【正文】 ual control, spot checks) ? 2 Regularly detected ? Failure will normally be detected (manual control, routine work with statistical control) ? 1 Always detected ? Failure can and will be detected in all cases (monitoring, technical solution available) EXAMPLE Annex I: Methods amp?？赡墚a(chǎn)生不符合 GMP法規(guī)或產(chǎn)品注冊(cè)。 not an official policy/guidance July 2022, slide 21 ICH Q9 QUALITY RISK MANAGEMENT FMEA: 風(fēng)險(xiǎn)數(shù)值 : 可能性 10 非常高 : 失效幾乎不可避免 每天發(fā)生超過(guò)一次或可能性大于 3/10 (Cpk or 1σ). 9 每三天或四天發(fā)生一次或可能性是 3/10(Cpk ~ or ~1 σ). 8 高 : 重復(fù)失效 每周一次或可能性為 5/100(Cpk ~ or ~2 σ). 7 每月發(fā)生一次或可能性為 1/100(Cpk ~ ~ σ). 6 中 : 偶爾失效 每三個(gè)月發(fā)生一次或可能性為 3/1000(Cpk ~ or ~ 3 σ). 5 每六個(gè)月到一年發(fā)生一次或可能性為 1/10， 000(Cpk ~ or ~ σ). 4 一年發(fā)生一次或可能性為 6/100， 000(Cpk ~ or ~ 4 σ). 3 低 : 相對(duì)很少失效 每一年至三年發(fā)生一次或可能性為 6/10， 000， 000(Cpk ~ or ~5 σ). 2 每三至五年發(fā)生一次或可能性為 1/1， 000， 000， 000(Cpk ~ OR ~6 σ). 1 微笑 : 失效幾乎不太可能 超過(guò)五年發(fā)生一次或小于 2/1， 000， 000， 000(Cpk OR 6 σ). For batch failures use the time scale for unit failures use the unit ，對(duì)于單元失效使用單位尺度 Dr. Gary Harbour, Pfizer EXAMPLE Annex I: Methods amp。 1 幾乎確定 缺陷很明顯，定期校驗(yàn)的 100%的自動(dòng)檢查和檢查設(shè)備的預(yù)防性維護(hù)。 not an official policy/guidance July 2022, slide 26 ICH Q9 QUALITY RISK MANAGEMENT : 失效模式效應(yīng)分析 (FMEA) ? 嚴(yán)重性 (S) 聯(lián)系最終產(chǎn)品功能性失效 引入醫(yī)學(xué)部門(mén) ? 可能性 (P) 使用歷史數(shù)據(jù) 類似工藝產(chǎn)品 ? 可檢測(cè)性 方法驗(yàn)證研究 歷史數(shù)據(jù) EXAMPLE Takayoshi Matsumura, Eisai Co. 干燥過(guò)程 /工藝 Annex I: Methods amp。 not an official policy/guidance July 2022, slide 30 ICH Q9 QUALITY RISK MANAGEMENT 工藝 潛在失效模式 潛在原因 S P D RPN 1. 進(jìn)料 污染 操作者不潔凈的服裝 設(shè)備清洗不充分 2. 開(kāi)始干燥 污染 進(jìn)口過(guò)濾器損壞 產(chǎn)品降解 溫度計(jì)損壞 3. 保持溫度 長(zhǎng)的烘干時(shí)間 不穩(wěn)定的供應(yīng)空氣體積 高的干燥失重 計(jì)時(shí)器損壞 低的干燥失重 高露點(diǎn) 不均勻的干燥失重 不均勻的溫度分布 干燥過(guò)程 /工藝 : 失效模式效應(yīng)分析 (FMEA) Takayoshi Matsumura, Esai Co EXAMPLE RPN: 風(fēng)險(xiǎn)優(yōu)先因子 = S*P*D Annex I: Methods amp。 Tools prepared by some members of the ICH Q9 EWG for example only。 EXAMPLE S. R246。 a u t o m a t is a t ion n o t p o s s ible a t t h a t t im eGr a n u lati o n p o w e r c o n s u m p t ionn o t m e e t s p e c if ic a t ion o f d is s o luti o n3 2 1 6t r y t o g e t t o a m inu m u m a n o p t im u m o f k n e e d ing t im e3 2 1 6 0d e p e n d ing o n k n e e d ing t im e d e p e n d ing o n m a t e r ial p r o p e r t iesP r e m ix ing m ix ing t im en o t m e e t s p e c if ic a t ion o f c o n t e n t u n if o r m it y3 2 3 18 I P C m e a s u r e o n c o n t e n t u n if o r m it y 3 2 1 6 12 infl u e n c e o n e f f ic a c yP r e m ix ing Gr a n u lati o n s p e e d o f a d d ing w a t e rn o t m e e t s p e c if ic a t ion o f d is o luti o n a n d d e s inte g r a t ion3 3 3 27A n a ly s e ( s e e v ing o f g r a n u late s iev e a n a ly s is ) 。 Tools prepared by some members of the ICH Q9 EWG for example only。 需要進(jìn)一步控制 干燥過(guò)程 /工藝 工藝 潛在原因 RPN 建議措施 S P D RPN 1. 進(jìn)料 操作者不潔凈的服裝 120 使用長(zhǎng)手套和眼睛 3 2 8 48 設(shè)備清洗不充分 112 變更清洗程序 7 2 4 56 2. 開(kāi)始干燥 進(jìn)口過(guò)濾器損壞 126 變更維護(hù)周期 7 2 6 84 溫度計(jì)損壞 63 變更檢驗(yàn)周期 7 2 3 42 3. 保持溫度 不穩(wěn)定的供應(yīng)空氣體積 40 ― 2 4 5 40 計(jì)時(shí)器損壞 8 ― 2 2 2 8 高露點(diǎn) 27 ― 3 3 3 27 不均勻的溫度分布 45 ― 3 5 3 45 : 失效模式效應(yīng)分析 (FMEA) Based on Takayoshi Matsumura, Esai Co. EXAMPLE RPN: 風(fēng)險(xiǎn)優(yōu)先因子 = S*P*D Annex I: Methods amp。 not an official policy/guidance July 2022, slide 31 ICH Q9 QUALITY RISK MANAGEMENT Existing controls: IPC of LOD and degradation product after drying process Drying Process Process Potential Failure Mode Potential Cause S P D RPN 1. Set up contamination disheveled gown of operator 3 5 8 120 insufficient cleaning of equipment 7 2 8 112 2. Start drying contamination damage of inletair filter 7 3 6 126 degradation of product damage of thermometer 7 3 3 63 3. Maintain temperature long drying time unstable supplyair volume 2 4 5 40 high LOD malfunction of timer 2 2 2 8 low LOD high duepoint 3 3 3 27 nonuniformity of LOD uneven temperature distribution 3 5 3 45 : Failure Mode Effects Analysis (FMEA) Takayoshi Matsumura, Eisai Co EXAMPLE RPN: Risk Priority Number = S*P*D Annex I: Methods amp。 not an official policy/guidance July 2022, slide 27 ICH Q9 QUALITY RISK MANAGEMENT Ranking Severity (S) Probability (P) Detection (D) 10 Death More than once a day Impossible to detect 9 ↓ 3 – 4 times a day Remote 8 Permanent injury Once a week Very slight 7 ↓ Once a month Slight 6 Temporary injury Once in three month Low 5 ↓ Once in half – one year Medium 4 Reported/ dissatisfied Once a year Moderately high 3 ↓ Once in 1 – 3 years High 2 Notice/ no report Once in 3 – 5 years Very High 1 ↓ Less than once in 5 years Virtually certain : Failure Mode Effects Analysis (FMEA) Takayoshi Matsumura, Esai Co EXAMPLE Drying Process Annex I: Methods amp。 Tools prepared by some members of the ICH Q9 EWG for example only。 not an official policy/guidance July 2022, slide 22 ICH Q9 QUALITY RISK MANAGEMENT FMEA: Quantitation of Risk: Detection 10 Absolute Uncertainty The product is not inspected or the defect caused by the failure is not detectable. 9 Very Remote Product is sampled, inspected, and released based on Acceptable Quality Level (AQL) sampling plans. 8 Remote Product is accepted based on no defects in a sample. 7 Very Low Product is 100% manually inspected in the process. 6 Low Product is 100% manually inspected using go/nogo or other mistakeproofing gauges. 5 Moderate Some Statistical Process Control (SPC) is used in the process and product is final inspected offline. 4 Moderately High SPC is used and there is immediate reaction to outofcontrol conditions. 3 High An effective SPC program is in place with process capabilities (Cpk) greater than . 2 Very High All product is 100% automatically inspected. 1 Almost Certain The defect is obvious and there is 100% automatic inspecti