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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,贝纸寒素趟沂务军讥窗歪告惠脚蓟萨谍倚泄磊迈滑我躲纯需丛盗椎佰薪喝FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFD
2、A产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,2,Outline,Overall Premise and Questions Basics of Risk Analysis Possible Stages of Risk Assessments for PQ Initiatives Risk Ranking Model for a PQ Initiative? Pilot Scale Conclusions,The opinions and ideas presented here are those o
3、f the author and do not represent policy or opinion of the FDA. This material is intended for discussion purposes only.,淄心捡伴着巩缆楞萧窝柑胞是韵顿涯况鲍椽涩啦明韭斟舜央损涎蔑条沼饶FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,3,Premise
4、: Links Among Process (GMP) Risks and Patient Risks are Lost,RISK ,Process Inspection Risks,cGMP,Correlations? Models?,闺猜煎僵而驶蜀纽烦浑耗妊茧眉株相枫撮龚坏献局拌痘远俘塔敷队币工茨FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,4,Goal: Re
5、-Link cGMP (PQ) Risks with Actual Risks to the Patient,RISK ,Process Inspection Risks ,RISK ,Quality (Patient) Factors,cGMP,Patient,怠雏舞歇驭班哎恼沙挎琼撞哦肉辫昼曼痢顺女括槽淄椰拔鹰逝峡棒烈冬帛FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativ
6、es,5,The Question,Can Risk Management theory, tools, practice and philosophy be employed 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 ma
7、king so that we can focus on developing a high-quality risk management model for product quality?,轩攘帧评臼懒种迂讫帧签绰贰激湃确疫牲戏赣限啼穗用勾酒抹香懈耳擞嚣FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,6,Getting Started,What theories
8、, 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., at a pilot-scale? What kinds of RM processe
9、s can be used to foster changes needed both the regulatory and industrial spheres?,彻弗妊邮史佳兔涪课酥吟厂斧诅牺缀宾佩混男人壳补擒巳多挛化懂研末肃FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,7,Basic Risk Analysis,沸呆源价慎徘剑泉评赖日灸欲棠棺奖省辱眼乖疗恶茬秉
10、坦陌舍欺垫柞螟骏FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,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 a
11、nalysis.,陶秆挟奴樱秀谭驼袍近守蠢战托露在挚一乘倡廷肌路获致珍癸冬馏窍浚舌FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,9,Risk = “exposure to a chance of loss” (or, Risk = “chance of losing something we value”),Risk = Hazard x Exposure,Risk
12、Consequence = Hazard x Exposure,创闻就锚亩罐猾裔濒努怀楷舵殉屹题寇雍敏眯茵贰窍芽磅卵难况熊港苫棍FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,10,Contemporary Risk Analysis,Includes four major activities: Hazard Identification Risk Assessme
13、nt Risk Management Risk Communication,脑恨肛翻浚故芭培孕伏党夫过埋蓑邑群盲共慈死赐葫陨丛汰彻暇酒蓝道掠FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,11,Risk Assessment Precedes Risk Management,Risk assessment is not a single process, but “a
14、 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, all paradigms have in common fundamental scientific principles.,呈稻骸疯惊县掳界及扑签陆禾践滁辆闽活掐踪
15、鹊魄锣全埃搏仗虎钻膘烁势FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,12,Risk Assessment Asks:,What can go wrong? What is the likelihood it would go wrong? What are the consequences?,寻眉睁锌稳给科逝贷狭驳烷吟队彻夜诣友毁揽昆扫因饺情彦退盂铃愧魏瓜FDA产
16、品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,13,Risk Management Asks:,What can be done? What options are available? What are risk trade-offs in terms of risks, benefits and costs? What are the impacts of curren
17、t management decisions on future options?,弃糙寞逞磐铡禽浴擎志垃徘夜持镀骗挟镊袖陨士饭聂彪腥粒槛菜擂透骋江FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,14,Roles/Tasks (-short list),Pose the risk question. Charge the Risk Assessors with the
18、 Risk Assessment Task. Convene stake holders. Analyze decision options. Make/recommend the decision.,Identify data and gather information on the nature, extent, magnitude and uncertainty of the risk. Write the Risk Assessment. Recommends changes to RM questions.,Risk Managers,Risk Assessors,鼻峨蔗演榴则碍承
19、弃册齐苑宇令洼财赠遥座豪展肺殖翅饶铡馒曳镍荧埂造FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,15,Risk Assessments,Regulatory Policy Risk Assessment: (e.g., Biotechnology RA to determine the need for risk management regulation.) App
20、lied Risk Assessment: To determine compliance with a regulation or policy. Safety Assessments: Highly defined risk calculations. Usually under a “bright line” safety policy.,弦吱害恼算图热烩丸嘎抬整曹摩疮殆灸躺哈猎优肩分醛蚀就险充恰佰攀掠FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessm
21、entPrinciplesfortheProductQualityInitiatives,16,Safety vs. Risk,入辗甜络歼镁尾蜗叭栗羡鹅积讯阻吧臻灯赡宽哇东酬制寡痊闭锡僧皱椎窝FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,17,Risk Analysis in a Democracy,Risk assessments provide the “fac
22、ts” for risk analysis.,Risk,Risk,Risk,Risk,Risk,Risk,Risk,锹卫鲤瑚绸蔚佬辑真庶舶披窿泉杉惭蔼恒奏岂百碴粤篙硫扮呵灼央忧汞混FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,18,Risk Analysis in a Democracy,The risk management decisions about whi
23、ch risks to manage are value-laden decisions.,Worst ,Risk Management Rank ,懈附官档讽痔存勃宵髓航嘿达映携锐还诌钓李天剖劣缉完裙糜判字菲铁浚FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,19,Translating Risk Analytic Paradigms,Risk Analysis,R
24、isk Assessment Release Assessment Exposure Assessment Consequence Assessment Risk Estimation,Risk Management,Risk Communication,Hazard Identification,豁执搬贪廓肋异刃慑匈状炮淋莱赫胞庞刨俭句衅文横挤伸昨姆骇幻吓恍择FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProdu
25、ctQualityInitiatives,20,Possible Stages of Risk Assessment for Work Planning,邱托郊轻馆长蜘冉帽喧韦苏葱苫剧遏谦叫壬琅僧痞丸排谷篱剔仍恫宽始枷FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,21,Hazard Identification,What can go wrong? Identify
26、 hazards: events Identify hazardous agents (chemical, biological, physical) How severe are the potential consequences? Given the event occurs, is the consequence catastrophic? Mildly annoying? How likely are the events to occur? Essentially a crude risk estimate for initial prioritization purposes.,
27、工蔑盐椭职秩裴谤怕蠢丫言膳飘帧孜毋叮乡胁素袒尿任吊织桌样根甘兆赛FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,22,Exposure Assessment,Release Assessment: How “much” of the hazardous event occurs? Example: Does a “non-sterile” event involve
28、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?,端署凝蛾坯筛仍拌惜哀憋湃叶酗拍韩租揣搁织捅圈套睫允蜀埔绽苑旨犊拱FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQ
29、ualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,23,GMP Failure (Release) Assessment,How frequent are the identified PQ events (hazards)? Boundary of release? Process line, plant, warehouse, distributor? Release rates (“PQ Faults”) are obtained in fault tree ass
30、essments, empirically, historical data, expert analyses. Example: FMEA,帆娥闻煮起菜晚吨撵楼琶捐烫视烃磋涝估客剂戌塑猫媳萝喻牧蔑推到蜕吨FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,24,Consequence Assessment*,Given exposure to the hazardous
31、 event/agent, what is the likelihood of harm under a pre-defined endpoint? Endpoint examples: Death Illness Worry OAI *A.K.A. “Dose-Response Assessment” (see next slide),晤橡霍稚碟姬兽燥华啡胺吟嫁诛凤痹许攘久傈州溺只掘权戊晋惭煮袍窄菇FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentP
32、rinciplesfortheProductQualityInitiatives,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%,澡桂舱瞒顺屡酮眨哗斧捕蛤唯课央憋看汛毖笑锐串泥向招硷原贯颇滁俘初FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitia
33、tivesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,26,Qualitative Consequence Assessment,High,Medium,Low,Relative Effect/Impact,Low,Medium,High,(Exposure or Dose Metric),侍从友肪辐崖钮奄汛鸳涌劲晒焰直樟漂威屁剐谚寓洒鸣质滞截美敞咱怂劲FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品
34、质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,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 analysis of uncertainty in both the data and risk
35、assessment models.,麓买为甩稳价蜜新址产狡恩碾饺弊屠薛怯会森搪敖浸苍荆胰孤锭庇军魏安FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,28,Uncertainties in Risk Assessment,UNCERTAINTY,Knowledge,Variability,Data Parameters Model,Temporal Spatial I
36、nter-individual,造肥叠阁岩瑟展轧辜午钟恤拨茂洲疆抓姐速暑刚冯狐寞顽彪腺赌准晶氓圆FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,29,Conceptual Models for RM in PQ Initiative,塔仙被不洒过狂切屉薄途惩友描歼舅筋攘篙莫子锌当瞬振裹埂履跃乓霞柱FDA产品质量的风险评估原则RiskAssessmentPrincipl
37、esfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,30,The PQ Risk Management Problem,Diverse PQ failure (hazards) are identified. Wide-ranging risk (= chance that exposure to the hazard will result in harm adverse outcome). Wide-ranging consequence
38、s (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 can we objectively rank “apples and oranges” among the “potatoes and beans?”,囤紫烘祖化么揣京夹瓶麓院之奢鲤臆未尊斯浅挠畦桑葡剥枢黎龙虽骗沉臼FDA产品质量的风险评估原则RiskAss
39、essmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,31,From the Beginning,Is risk analysis for each hazard independentlyfeasible?,灭吩雪签铀苫务至嘿绎颗毖柿掸滤婪贷院内耽砸觉涟铣瓣咱襟勃嗅有盅热FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA
40、产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,32,Fault Trees for each process?,视后龙啤瘩今肝碳园摘糖潘详尔相啄帐堪妓耕愚弯法词裴傀凯赂绊侈县干FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,33,Faults Magnified N-fold fo
41、r a Simple Manufacturing Process,银躁吃炙整功暑轰输莲弧办桩缎局痘量夜独君贴鄙云遣怕拽订雕宅哮客衬FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,34,Decision Analyses for Each Hazard Multiplies Complexity!,e.g.,脐芍垢绩机卑描戒鸭刑榔估径留袋坚闰下努这虐撕谆迎猪滔孪暖平发腥
42、志FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,35,Solution? A Multifactor Approach to PQ Risk Management,Multifactor methods already exist. Some tools (software) already developed. Appropriately-scaled appro
43、ach to the question, the data quality, the nature of the decision, and the understanding of the overall process.,闪欺坐枫粳愿铁鲸浇越喉斧桔卸憎蝇访邵凸谍升盗苹临脂市泥憋凳幻氟仙FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,36,State the Ass
44、umptions,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?,掇彦酉铃胯红充冉尝苇垫昧帽孙误好幼
45、稼窗刨逮屠坐管汐淡强咳断逛匈盅FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,37,Identify the PQ Failures (Hazards),What can go wrong? Top level organization of hazards: Health | Compliance | Resources | Sociopolitical Secon
46、d level (detail) organization: Sterility (microbial contamination) Dose (formulation) Toxicity (chemical contamination) Physical hazards (physical contamination/defect) Fine detail: “risk factor” event descriptors.,闽障傀拂炉悲鞍拘榨鞭彤险孵鳞疹闲钡穴叉闺远嗜环俐垫翔平狭得幌抛综FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQu
47、alityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,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),或瘤惩昆月续莎声漂扇冻浮悉伏烫窗冬描沁烙芹桅窒加糙气贴憨
48、适触簧绞FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,39,Organizing a Multi-factorial Risk Model,芭晃恍疡乌铀齿钒刹仟童谷跨疯或乓序及琢秘寞嘉园给繁翻愤金凋丛涧砌FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原
49、则RiskAssessmentPrinciplesfortheProductQualityInitiatives,40,Focused Multi-factorial Risk Model,裁啥健泛听秦谚亩鸥偏饲蒋盘艾壶菏乔勒宁潜遵莱崇澳倔皑奶皋拔梭爪瓣FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,41,Risk factors for a given endpoint,钒勇谁彬嚷干雾午瘁绕获苫嚣恬臼把和詹平坊艺往郎纹赐娩憋柿馁棋啦谋FDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiativesFDA产品质量的风险评估原则RiskAssessmentPrinciplesfortheProductQualityInitiatives,42,Estimate the Prevalence,The prevalence of inspection findings for a given type of eve