2 Contents Objective Definitions and terminology General investigation principlesInvestigation stagesInitial Laboratory InvestigationFull-Scale OOS InvestigationAdditional Laboratory TestingReview of ProductionImportance of corrective and preventive actions
3 Manufacturing of batch Process overviewManufacturing of batchSamplingAnalysis of sampleEvaluation of results
4 Cause for an investigation Manufacturing of batchSamplingAnalysis of sampleEvaluation of resultsOut of Specification arises:Production error?Analytical (lab) error?InvestigationRoot cause assigned?Corrective and Preventive Action?
5 ReferencesFDA Guidance for Industry : Investigating Out-of-Specification (OOS)Test Results for Pharmaceutical Production, October 2006 : Contains Nonbinding RecommendationsUSP– NF General Chapter <1010> Analytical Data – Interpretation and treatmentICH Q7A Note for Guidance on Good Manufacturing Practice for Active Pharmaceutical Ingredients, November 2000EU Guidelines to GMP Part I Chapter 6 Quality Control Section 6.32.
6 Definitions and Terminology (1) Out of Specification (OOS) ResultReportable result that falls outside established specifications or acceptance criteria.Do not include situations where Control test is not continued due to violations of system suitability tests (SST) limitsIdentification of gross operator-errors during a run: e.g. wrong instrument settingsSuch deviation cases should be tracked in order to apply CAPA if appropriateReportable ResultResult that must be compared to a particular acceptance criterion.May be “an average value, an individual measurement, or something else”, as defined in the control test [USP]
7 Definitions and Terminology (2) Established Specifications or Acceptance criteria:Approved specifications or acceptance criteria (e.g. limits) with respect to the final result (reportable result) in order to evaluate the quality of a product or sample.May be official (part of a regulatory file) or internal (e.g. additional or alternative control tests)These do not apply to:Acceptance criteria during the course of analysis (before the reportable result) such as system suitability tests (SST), warning limits, in-process control limits for process adjustmentsAtypical Test Result or Out of Trend / expectation, suspect, …Result within specificationResult different from those usually obtained or expectedSame general investigation principles as OOS resultsSite Quality Control Manager must determine extent and depth of anyinvestigation
8 Definitions and Terminology (3) Re-analysisAnalysis of retained sample preparationsRepeating some part of the testing, e.g.re-measurementre-injectionredilution of sample and standard preparationsFurther extractionFresh analysisPerforming the testing as normal (New execution of the control test)As described in the control testOnly allowed if initial results could be invalidated
9 Definitions and Terminology (4) Retest :New preparation and analysis of a portion of the original samplePart of a full-scale OOS investigationUsing a predefined procedure/plan with a MAXIMUM number of retests,Used to verify/ reject the possibility of laboratory errorsControl Sample :A sample of material that has previously been tested and approved or well characterised.Re-sampling :Collecting and analyzing a new sample from the productMust have a documented rationale for re-sampling, (e.g. original sample not representative or compromised/contaminated)Used for confirmation of product failure
10 Presentation ScopeApplicable to QC laboratories, Manufacturing sites and AffiliatesAll GMP relevant laboratory testing including inprocess controlsWhere approved specification or acceptance limits are established.Note: Compendial testsWhere interpretation and handling of test results are described, those procedures are to be followed.
11 Principles of Investigation (1) All OOS or atypical test results must be thoroughly investigated and documentedIncludes identification of root causeOOS or Atypical test results are only allowed to be invalidated if a laboratory error can be assignedDemonstrated or indicated with high probability and/or a product failure definitely excludedSupporting information and/or dataTimely initiation (e.g. 2 business days) and completion (e.g. 20 business days)Otherwise written rationaleSterile products: a parallel investigation in the manufacturing area must be initiated immediatelyA risk assessment and notification in case of confirmed OOS for product already on the market or for a risk that could affect other batches or products on the market
12 Principles of Investigation (2) Consider:Problem has occurred previously (historical data)Possibility that other batches or products are affectedCorrective actions must be defined as a conclusion of the investigation and followed through to prevent reoccurenceA system must be in place for the tracking of OOS resultsInvestigation phasesInitial Laboratory InvestigationFull-Scale OOS InvestigationAdditional Laboratory TestingReview of Production
13 Responsibilities (1) Analyst Achieves accurate analytical results Should not use systems that do not meet system suitability requirements (SST); or in such case during analysis identifies data collected during suspect time period (e.g. reference standard injection runs in a chromatographic system)Should not continue test in case of obvious error (spilling of a sample solution, incorrect dilution etc.)Immediately reports the OOS to his/her supervisorRetains the original test solutions, materials and source dataParticipates in the investigation
14 Responsibilities (2) Supervisor / QC Manager Site Quality Manager Conducts an objective and timely investigationInforms Site Quality Manager (immediately in the case of a sterile product)Decides upon investigation of atypical resultsSite Quality ManagerEnsures specific site procedures and systems existEnsures appropriate training givenMakes batch related decisions when an OOS or atypical result is confirmedInforms all relevant departmentsAssuring that corrective actions are taken to prevent reoccurrenceFor sterile products, promptly initiates parallel investigation in laboratory AND manufacturing area.
15 Initial Laboratory Investigation OOS/OOT results identified by Analyst. Supervisor informed immediatelyINITIAL LABORATORY INVESTIGATIONAssess whether the test procedure was followed correctly(calculation; sampling; sample preparation; equipment functionality& qualification; training etc)Laboratory Error Identified?YESNOSee slide 18(Lab error IS identified)Full scale OOS investigation required(See slide 20 )
16 Initial Laboratory Investigation: examples (1) Method discussed between analyst and supervisor : confirm analyst knowledge of and performance of the correct procedureVerification of calculationsReview of samples for correct labelling and identificationVerification of correct laboratory test methodsExamination for proper documentationReview of chromatograms, spectra, data and calculationsReview of reagents, media, diluents, controls and standardsExamination of the instruments and laboratory systems (qualification, calibration, maintenance)Review other samples run concomitantly (if any)
17 Initial Laboratory Investigation: examples (2) Verification of analyst’s training historyInspection of prepared sampleReanalysis/Redilution of test samples (if stable)Supervisor fully document and preserve records of the Initial AssessmentEverything except new sample preparation
18 Laboratory Error is Identified (Initial Lab investigation- slide 15)Laboratory error IS identifiedInvalidate original test resultsConsider Implication on other analytical tests/productsCAPA planFresh analysisEvaluation if positiveImplement CAPA action plan and follow throughNew EvaluationConclusion
19 Categorising ErrorsError type:Description:Transcription ErrorWrong interpretation or calculationIdentifiable Analytical ErrorNon-adherence to control test instructions(wrong materials, dilutions, instrument settings etc.)Equipment malfunctionsAnticipated OOSE.g. stability, accelerated conditions or beyond shelf-lifeConsider Actions for improvement of processes/ prevention of errors – e.g. training analysts; instrument re-qualification, update to procedures.
20 Full scale OOS Investigation Laboratory error is NOT identified (from slide 15):Full Scale OOS investigationReview of Production (slide 22)Additional Laboratory testingFull Laboratory investigationAreas to review will include:Batch Dossier EvaluationEquipment: Validation, Qualification, CalibrationTraining of PersonnelRisk Management EvaluationFollow Company protocols on:Re-testingRe-samplingOOS Confirmed?(See slide 21)NODeviation explaining OOS confirmed?YESBatch Failure Investigation(See slide 21)
21 Evaluate rejection of batch OOS Confirmed?YES(Additional Laboratory testing, slide 20)OOS Confirmed?NOYESBatch Failure InvestigationLab error identified?See slide 18, above.NOEvaluate rejection of batchRisk AssessmentQuality Alert NotificationTake all results into considerationImpact on Other Products?Investigation reportDocument.If yes, further evaluation required
22 Review of ProductionInvolvement required of all departments that could be implicated: Manufacturing, Process Development, Maintenance, Engineering, Sub-contractorTimely, thorough, well-documented reviewReview of: batch dossier, equipment (qualification, calibration), personnel training and risk management evaluation, etc.Once Root cause is identified and CAPA plan implemented: OOS investigation may be terminated
23 Additional Laboratory testing; retesting; Maximum number; design Variables : number specified in advance, analyst, control samples …Must be defined before testingCase-by case decision, e.g. depending onPossible cause of the OOS (analyst, equipment, sample …)Level of confidence requiredAnalytical variability“Extent” of OOS
24 Additional Laboratory testing: Resampling Resampling to be carried out:in accordance with predetermined procedures and sampling strategieswhere it is identified that the original sample was improperly prepared and not representative of batch qualityUse same sampling method unless it is demonstrated as inadequate
25 Reporting Testing results: Averaging General Considerations MeanEstimate of the true valueReliability increases with the number of determinationsHowever: may hide (unacceptable) variabilityReportable results and acceptance limitsCorrelatedEvaluation of single results requires wider limits due to the broader distributionIf the mean is defined as reportable result, the variability should be checked (standard deviation or range)
26 Reporting Testing results: Appropriate and Inappropriate Uses of Averaging When sample assumed homogeneous and if the written and approved test method specify that the average of multiple replicates (assays) is considered one test and represents one reportable resultInappropriateWhen testing is intended to measure variability of a product (blend uniformity, content uniformity)In case of additional testing during OOS investigation because variability is hiddenSpecifically when some results are OOS and other within specificationsProvide all individual results to quality management responsible for approving or rejecting the product
27 Reporting Testing results: Outlier Tests Outlier result, Definition: A value obtained, on rare occasions, markedly different from the others in a series, with a validated methodOutlier testing: statistical procedure for identifying from an array those data that are extreme:SOP is mandatory (includes minimum number of results required, to obtain a statistically significant assessment)Used when it is not possible to reveal the root cause of OOS/ deviationMay be used as investigative toolShould not be used as sole criteria to invalidate data
28 Concluding the Investigation Results evaluated, batch quality determined, release/rejection: decision by Quality ManagementOOS cause revealed:Suspect result invalidated and not usedOOS confirmed and is caused by factor affecting batch qualityOOS result used to evaluate quality of lotOOS Cause not revealed:Inconclusive investigationOOS not confirmedOOS result given full consideration for batch decision
29 Reporting and Documentation OOS report should include the following:Chronology of the investigationFull description of the initial laboratory investigation including an analysis of all data derived from all testingBatches or products involvedJustification for invalidating any dataConclusion including conformity of final results and batchdispositionCorrective and preventive actions taken to prevent the OOSfrom occurring againUniquely numbered to permit trackingMaintained in a controlled and retrievable manner
30 OOS Investigations Clear definition of the reportable result Thorough, timely, well documented, scientifically justified with no preconceived assumptionsClear and methodical escalationObjective to assign a causeProduct failureLaboratory (analytical) errorCorrective actions to prevent reoccurrenceAtypical results: chance to increase data qualityE.g. in stability studies
31 Examples: Identification of Analytical Errors Examples of ErrorsSolutionsOne injection OOS, reanalysis/reinjection okInstrument failure (consider maintenance, repair, qualification)All injections of one sample preparation OOS, redilution okDilution error (consider training, clarification of control test)One sample preparation OOS, retesting 2nd analyst okAnalyst error (consider training, clarification of control test)Results near limit, one result just OOS; 1 out of 4 retests also OOSReportable result? May indicate unsuitable specification limits (too tight for the analytical variability)All sample preparations OOS, retestingOOS, control samples okSampling error or batch failure