1、1,Risk Assessment Principles for the Product Quality Initiatives,H. Gregg Claycamp, Ph.D., CHP Center for Veterinary Medicine Office of New Animal Drug Evaluation hclaycamcvm.fda.gov June 25, 2003,2,Outline,Overall Premise and Questions Basics of Risk Analysis Possible Stages of Risk Assessments for
2、 PQ Initiatives Risk Ranking Model for a PQ Initiative? Pilot Scale Conclusions,The 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.,3,Premise: Links Among Process (GMP) Risks and Pati
3、ent Risks are Lost,RISK ,Process Inspection Risks,cGMP,Correlations? Models?,4,Goal: Re-Link cGMP (PQ) Risks with Actual Risks to the Patient,RISK ,Process Inspection Risks ,RISK ,Quality (Patient) Factors,cGMP,Patient,5,The Question,Can Risk Management theory, tools, practice and philosophy be empl
4、oyed to re-link risks to the patient with the risks identified, perceived or otherwise implicated in product quality terms?How 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 prod
5、uct quality?,6,Getting Started,What theories, tools and lessons learned in risk analysis can help address these questions? Given 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.,
6、 at a pilot-scale? What kinds of RM processes can be used to foster changes needed both the regulatory and industrial spheres?,7,Basic Risk Analysis,8,Starting with the Some Basics,Risk is intuitive and familiar to everyone, yet few among us define risk carefully and formally enough for complex risk
7、 analysis.,9,Risk = “exposure to a chance of loss” (or, Risk = “chance of losing something we value”),Risk = Hazard x Exposure,RiskConsequence = Hazard x Exposure,10,Contemporary Risk Analysis,Includes four major activities:Hazard IdentificationRisk Assessment Risk ManagementRisk Communication,11,Ri
8、sk Assessment Precedes Risk Management,Risk 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) Various paradigms exist for the execution of a risk assessment in public health; however
9、, all paradigms have in common fundamental scientific principles.,12,Risk Assessment Asks:,What can go wrong? What is the likelihood it would go wrong? What are the consequences?,13,Risk Management Asks:,What can be done? What options are available? What are risk trade-offs in terms of risks, benefi
10、ts and costs? What are the impacts of current management decisions on future options?,14,Roles/Tasks (-short list),Pose the risk question. Charge the Risk Assessors with the Risk Assessment Task. Convene stake holders. Analyze decision options. Make/recommend the decision.,Identify data and gather i
11、nformation on the nature, extent, magnitude and uncertainty of the risk. Write the Risk Assessment. Recommends changes to RM questions.,Risk Managers,Risk Assessors,15,Risk Assessments,Regulatory Policy Risk Assessment: (e.g., Biotechnology RA to determine the need for risk management regulation.) A
12、pplied Risk Assessment: To determine compliance with a regulation or policy. Safety Assessments: Highly defined risk calculations. Usually under a “bright line” safety policy.,16,Safety vs. Risk,17,Risk Analysis in a Democracy,Risk assessments provide the “facts” for risk analysis.,Risk,Risk,Risk,Ri
13、sk,Risk,Risk,Risk,18,Risk Analysis in a Democracy,The risk management decisions about which risks to manage are value-laden decisions.,Worst ,Risk Management Rank ,19,Translating Risk Analytic Paradigms,Risk Analysis,Risk AssessmentRelease AssessmentExposure AssessmentConsequence AssessmentRisk Esti
14、mation,Risk Management,Risk Communication,Hazard Identification,20,Possible Stages of Risk Assessment for Work Planning,21,Hazard Identification,What can go wrong? Identify hazards: events Identify hazardous agents (chemical, biological, physical) How severe are the potential consequences? Given the
15、 event occurs, is the consequence catastrophic? Mildly annoying? How likely are the events to occur? Essentially a crude risk estimate for initial prioritization purposes.,22,Exposure Assessment,Release Assessment: How “much” of the hazardous event occurs? Example: Does a “non-sterile” event involve
16、 1 or 10,000 vials? Pathway analysis: If the hazardous event occurs, what pathways are there that expose humans to the hazard? Extent of exposure: If a hazardous event occurs, how many people are potentially exposed?,23,GMP Failure (Release) Assessment,How frequent are the identified PQ events (haza
17、rds)? Boundary of release? Process line, plant, warehouse, distributor? Release rates (“PQ Faults”) are obtained in fault tree assessments, empirically, historical data, expert analyses. Example: FMEA,24,Consequence Assessment*,Given exposure to the hazardous event/agent, what is the likelihood of h
18、arm under a pre-defined endpoint? Endpoint examples: Death Illness Worry OAI*A.K.A. “Dose-Response Assessment” (see next slide),25,Consequence Assessment,Quantity of contamination (“non-sterility”) i.e., in “bacteria counts per vial”,Proportion of exposed persons who become ill,100%,50%,0%,26,Qualit
19、ative Consequence Assessment,High,Medium,Low,Relative Effect/Impact,Low,Medium,High,(Exposure or Dose Metric),27,Risk Estimation,Bring together the information about the hazard, the extent of exposure to the hazard, the consequences of exposures, and then estimate the risk.Includes a critical analys
20、is of uncertainty in both the data and risk assessment models.,28,Uncertainties in Risk Assessment,UNCERTAINTY,Knowledge,Variability,Data Parameters Model,Temporal Spatial Inter-individual,29,Conceptual Models for RM in PQ Initiative,30,The PQ Risk Management Problem,Diverse PQ failure (hazards) are
21、 identified. Wide-ranging risk (= chance that exposure to the hazard will result in harm adverse outcome). Wide-ranging consequences (death to worry). Quantitative risk analysis hazard-by-hazard too vast an undertaking. Ranking of risks for re-linking worst PQ risks with worst health risks, etc.,How
22、 can we objectively rank “apples and oranges” among the “potatoes and beans?”,31,From the Beginning,Is risk analysis for each hazard independentlyfeasible?,32,Fault Trees for each process?,33,Faults Magnified N-fold for a Simple Manufacturing Process,34,Decision Analyses for Each Hazard Multiplies C
23、omplexity!,e.g.,35,Solution? A Multifactor Approach to PQ Risk Management,Multifactor methods already exist. Some tools (software) already developed. Appropriately-scaled approach to the question, the data quality, the nature of the decision, and the understanding of the overall process.,36,State th
24、e Assumptions,E.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 quality Given the assumption, can GMP “compliance risk” be modeled as a surrogate of health risk?,37,Identify t
25、he PQ Failures (Hazards),What can go wrong? Top level organization of hazards: Health | Compliance | Resources | Sociopolitical Second level (detail) organization: Sterility (microbial contamination) Dose (formulation) Toxicity (chemical contamination) Physical hazards (physical contamination/defect
26、) Fine detail: “risk factor” event descriptors.,38,Sort the Hazards/Risks by Major Categories,Start with assumptions. State questions to be answered. Sort under the questions. Re-sort if new patterns emerge.For example, (next slide),39,Organizing a Multi-factorial Risk Model,40,Focused Multi-factori
27、al Risk Model,41,Risk factors for a given endpoint,42,Estimate the Prevalence,The prevalence of inspection findings for a given type of event are initial estimates of probabilities necessary for risk management modeling. Failure analysis “in plant.” Failure in compliance inspections. Human adverse e
28、vents.,43,For each hazard,44,The modelers view (for example),45,For each hazard,46,Scoring, then prioritize multiple hazards,PQ Fault A PQ Fault T PQ Fault C PQ Fault D PQ Fault X PQ Fault M,Scored and Prioritized,47,Risk Ranking & Filtering Model,Health,Compliance,Other,(Risk Ranking and Filtering)
29、,48,Risk Analysis Cycle,Multi-Factorial Risk Model,Risk Ranking and Filtering,Work Planning,cGMP/Compliance Inspections,Assessments (Data Bases),Start,49,Conclusions,Risk Assessment provides a process for organizing information in support of risk-based decision making. Risk 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. Multifactor Risk Ranking and filtering approach might be robust enough to employ in the GMP Initiative.,
