Failure Investigations,Inspectors ExpectationsBarbara W.UngerDon Hill and Associates Inc.(317) 582-1504bwunger@midlink.comManaging Process Deviations and Failure InvestigationsMarch 18-19, 2003Copyright 2003, Barbara W. Unger

Barbara W. Unger

Topics to be CoveredGlobal Governing AuthorityExpected Content of Deviation ReportWhere Companies Have DifficultyExample CitationsSummaryReferences

Barbara W. Unger

Governing Authority, US21 CFR 211.192 and Multiple Other Provisions within 211Any unexplained discrepancyshall be thoroughly investigatedThe investigation shall extend to other batches that can have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow-up.

Barbara W. Unger

Governing AuthorityICHQ7A, GMPs for Active Pharmaceutical IngredientsAny deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. All deviation, investigation and OOS reports should be reviewed as part of the batch record review before the batch is released.

Barbara W. Unger

Governing Authority, EUEC Guide to Good Manufacturing Practice, Chapter 5Any deviations from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by a competent person

Barbara W. Unger

U.S. Legal Opinion United States v Barr Laboratories, Inc. 1993 Described Requirements for InvestigationsSpecifies Content of Failure Report;Requires Listing and Evaluation of Lots Potentially Affected;Elements of Thoroughness Vary Depending on Nature and Impact of the Event;Defines Promptly as 30 days from Event

Barbara W. Unger

Linkage of SystemsEVENTInvestigationCorrective ActionPreventive ActionRoot CauseIdentify All LotsConsider All PossibilitiesProduct ImpactLot Disposition

Barbara W. Unger

Scope and DefinitionDefinition of DeviationDeparture from Written Instructions,Unexpected Event, Departure from cGMP;Identify Exempted Incidents, Generally DocumentationMultiple Systems Can be ProblematicCreate Confusion and Difficult to TrackMinimize Notes or CommentsMany Should be Deviations with Abbreviated Investigations

Barbara W. Unger

Scope and DefinitionPurpose of Investigations Identify CorrectEvaluate Product Impact / Disposition Prevent Similar Events from Happening in the Future;The Deviation Event is the Initiating Feature of the CAPA Program

Barbara W. Unger

Content of Investigation ReportReason for the InvestigationWhat Event or Finding Prompted InvestigationHow and When IdentifiedRemember to Consider Tracking / Trending EvaluationConsider Related Activities, Think GlobalDescribe What HappenedWhatWhenWhereWhat Immediate Actions Were Taken

Barbara W. Unger

Content of Investigation ReportIdentify Other Batches Potentially AffectedJustify SelectionRemember Distributed LotsIdentify Root Cause, Where PossibleWhy, Why, WhyDocument Factors Considered Ensure Data Support ConclusionsAvoid Conjecture Often a Multi-Disciplinary Exercise

Barbara W. Unger

Content of Investigation ReportIdentify Corrective ActionsResist: Operator Error Corrected with RetrainingMay Include Additional Monitoring / AssessmentImplementation Must be TimelyIdentify Preventive ActionsSuccess Depends on Adequate Identification of Root CauseInterim Solution May Include Additional Monitoring

Barbara W. Unger

Content of Investigation ReportEvaluate Product Impact / Disposition Additional Testing / Results Justify Accept / Reject CriteriaJustify if Differences in Lot DispositionRemember to Consider Tox EvaluationProvide Follow-up to Assure EffectivenessDoes Preventive Action Provide a Durable FixWhat are Criteria for Durable Fix

Barbara W. Unger

Where are the Deficiencies?Lack of Documented InvestigationIncomplete InvestigationFactors Not Considered / DocumentedAssociated Lots Not Identified / EvaluatedRoot Cause Not Established or JustifiedConclusions Not Supported by DataTimelines Not Followed, Not ExtendedCorrective / Preventive Actions Not Implemented, Tracked or CompletedEffectiveness Not Verified

Barbara W. Unger

Operator Error is Not SpecificOperator ActionInattention to DetailVerbal or Written Communication ProblemOperator Monitoring Multiple ProcessesOperator Training:Not Trained on ProcedureNot Trained on Current Version of ProcedureInsufficient Practice or ExperienceInadequate Content in Training

Barbara W. Unger

Operator ErrorManagement SystemInadequate Administrative ControlWork Organization / Planning DeficiencyInadequate SupervisionImproper Resource AllocationInformation Not Adequately Defined, Disseminated or Enforced

Barbara W. Unger

Equipment Equipment FailureCalibration Not Current Multiple Work Order(s) Addressing Same Issue Didnt Correct ProblemPreventive Maintenance Not CurrentOut of ToleranceEquipment Not Operated According to Validated ProcedureDefective PartImproper PartNo IQ/OQ or Inadequate IQ/OQElectrical Power Failure or Surge

Barbara W. Unger

Example Citation, 2002Unknown Peak, 13 Lots of TabletsInitial Investigation Suggests Contamination in Handling18 Months Later, Investigation Indicates TolueneToluene Source Not Confirmed Until Inspectors Prompt the Company, Another 18 Months LaterEvaluation Revealed Ink as the SourceResponse to 483 Indicates Different Source for the Toluene with No Supporting Data

Barbara W. Unger

Example Citation, 2001Three Month Accelerated Stability FailureInvestigation Did Not Indicate if Batch Records Were ReviewedDid Not Assess All Possible Reasons for Test FailureDid Not Review Additional BatchesDid Not Indicate Corrective or Preventive Actions.

Barbara W. Unger

Example Citation, 2002Mechanic Discovered Black Particles in a Nozzle During Primary PackagingParticles Not Retained for AnalysisInvestigation Not Extended to Other Lots that Used Same EquipmentParticles Concluded to be from Deteriorating Butterfly Gasket but No Reason for DeteriorationNo Evaluation of Product Impact Because Partial Lot Released When Visual Exam Alone Could Not Assure Absence of Particles

Barbara W. Unger

Summary of Inspector ExpectationsImplement and Follow an Adequate ProcedurePerform and Document Thorough Investigations and Testing Commensurate with Event and Potential ImpactAdhere to Time LimitsIdentify Other Possibly Affected LotsEvaluate Impact on ProductImplement and Evaluate Corrective / Preventive ActionsQuality Unit to Review and Approve Report and Disposition Product

Barbara W. Unger

Selected References21 CFR 21121 CFR 820, see Quality SystemsThe Rules Governing Medicinal Products in the European Community. Vol IVICH Q7A; cGMP for APIsOpportunity for a Hearing, Barr Laboratories in Federal Register Vol. 58 No. 102, May 28, 1992, pages 31035 31043BioPharm, August 2001, pages 12-17, 63BioQuality, all issues BioPharm, October 2002, pages 36-40

Barbara W. Unger

Selected ReferencesProposed US FDA Rule, cGMP: Amendment of Certain Requirements for Finished Pharmaceuticals (Federal Register 61(87) 3 May 1996, page 20104)US FDA Guide to Inspection of Quality SystemsInvestigating OOS Test Results for Pharmaceutical Production (FDA, draft 9/1998)US Department of Energy Guideline, Root Cause Analysis Guidance Document, February 1992US FDA Compliance Program Guidance Manual, 7356.002

Barbara W. Unger