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1、FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesStillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望OutlinenOverall Premise and QuestionsnBasics of Risk AnalysisnPossible Stages of Risk Assessments for PQ InitiativesnRisk Ranking Model for a PQ Initia
2、tive?nPilot ScalenConclusionsThe opinions and ideas presented here are those of the author and do not represent policy or opinion of the FDA. This material is intended for discussion purposes only.2Premise: Links Among Process (GMP) Risks and Patient Risks are LostRISK Process Inspection RiskscGMPRI
3、SK Quality (Patient) Factors PatientCorrelations?Models?3Goal: Re-Link cGMP (PQ) Risks with Actual Risks to the PatientRISK Process Inspection Risks RISK Quality (Patient) FactorscGMPPatient4The QuestionnCan Risk Management theory, tools, practice and philosophy be employed to re-link risks to the p
4、atient with the risks identified, perceived or otherwise implicated in product quality terms?nHow can we share a common language about risk, risk management,and science-based decision making so that we can focus on developing a high-quality risk management model for product quality?5Getting Startedn
5、What theories, tools and lessons learned in risk analysis can help address these questions?nGiven the need for a significant shift in the approach to risk management, how do we begin the change process?Are there off-the-shelf models and tools that might be used, i.e., at a pilot-scale?What kinds of
6、RM processes can be used to foster changes needed both the regulatory and industrial spheres?6Basic Risk Analysis 7Starting with the Some BasicsRisk is intuitive and familiar to everyone, yet few among us define risk carefully and formally enough for complex risk analysis.8Risk = “exposure to a chan
7、ce of loss” (or, Risk = “chance of losing something we value”)Risk = Hazard x ExposureRiskConsequence = Hazard x Exposure9Contemporary Risk AnalysisnIncludes four major activities:Hazard IdentificationRisk Assessment Risk ManagementRisk Communication10Risk Assessment Precedes Risk ManagementnRisk as
8、sessment is not a single process, but “a systematic approach to organizing and analysing scientific knowledge and information” to support a risk decision. NRC (1994) nVarious paradigms exist for the execution of a risk assessment in public health; however, all paradigms have in common fundamental sc
9、ientific principles.11Risk Assessment Asks:nWhat can go wrong?nWhat is the likelihood it would go wrong?nWhat are the consequences?12Risk Management Asks:nWhat can be done?nWhat options are available?nWhat are risk trade-offs in terms of risks, benefits and costs?nWhat are the impacts of current man
10、agement decisions on future options?13Roles/Tasks (-short list)nPose the risk question.nCharge the Risk Assessors with the Risk Assessment Task.nConvene stake holders.nAnalyze decision options.nMake/recommend the decision. nIdentify data and gather information on the nature, extent, magnitude and un
11、certainty of the risk.nWrite the Risk Assessment.nRecommends changes to RM questions.Risk ManagersRisk Assessors14Risk AssessmentsnRegulatory Policy Risk Assessment: (e.g., Biotechnology RA to determine the need for risk management regulation.)nApplied Risk Assessment: To determine compliance with a
12、 regulation or policy.nSafety Assessments: Highly defined risk calculations. Usually under a “bright line” safety policy.15Safety vs. RiskRisk Limite.g., Limit exceeded “10 times in 100”Safety Limit“Unsafe”“Safe”e.g., Declared “unsafe”Estimates of risk16Risk Analysis in a DemocracynRisk assessments
13、provide the “facts” for risk analysis.RiskRiskRiskRiskRiskRiskRiskRisk AssessmentRiskRiskRiskRiskRiskRiskRiskWorst 17Risk Analysis in a DemocracynThe risk management decisions about which risks to manage are value-laden decisions.Risk ManagementRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRis
14、kValuesCostsWorst Risk Management Rank 18Translating Risk Analytic ParadigmsRisk AnalysisRisk Assessment Release Assessment Exposure Assessment Consequence Assessment Risk EstimationRisk ManagementRisk CommunicationHazard Identification What can go wrong? What are the consequences? What is the likel
15、ihood that it would go wrong? What can be done? What are the trade-offs in terms of costs, benefits and risks? What is the impact of decisions on future RM options?Risk AssessmentPQ Failures Exposure Assessment Consequence Assessment Risk EstimationA simple change to apply a contemporary model.19Pos
16、sible Stages of Risk Assessment for Work Planning20Hazard IdentificationnWhat can go wrong?Identify hazards: events Identify hazardous agents (chemical, biological, physical)nHow severe are the potential consequences? Given the event occurs, is the consequence catastrophic? Mildly annoying? nHow lik
17、ely are the events to occur?Essentially a crude risk estimate for initial prioritization purposes.21Exposure AssessmentnRelease Assessment: How “much” of the hazardous event occurs? Example: Does a “non-sterile” event involve 1 or 10,000 vials?nPathway analysis: If the hazardous event occurs, what p
18、athways are there that expose humans to the hazard?nExtent of exposure: If a hazardous event occurs, how many people are potentially exposed?22GMP Failure (Release) Assessment nHow frequent are the identified PQ events (hazards)?nBoundary of release? Process line, plant, warehouse, distributor?nRele
19、ase rates (“PQ Faults”) are obtained in fault tree assessments, empirically, historical data, expert analyses.Example: FMEA23Consequence Assessment*nGiven exposure to the hazardous event/agent, what is the likelihood of harm under a pre-defined endpoint?Endpoint examples:nDeathnIllnessnWorrynOAI*A.K
20、.A. “Dose-Response Assessment” (see next slide)24Consequence AssessmentQuantity of contamination (“non-sterility”) i.e., in “bacteria counts per vial” Proportion of exposed persons who become ill 100%50%0%ED5025Qualitative Consequence AssessmentHighMediumLowRelative Effect/ImpactQuantitative relatio
21、nships known in few casesLowMediumHigh(Exposure or Dose Metric)26Risk EstimationnBring together the information about the hazard, the extent of exposure to the hazard,the consequences of exposures, and thenestimate the risk.nIncludes a critical analysis of uncertainty in both the data and risk asses
22、sment models.27Uncertainties in Risk AssessmentKnowledgeVariabilityDataParametersModelTemporalSpatialInter-individual 28Conceptual Models for RM in PQ Initiative29The PQ Risk Management ProblemnDiverse PQ failure (hazards) are identified.nWide-ranging risk (= chance that exposure to the hazard will
23、result in harm adverse outcome).nWide-ranging consequences (death to worry).nQuantitative risk analysis hazard-by-hazard too vast an undertaking. nRanking of risks for re-linking worst PQ risks with worst health risks, etc. How can we objectively rank “apples and oranges” among the “potatoes and bea
24、ns?” 30From the BeginningIs risk analysis for each hazard independentlyfeasible?31Bulb FailsNo electricityPower Plant FailsPower Line FailsGlass BrokenFilament BrokenConnector CorrodedVacuum LeakTree Breaks LineWind Breaks LineImpurities VibrationsFault Trees for each process?32Faults Magnified N-fo
25、ld for a Simple Manufacturing Process33Decision Analyses for Each Hazard Multiplies Complexity!e.g.,34Solution? A Multifactor Approach to PQ Risk ManagementnMultifactor methods already exist.nSome tools (software) already developed.nAppropriately-scaled approach to the question,the data quality, the
26、 nature of the decision, and the understanding of the overall process.35State the AssumptionsnE.g., assume that health risks were linked to PQ “compliance risks” previously, i.e., the historical basis of regulation.Historically based assumption: compliance Health risk qualitynGiven the assumption, c
27、an GMP “compliance risk” be modeled as a surrogate of health risk?36Identify the PQ Failures (Hazards)nWhat can go wrong? nTop level organization of hazards: Health | Compliance | Resources | Sociopolitical nSecond level (detail) organization: Sterility (microbial contamination)Dose (formulation) To
28、xicity (chemical contamination) Physical hazards (physical contamination/defect)nFine detail: “risk factor” event descriptors. 37Sort the Hazards/Risks by Major CategoriesnStart with assumptions.nState questions to be answered.nSort under the questions.nRe-sort if new patterns emerge.For example, (n
29、ext slide)38RiskHealthComplianceResourceDeathChronic IllnessAcute IllnessMental HealthVAIOAIHumanInspection $Socio-PoliticalPublicIndustryThe HillOrganizing a Multi-factorial Risk Model39RiskHealthComplianceDeathChronic IllnessAcute IllnessMental HealthVAIOAIFocused Multi-factorial Risk ModelExample
30、 health risk endpointsExample compliance risk endpoints40Risk factors for a given endpointHealthDeathSterilityLyophilizationFinal Sterilityetc. ComplianceOAISterilityLyophilizationFinal Sterilityetc. 41Estimate the PrevalencenThe prevalence of inspection findings for a given type of event are initia
31、l estimates of probabilities necessary for risk management modeling.nFailure analysis “in plant.” nFailure in compliance inspections. nHuman adverse events.42For each hazardHealth Endpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMed
32、iumHighHighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMedium43The modelers view (for example)Health Endpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeath54321Chronic Illness65432Acute Illness76543Worry8765444For each hazardCompliance Endpoint Prior History of ActionsNever
33、 ViolationsFew Viol. Average Viol.Some Viol.Many Viol.OAIMediumMediumHighHighHighVAILowLowMediumHighHighOther?LowLowLowMediumHigh45Scoring, then prioritize multiple hazardsEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighH
34、ighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpoint Probability of OccurrenceVery LowLo
35、wMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMe
36、diumMediumHighWorryLowLowLowMediumMedium1.PQ Fault A2.PQ Fault T3.PQ Fault C4.PQ Fault D5.PQ Fault X6.PQ Fault MScored and Prioritized 46Risk Ranking & Filtering ModelHealthComplianceOther1.PQ Fault M2.PQ Fault T3.PQ Fault C4.PQ Fault D5.PQ Fault X6.PQ Fault AScored and Prioritized Under Multiple Cr
37、iteria(Risk Ranking and Filtering) 47Risk Analysis CycleMulti-Factorial Risk Model Risk Ranking and FilteringWork PlanningcGMP/Compliance InspectionsAssessments (Data Bases)Risk ManagementRisk AssessmentStart48ConclusionsnRisk Assessment provides a process for organizing information in support of ri
38、sk-based decision making.nRisk assessment is one of the tools available for Risk Management, the activity in which the options for controlling risks are examined in light of costs, benefits and risk trade-offs. nMultifactor Risk Ranking and filtering approach might be robust enough to employ in the GMP Initiative.49
