Pa#entSafety:ImportanceofDataIntegrityinensuringqualityofmedicineDineshSThakurExecu#veChairman
Context&Agenda
• Data Integrity – why does it matter?
• Real cost of breach of data integrity
• Why does it take so long to fix this problem?
• Closing thoughts
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Streptokinaseac#vity
3
Hermintin et al, European Heart Journal (2005) 26, 933-940
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100%ofErgometrinetabletsfailassay
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GenericClopidogrel
5
Analysis of Purity in 19 drug product tablets containing Clopidogrel: 18 copies vs the original brand Gomez et al., Journal of Pharmaceutical and Biomedical analysis, 34 (2004) 341-348
R-isomer Hydrolysis Product
Total Impurities
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Clinical implications of substandard, non-proprietary medicines in multiple sclerosis : focus on fingolimod, J. Correale et al. Drug Design, Development & Therapy, V10, 2109-2117, 2016
Impactofexcipients
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BreachofDIinwarningleSers
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DataIntegrityCon#nuum
Ignorance Sloppiness Intentional Falsification
Outright lies
cGMPregula#onsdonotrequiredeterminingintentwhileassessingDataIntegrity.Therefore,USFDAobserva#onsonForm-483donotmakeadis#nc#on
betweenignorance,sloppinessandmalfeasance.
WithoutaunderstandingoftheTRUEunderstandingoftheroot-causeforhumanmisbehavior,companiesaretakingwidespreadac#onswhichmaynot
helpaddresstheproblemintheleast.
Unintended Error Deliberate Falsification
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Dowehavetherightdiagnosis?
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10
Hereisoneperspec#ve
Source: Deloitte, Managing growth though better compliance management, June 2015
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Letslookatitfromadifferentperspec#ve
Regulatory Approach to Ensure Quality of Products - An Indian Perspective of Missing Linkage – Kumar N & Jha A, Pharmaceutical Regulatory Affairs
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USPVSCountrySpecificStandards(India)USP IP
>4200ReferenceStandards ~700ReferenceStandards
99.7%availability 0.5%availability
For Uncoated, Plain Coated Tablets & Capsules
For Extended Release & Enteric Coated
Dissolu#onApparatus
USP IP
Type1:PaddleTypeType2:BasketType
TypeI:BasketTypeTypeII:PaddleType
TypeIII:Reciproca#ngCylinder
TypeIV:FlowThroughCellType
TypeV:PaddleOverDiscTypeVI:CylinderTypeTypeVII:Reciproca#ng
Holder
For Transdermal Patches
INDIAN PHARMACOPOEIA -2007, P.NO.:179 to182 UNITED STATES PHARMACOPOEIA (USP XXVI), P.NO.:2155 to 2165
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Howeffec#vearethecorrec#veac#ons?
Incen)ve/Pressure•OOSarefrowneduponandalwaysblamedontheanalyst•Wedon’thaveenoughlicensesforthesoiwarebecausetheyareexpensive•Wedon’thaveenoughinstruments/columns•Columnsareexpensivesowedonotreplacein#me
Opportunity•Nosystemormethodaudittrail•Noindividualuserlogonandprofiles–allhaveadministratorrights•Archivalofdataisminimal•Methodsarenotlockeddown•Supervisoronlyreviewspaperprintouts
A6tude/Ra)onaliza)on•Mysourcedataismypaperrecord;noonewillknow•Re-integra#onisrou#ne;Idon’tneedauthoriza#on•Itsonlyjustoutofspecifica#on–itwillnotaffectthepa#ent•OOSrootcauseanalysistakestoolongtoperformanditsonlyfortheFDA•WeareallunderpressureandImustcompletemyalloca#on;otherwiseIwontlookgoodamongmypeersandbepenalized•Themethodhasbeenvalidated;soitmustbeme•Myfamilydependsonme•Thewholeindustryworksthisway!
Culture
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Areallifeexample
• TevaPharmaceu#calIndustriesLtd.VsFERNANDOESPINOSAABDALÁ;LEOPOLDODEJESÚSESPINOSAABDALÁ;andPPTMINTERNATIONALS.à.r.l.,filedSeptember26,2016intheSupremeCourtofNY:CommercialDivision
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15
CulturaldeterminantsofQuality
Leadership Environment Message Credibility
Empowerment
Quality by Design
Reuters, Jul 24, 2014
The Hindu, July 25, 2014
Indian Express, August 11, 2016
Indian Express, August 11, 2016
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CulturaldeterminantsofQuality
Leadership Environment Message Credibility
Empowerment
Quality by Design
• How do you make the message credible? • How do you create an environment where
employees speak up for what is right? • How do you empower employees to do the
right thing?
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GewngtotheREALrootcause
• FromRickFriedman’spresenta#onattheFDLIWorkshopinWashington,DC–July14-15,2014:– Alargenumberofrecentmanufacturingfailurescanbetracedto
failuresinthefirm’sQualitySystem– Insomecases,thequalitysystemignoredorfailedtofollowupon
customercomplaints– Inothercases,mul#plerepeateddevia#onsweretreatedasseparate
incidents,ratherthananobvioustrend– Anotherrecurringthemehasbeeninves#ga#ons“tonowhere…”
Theseendwithnoaddi#onalunderstadningorinsightintowhytheproblemmayhaveoccuredandthusnohopeforpreven#on
– Allofthesefailuressuggestaqualitymanagementsystemthatisinsufficientlyempoweredorresourcedtoadequatelycarryoutitsessen#alfunc#ons
Wheredoesthebuckstop?
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