FDA产品质量的风险评估原则ppt课件

1、Risk Assessment Principles for the Product Quality InitiativesH. Gregg Claycamp, Ph.D., CHPCenter for Veterinary MedicineOffice of New Animal Drug EJune 25, 2003OutlinenOverall Premise and QuestionsnBasics of Risk AnalysisnPossible Stages of Risk Assessments for PQ Initia

2、tivesnRisk Ranking Model for a PQ Initiative?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.Premise: Links Among Process (GMP) Risks and Patient Risks are

3、LostRISK Process Inspection RiskscGMPRISK Quality (Patient) Factors PatientCorrelations?Models?Goal: Re-Link cGMP (PQ) Risks with Actual Risks to the PatientRISK Process Inspection Risks RISK Quality (Patient) FactorscGMPPatientThe QuestionnCan Risk Management theory, tools, practice and philosophy

4、be employed to re-link risks to the patient 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

5、for product quality?Getting StartednWhat 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?nAre there off-the-shelf models and tools that might be used,

6、i.e., at a pilot-scale?nWhat kinds of RM processes can be used to foster changes needed both the regulatory and industrial spheres?Basic Risk Analysis Starting with the Some BasicsRisk is intuitive and familiar to everyone, yet few among us define risk carefully and formally enough for complex risk

7、analysis.Risk = “exposure to a chance of loss (or, Risk = “chance of losing something we value)Risk = Hazard x ExposureRiskConsequence = Hazard x ExposureContemporary Risk AnalysisnIncludes four major activities:nHazard IdentificationnRisk Assessment nRisk ManagementnRisk CommunicationRisk Assessmen

8、t Precedes Risk ManagementnRisk assessment 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 paradi

9、gms have in common fundamental scientific principles.Risk Assessment Asks:nWhat can go wrong?nWhat is the likelihood it would go wrong?nWhat are the consequences?Risk Management Asks:nWhat can be done?nWhat options are available?nWhat are risk trade-offs in terms of risks, benefits and costs?nWhat a

10、re the impacts of current management decisions on future options?Roles/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 natur

11、e, extent, magnitude and uncertainty of the risk.nWrite the Risk Assessment.nRecommends changes to RM questions.Risk ManagersRisk AssessorsRisk AssessmentsnRegulatory Policy Risk Assessment: (e.g., Biotechnology RA to determine the need for risk management regulation.)nApplied Risk Assessment: To de

12、termine compliance with a regulation or policy.nSafety Assessments: Highly defined risk calculations. Usually under a “bright line safety policy.Safety vs. RiskRisk Limite.g., Limit exceeded “10 times in 100Safety Limit“Unsafe“Safee.g., Declared “unsafeEstimates of riskRisk Analysis in a DemocracynR

13、isk assessments provide the “facts for risk analysis.RiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskWorst Risk Analysis in a DemocracynThe risk management decisions about which risks to manage are value-laden decisions.RiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskRiskValuesCostsWorst

14、 Risk Management Rank Translating 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 likelihood that it would

15、 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.Possible Stages of Risk

16、Assessment for Work PlanningHazard IdentificationnWhat can go wrong?nIdentify hazards: events nIdentify hazardous agents (chemical, biological, physical)nHow severe are the potential consequences? nGiven the event occurs, is the consequence catastrophic? Mildly annoying? nHow likely are the events t

17、o occur?nEssentially a crude risk estimate for initial prioritization purposes.Exposure AssessmentnRelease Assessment: How “much of the hazardous event occurs? nExample: Does a “non-sterile event involve 1 or 10,000 vials?nPathway analysis: If the hazardous event occurs, what pathways are there that

18、 expose humans to the hazard?nExtent of exposure: If a hazardous event occurs, how many people are potentially exposed?GMP Failure (Release) Assessment nHow frequent are the identified PQ events (hazards)?nBoundary of release? Process line, plant, warehouse, distributor?nRelease rates (“PQ Faults) a

19、re obtained in fault tree assessments, empirically, historical data, expert analyses.nExample: FMEAConsequence Assessment*nGiven exposure to the hazardous event/agent, what is the likelihood of harm under a pre-defined endpoint?nEndpoint examples:nDeathnIllnessnWorrynOAIn*A.K.A. “Dose-Response Asses

20、sment (see next slide)Consequence AssessmentQuantity of contamination (“non-sterility) i.e., in “bacteria counts per vial Proportion of exposed persons who become ill 100%50%0%ED50Qualitative Consequence AssessmentHighMediumLowRelative Effect/ImpactQuantitative relationships known in few casesLowMed

21、iumHigh(Exposure or Dose Metric)Risk EstimationnBring together the information about nthe hazard, nthe extent of exposure to the hazard,nthe consequences of exposures, and thennestimate the risk.nIncludes a critical analysis of uncertainty in both the data and risk assessment models.Uncertainties in

22、 Risk AssessmentKnowledgeVariabilityDataParametersModelTemporalSpatialInter-individual Conceptual Models for RM in PQ InitiativeThe PQ Risk Management ProblemnDiverse PQ failure (hazards) are identified.nWide-ranging risk (= chance that exposure to the hazard will result in harm adverse outcome).nWi

23、de-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 beans? From the BeginningIs risk analys

24、is for each hazard independentlyfeasible?Bulb FailsNo electricityPower Plant FailsPower Line FailsGlass BrokenFilament BrokenConnector CorrodedVacuum LeakTree Breaks LineWind Breaks LineImpurities VibrationsFault Trees for each process?Faults Magnified N-fold for a Simple Manufacturing ProcessDecisi

25、on Analyses for Each Hazard Multiplies Complexity!e.g.,Solution? A Multifactor Approach to PQ Risk ManagementnMultifactor methods already exist.nSome tools (software) already developed.nAppropriately-scaled approach to nthe question,nthe data quality, nthe nature of the decision, and nthe understand

26、ing of the overall process.State the AssumptionsnE.g., assume that health risks were linked to PQ “compliance risks previously, i.e., the historical basis of regulation.nHistorically based assumption: n compliance Health risk n qualitynGiven the assumption, can GMP “compliance risk be modeled as a s

27、urrogate of health risk?Identify the PQ Failures (Hazards)nWhat can go wrong? nTop level organization of hazards: nHealth | Compliance | Resources | Sociopolitical nSecond level (detail) organization: nSterility (microbial contamination)nDose (formulation) nToxicity (chemical contamination) nPhysica

28、l hazards (physical contamination/defect)nFine detail: “risk factor event descriptors. Sort the Hazards/Risks by Major CategoriesnStart with assumptions.nState questions to be answered.nSort under the questions.nRe-sort if new patterns emerge.nFor example, (next slide)RiskHealthComplianceResourceDea

29、thChronic IllnessAcute IllnessMental HealthVAIOAIHumanInspection $Socio-PoliticalPublicIndustryThe HillOrganizing a Multi-factorial Risk ModelRiskHealthComplianceDeathChronic IllnessAcute IllnessMental HealthVAIOAIFocused Multi-factorial Risk ModelExample health risk endpointsExample compliance risk

30、 endpointsRisk factors for a given endpointHealthDeathSterilityLyophilizationFinal Sterilityetc. ComplianceOAISterilityLyophilizationFinal Sterilityetc. Estimate the PrevalencenThe prevalence of inspection findings for a given type of event are initial estimates of probabilities necessary for risk m

31、anagement modeling.nFailure analysis “in plant. nFailure in compliance inspections. nHuman adverse events.For each hazardHealth Endpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMediumMediumHighWorryL

32、owLowLowMediumMediumThe modelers view (for example)Health Endpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeath54321Chronic Illness65432Acute Illness76543Worry87654For each hazardCompliance Endpoint Prior History of ActionsNever ViolationsFew Viol. Average Viol.Some Viol.Many Viol.OA

33、IMediumMediumHighHighHighVAILowLowMediumHighHighOther?LowLowLowMediumHighScoring, then prioritize multiple hazardsEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic IllnessLowMediumMediumHighHighAcute IllnessLowLowMediumMediumHighWorryLowLowLowMediumMediumEndpoint Probability of OccurrenceVery LowLowMediumHighVery HighDeathMediumMediumHighHighHighChronic