Effective Investigations and Corrective Actions(CAPA)

1 Copyright, Globepharm Consulting, 20081 Effective Investigations and Corrective Actions (CAPA)P Iii f Qli EProper investigation of Quality EventsMichael H. AnisfeldGlobepharm ConsultingWhat Do You Do When The Bad Stuff Happens?IItPretend It Never HappenedIgnoreItAdvise BossCurseWalk AwayIt s a One-OffAdvise Your BuddyPretend It Never Happened!#&*!$%..2 Fix ItBlame Someone ElseInvestigate + FixInvestigate, Fix + DocumentInvestigate Copyright, Globepharm Consulting, 20082 Failure/Deviation SystemTh f f il /d i i i The purpose of a failure/deviation system is to assure that each failure/deviation does not adversely impact product qualityand that Effective Corrective actionis taken to reduce the probability of such failure in the future4 Copyright, Globepharm Consulting, 20083 Contributors to Failure MaterialsFacilitiesEquipmentInstrumentat ionPeople5 PeopleProcessesProceduresFailure / DeviationDefinitionFilFailureProduct does not meet may be detected in/by ProductionLaboratory6 DeviationChange in procedures, equipment, materials, personnel related to product manufacture having an impact on product quality Copyright, Globepharm Consulting.

2 20084 DefinitionsImmediate CauseSituation directly causing the problemRoot CauseBasic Causal Factor, which if corrected or removed prevents a repeat of the problemIntermediate CauseReason for problem at more fundamental level than the 7 Reason for problem at more fundamental level than the immediate cause, but not the root cause [why-2, why-3]Root Cause AnalysisStructured questioning process enabling identification of underlying beliefs and practices that result in poor quality Causes of FailureCmmn C [End mi Stmti](V i ti n)Common Cause [Endemic Systematic](Variation)Originates from the basic elements of the process:MachinesMaterialsMethodsManpower Measurement8 Assignable Cause [Special] (Variation)An unplanned variation originating outside expected operating process conditions [special cause variation] Copyright, Globepharm Consulting, 20085 Failure/DeviationsMeasuresThere are three key steps in this process and each of these should There are three key steps in this process and each of these should be monitored regularlyRecording the failures and deviationsTotal numberNumber by departmentAction on product batch(es)

3 Involved9 Audit by sampling to verify that Corrective action was takenCorrective action on root causesThere should be an elimination of failures/deviations due to causes for which Corrective actions have been implementedRegulators ExpectationsChi H A h T Comprehensive, Honest Approach To Investigate OOS Results/FailuresEvaluation Using Scientifically Valid PrinciplesLearning From Experiences10 Permanent Solutions To ProblemAuthorities Not The Ones To Find The Problem Copyright, Globepharm Consulting, 2008611 What to Do When the Unexpected HappensUNEXPECTED?UNEXPECTED?OOSL aboratoryManufacturingWater SystemOOTOOEOOY 12 Reconciliation Yield CheckReconciliation Packaging MaterialDeviationDiscrepancyUnusual Event Copyright, Globepharm Consulting, 2008713 What Do The US Regulations Say? In ti ti n pifill ttd in th GMP: investigation specifically stated in the cGMPs: - Responsibilities of quality control unit.

4 - Labeling issuance. - Reserve samples. - General requirements. - Master production and control records. 14p - Batch production and control records. - Production record review. - Complaint files. - Returned drug products. Copyright, Globepharm Consulting, 20088 What Does The EU Guide Say? Iti ti ifi ll t t d i th GMP investigation specifically stated in the Quality Quality Production/QC Responsibilities5 39 Packaging Quality ComplaintsFuture Regulations iil hid An international harmonized approach to Risk Management16 ICH-Q9 Copyright, Globepharm Consulting, 20089initiate risk management processrisk identificationsrisk assessmentICH-Q9 Risk Managementrisk analysisrisk evaluationrisk reductionik tnagement toolsrisk controlunacceptable17risk acceptancerisk communicationRisk manreview eventrisk communicationrisk acceptanceoutput/results of the risk management processOK Copyright, Globepharm Consulting, 200810 CAPA19 How do you know what s happening?

5 Ri h h i blRecognize that there is a problem:Capture The DataAnalyze The DataTrend The DataThen Fix the problem:20hen Fix the problemInvestigate the CauseAttempt to Get to Root Cause Implement Effective FixesMonitor the Fix Copyright, Globepharm Consulting, - CAPA Corrective and preventive action(a) Each manufacturer shall establish and maintain procedures for implementing Corrective and preventive action. The procedures shall include requirements for:(1) Analyzingprocesses, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems. 21gp,qypAppropriate statistical methodology shall be employed where necessary to detect recurring quality problems;(2) Investigatingthe cause of nonconformities relating to product, processes, and the quality system;(3) Identifyingthe action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems; - CAPA Corrective and preventive action (continued)(4) Verifyingor validating the Corrective and preventive action to ensure that such action is Effective and does not adversely affect the finished device;(5) Implementing and recordingchanges in methods and procedures needed to correct and prevent identified quality problems.

6 (6) Ensuring that information related to quality problems or fmi dt i di mi t dt th di tl 22nonconforming product is disseminatedto those directly responsible for assuring the quality of such product or the prevention of such problems; and(7) Submitting relevant information on identified quality problems, as well as Corrective and preventive actions, for management review.(b) All activities required under this section, and their results, shall be documented Copyright, Globepharm Consulting, 200812 CAPA Analyzing Sources of Quality DataEil CAPAC omplaints/ReturnsRepairs/Ser icingProcessDeviationsor FailuresAcceptance ActivitiesEnvironmental Monitoring23 CAPAS ervicingCalibration/MaintenanceStability DataAuditsYields/ScrapWhat To TrackTk BTrack By:ProductIn-process, release, stability, validationEventReason for investigationOperator/AnalystIf cause is operator/analyst errorInstrument/Equipment If cause instrument related24 CauseInvestigation conclusionCorrective ActionRemedy and preventionTimelinessTime to complete Investigations Copyright, Globepharm Consulting, 200813 Incidents Reported - 2003 CAPA Data Collection186178210165171143132130119150 200250 IncidentsQuestion:Are we Getting Better as a Company?

7 Or Dropping Off in Capturing Incidents?25988592050100 Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov DecRun Charts: Trend ChartsEnvironmental Data Purified Water SystemSpecificationSpecificationUpper LimitOOT? / OOE?26 SpecificationLower Limit Copyright, Globepharm Consulting, 200814 Tracking / TrendingPaper/PenPaper/PenSpreadsheet (Excel, Oracle)Dedicated Computer SystemsTrackwise (Sparta Systems: ) CATSweb(AssurX: ) 27pMetricStream(Metric Stream: ) SmartCAPA(SmartCAPA: )Others ..SmartCAPA ( )28 Copyright, Globepharm Consulting, 20081529 Purpose of InvestigationTh f ii i i The purpose of an investigation it to determine the cause of the if the batch is rejected based on the OOS result, the investigation is necessary to determine if the result is associated with other batches of 30if the result is associated with other batches of the same drug product or other productsFDA: Draft OOS Guideline, September 1998 Copyright, Globepharm Consulting, 200816 Failure / Deviation What To DoFil /D iti Dt tdIf QAFailure/Deviation DetectedPerform InvestigationRoot Cause AnalysisInform QABatch DispositionImmediate Fix24 hours30 days31 Communicate to ManagementCorrective/ preventive ActionAssess Effectiveness of FixInvestigations: You ve Got to Be A Detective!

8 32 Copyright, Globepharm Consulting, 200817 Investigations 101P p f n In ti ti nPurpose of an InvestigationObtain facts as to causeCommonSpecial - AssignableProcess of an InvestigationComplete description of problem33pppValidity of inputsReview key process variablesDetermine scope of investigationDocument investigationLearn How To Be A DetectiveWhat Equipment What Equipment, Machine, Tool?What Is Wrong?What Is the 34 What Is the Complaint?What is the Undesired Behavior? Copyright, Globepharm Consulting, 200818 Learn How To Be A DetectiveWh i I l d?Who is Involved?StaffConsultantsVendorsVisitors 35 Name names/positions!Learn How To Be A DetectiveWh d th bl When does the problem occur?DayDateTimeShiftPhase of operation36 Phase of operationWhen in equipment life cycleAre there time patterns? Copyright, Globepharm Consulting, 200819 Learn How To Be A DetectiveWhi hWhich:UnitAreaDepartmentLineMachine37 Location of defective item, or where on defective itemLearn How To Be A DetectiveHow is the what or who How is the what or who impacted?

9 Injury / DeathShut-Down /Start-UpDamageType Classification of Defects38 How MuchHow ManyHow Big An IssueWhat resources are needed to handle/resolve the issue! Copyright, Globepharm Consulting, 200820 Change AnalysisEPROBLEM?COMPARISON?WHAT?What is the object or process with the problem?What is wrong?What similar object or process doesn t have the problem? What else could be wrong?WHERE?Where does the problem occurWhere else could the problem occur?39occurproblem occur?WHEN?When did the problem happen?When did the problem not happen?HOW BIG?How large is the problem?How large could it be? investigation Documentation40 ABCDE Copyright, Globepharm Consulting, 200821 investigation DocumentationDt p blm dDate problem occurredStatement of the Problem Listing of batches impactedList of personnel interviewedStatement of each person s opinions and memory of eventDiscussion of potential causesDiscussion of potential impact41 Discussion of potential impactDiscussion of extent of problemRecommendations for fixesStatement of actions taken to fixFinal decisions regarding batchManagement approvals42 Copyright, Globepharm Consulting, 200822 Root Cause AnalysisCti ti t bti (ll t) Corrective actions to observations (usually symptoms)

10 Have limited effect on sustained improvement or elimination of recurrence of the failureCorrective actions need to address the underlying causes and root causes of a problem in order to 43eliminate the situation from recurringRoot Cause AnalysisEquipmentDesign CapabilityManagement SystemsQualified SupervisionDesign, CapabilityMaintenanceOperator ErrorProceduresNo ProcedureWrong Procedure UsedProcedure Not AvailableProcedure Difficult To UseTrainingNoneQualified SupervisionAuditsFeedbackPrior Corrective Actions TakenCommunicationPlanningProcess CapabilityAdequate Time To Perform TaskStandardsManpowerInformation Available44 NoneWhenEffectivenessQuality ControlInspection RequiredInspection PerformedInformation AvailableAdequateTimelyPersonnel ProblemsTrainingFail/Safe ProcessesEnvironmentLightingNoiseFatigue Copyright, Globepharm Consulting, 200823 Corrective ActionWh i h l l l hi h What is the lowest level at which we can do something to prevent the problem from re-occurring?