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NonUSSites

MostlyGMP,butGCPandGLPincreasing
ReasonsforauditofnonUSsites
Insufficientdomesticdata
ConflictingresultsfromUSandnonUSsites
Suspicionoffraudorunreliablepractices

FrequencyofnonUSsiteaudits
IncreasingduetotrendsinmorenonUSdata
Increasing due to trends in more non US data
IncreasingnumberofnonUSaudits

FDAsinternationalcollaborations
MOUswithotherregulatoryagencies
HarmonizationwithICHguidancedocuments
FDAsinternationaloffices

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