偏差處理案例分析

1、Causal Analysis Report /因果分析報告Event Description / 事件描述The detergent result of Glatt Granulation train (Sample No.37.2) in cleaning periodic revalidation for Xeloda was out of acceptance criteria.希羅達周期性清潔再驗證中，Glatt制粒干燥系統(tǒng)的清潔劑結(jié)果（樣品編號37.2）超出接受標準。Discrepancy ID number / 差異ID號碼TW1079413Causal Analysis Tea

2、m Participants / 因果分析小組成員Function / 職能Name / 姓名QALily Zhou/周玲潔QVLily Li/李志珍Prod-SMEZhao Bin/趙斌Prod-SMEXu Feng/徐鋒Prod-SMEAlex Yu/郁昊MSAT-SMEChen Jie/陳潔Documentation of all information/data available from the initial Investigation /初步調(diào)查中獲取的所有信息/數(shù)據(jù)的記錄1. RCA/因果分析Fishbone diagram /因果分析魚骨圖1.1 Material/物料方面

3、：l Possible cause 1: Citric Acid可能原因1：檸檬酸The supplier for citric acid is not changed since last cleaning validation(2013.01)自從上次清潔驗證（2013.01）至今，檸檬酸的供應(yīng)商未發(fā)生過變更。The quantity of citric acid was weighed by two operators and formulation of citric acid solution was performed by two operators. Citric acid s

4、olution was pumped into detergent storage container for use. Operator checked the set point of dosing pump was correct. During WIP process, operator was always beside the detergent storage container and confirmed all citric acid solution was used up. No remark of abnormity was found on logbook.檸檬酸由雙

5、人稱量，檸檬酸溶液由雙人配制。使用前，檸檬酸溶液被吸入清潔劑儲罐中待用。員工檢查計量泵的設(shè)定值正確。在WIP期間，員工始終在清潔劑儲罐旁邊并確保所有檸檬酸溶液用盡。查看相關(guān)日志，沒有發(fā)現(xiàn)異常情況。Outcome: No.結(jié)果：不是可能原因。l Possible cause 2: CIP100可能原因2：CIP100The supplier for CIP100 is not changed since last cleaning validation(2013.01)自從上次清潔驗證（2013.01）至今，CIP100的供應(yīng)商未發(fā)生過變更。Two whole drums of CIP100 a

6、re used for WIP. CIP100 is pumped into detergent storage container for use. Operator checked the set point of dosing pump was correct. During WIP process, operator was always beside the detergent storage container and confirmed all CIP100 were used up. No remark of abnormity was found on logbook.兩整桶

7、CIP100用于WIP。CIP100被吸入清潔劑儲罐中待用。員工檢查計量泵的設(shè)定值正確。在WIP期間，員工始終在清潔劑儲罐旁邊并確保所有CIP100用盡。查看相關(guān)日志，沒有發(fā)現(xiàn)異常情況。Outcome: No.結(jié)果：不是可能原因。l Possible cause 3: Glove (for cleaning)可能原因3：手套（用于清潔）The supplier for rubber glove is not changed since last cleaning validation (2013.01)自從上次清潔驗證（2013.01）至今，手套的供應(yīng)商未發(fā)生過變更。Rubber glove

8、is single used. 70% Ethanol is only used during gowning before entering granulation room. No 70% ethanol is used during manual cleaning.乳膠手套為一次性使用。只在進入制粒間前的更衣時使用過70% 乙醇。在手工清潔期間沒有使用過70% 乙醇。According to current sampling procedure (sop0105674 v2.0), the Sterile glove is used during CV visual inspection

9、 form 2015.06.12. Before 2015.06.12, the rubber glove is used during CV visual inspection. The Sterile glove and rubber glove is single used, and no 70% ethanol is used when wearing glove.依據(jù)現(xiàn)行版取樣程序（sop0105674 v2.0），自2015.06.12起，清潔驗證目檢時使用無菌手套。在2015.06.12前，清潔驗證目檢時使用乳膠手套。無菌手套和乳膠手套均為一次性使用，戴手套時不使用70%

10、0;乙醇。Sterile glove is used during visual inspection and CV sampling after clearance. Sterile glove is single used, and no ethanol is used when wearing sterile glove during visual inspection before CV sampling. 在清場后的目檢核清潔驗證取樣期間使用無菌手套。無菌手套為一次性使用。在清潔驗證前的目檢期間，戴無菌手套時不使用酒精。According to current sampling pr

11、ocedure (sop0105674 v2.0), the Sterile glove is used during production visual inspection form 2015.06.12. Before 2015.06.12, the rubber glove is used during production visual inspection. The Sterile glove and rubber glove is single used, and no 70% ethanol is used when wearing glove.依據(jù)現(xiàn)行版取樣程序（sop010

12、5674 v2.0），自2015.06.12起，生產(chǎn)部在目檢樣時使用無菌手套。在2015.06.12前，生產(chǎn)部目檢時使用乳膠手套。無菌手套和乳膠手套均為一次性使用，戴手套時不使用70% 乙醇。 Above all, interference of 70% ethanol to the detergent result can be excluded. 綜上，70%乙醇對酒精對清潔劑結(jié)果的干擾可以被排除。Outcome: No.結(jié)果：不是可能原因。l Possible cause 4: Glove (for Sampling)可能原因4：手套（用于取樣）The supplier for glov

13、e is not changed since last cleaning validation (2013.01). According to current sampling procedure (sop0105674 v2.0), the Sterile glove is used during visual inspection and TOC sampling form 2015.06.12. Before 2015.06.12, the rubber glove is used during visual inspection and TOC sampling. The Steril

14、e glove and rubber glove is single used, and no 70% ethanol is used when wearing glove.自從上次清潔驗證（2013.01）至今，手套的供應(yīng)商未發(fā)生過變更。自2015.06.12起，依據(jù)現(xiàn)行版取樣程序（sop0105674 v2.0），在目檢和TOC取樣時使用無菌手套。在2015.06.12前，目檢和TOC取樣時使用乳膠手套。無菌手套和乳膠手套均為一次性使用，戴手套時不使用70% 乙醇。Outcome: No.結(jié)果：不是可能原因。l Possible cause 5: Low fibre wiper可能原因5：

15、低纖維抹布Low fibre wiper is used during manual cleaning for machine and parts. Visual inspection before sampling met the acceptance criteria.低纖維抹布用于設(shè)備和部件的手工清潔。取樣前的目檢結(jié)果符合可接受標準。Outcome: No.結(jié)果：不是可能原因。l Possible cause 6: Drinking water可能原因6：飲用水The quality monitoring parameters (hardness, chlorine and conduc

16、tivity) are all within acceptance criteria during clearance according to SRD-0101917 “Operational Log Sheet of SHiP PW system”. And, no abnormal trend for these parameters was found.根據(jù)SRD-0101917 SHiP飲用水系統(tǒng)運行記錄表”，清場期間的水質(zhì)監(jiān)測參數(shù)（硬度、余氯和電導(dǎo)率）均在可接受標準內(nèi)。且沒有發(fā)現(xiàn)數(shù)據(jù)有不良趨勢。Outcome: No.結(jié)果：不是可能原因。l Possible cause 7: Pu

17、rified water可能原因7：純水The quality monitoring parameters (ozone and conductivity) are all within acceptance criteria during clearance according to printout of SHiP PUW system. And, no abnormal trend for these parameters根據(jù)SHiP純水系統(tǒng)的打印記錄，清場期間的水質(zhì)監(jiān)測參數(shù)（臭氧和電導(dǎo)率）均在可接受范圍內(nèi)。且沒有發(fā)現(xiàn)數(shù)據(jù)有不良趨勢。Outcome: No.結(jié)果：不是可能原因。l Pos

18、sible cause 8: TX761 sampling swab 可能原因8：TX761取樣棉簽Type of sampling swab is Texwipe TX761, and it is used in the analytical method validation and cleaning validation of detergent sampling activities, and it is used blank swab as blank sample. Abnormal result is never found till now.取樣棉簽的型號是Texwipe TX

19、761，在分析方法驗證和清潔驗證過程中所有的清潔劑取樣中均使用該棉簽進行取樣，同時，進行使用空白棉簽作為空白對照樣品，至今未發(fā)現(xiàn)異常結(jié)果。Outcome: No.結(jié)果：不是可能原因。1.2 Man/人員方面l Possible cause 1: Qualification for Operator (Cleaning)可能原因1：操作員工的清潔資質(zhì)All operators participated in the clearance are trained of current SOP-0102731”Cleaning procedure for Glatt granulation train

20、 in HP plant”. They are all qualified for manual cleaning with qualification certificate.所有參與清場的員工都被培訓(xùn)過現(xiàn)行版SOP-0102731“高致敏車間Glatt 制粒干燥系統(tǒng)的清潔程序”。他們均有手工清潔的資質(zhì)認證證書。Outcome: No.結(jié)果：不是可能原因。l Possible cause 2: Qualification for sampling staff 可能原因2：取樣員工的資質(zhì)Sampling person is trained and qualified, and have tak

21、en CV samples for almost 3 years.取樣員工受過培訓(xùn)過，是有資質(zhì)的，且已進行近3年的清潔驗證取樣。Outcome: No.結(jié)果：不是可能原因。1.3 Measure/測量方面l Possible cause 1: alarms during WIP可能原因1：WIP期間的報警Checking printout of WIP process, it was found that at 10:16 2015.08.31, alarm 5452-1”Tank loop water flow-actual value<min” occurred in “WIP ST

22、OP” step. In “WIP STOP” step, washing for Glatt paused and water replenishing of drinking water tank was in-process. It caused the alarm 5452-1 that the value of water flow for replenishing drinking water was too low. Before “WIP STOP” step, 7 steps for drinking water washing/rinse (4 steps for VG a

23、nd 3 steps for FBD) had completed and 3 steps for drinking water washing/rinse (1 step for VG and 2 steps for FBD) 中英文不一致，確認一下！was not performed. And, steps for drinking water washing/rinse were after CIP100 washing.查看WIP程序的打印報告，發(fā)現(xiàn)在2015.08.31 上午10：16，5452-1報警”Tank loop water flow-actual value<min

24、”發(fā)生在“生在“暫?！辈襟E。在“驟。在暫?！辈襟E，對Glatt的清洗暫停，飲用水儲罐正在補水。飲用水補水流量太小導(dǎo)致了5452-1報警的發(fā)生。在“警的發(fā)暫?！辈襟E前，7步飲用水清洗/淋洗（4步VG，3步FBD）已完成，剩余3步飲用水清洗/淋洗（21步VG，12步FBD）還未進行。飲用水清洗步驟是在CIP100清洗步驟后進行的。During stopping period of machine, alarm 138-3 “Product container seal-leak” occurred and caused the upper seal of FBD deflated. At that

25、 time, drinking water might enter the gap between upper seal and FBD bowl rim. The alarm was caused by leakage of compressed air duct. The duct was replaced and alarm was removed after about 16min and the upper seal inflated. Some drinking water might residue in the space between the upper seal and

26、FBD bowl rim.在設(shè)備停止期間，138-3報警“Product container seal-leak”發(fā)生并導(dǎo)致FBD上上密封圈泄氣，這里是否只寫FBD密封圈泄氣更合適??？密封圈放氣。此時，飲用水可能進入上密封圈和FBD碗形腔體邊緣的間隙中。該報警是由于壓縮空氣管道漏氣導(dǎo)致的。報警發(fā)生16分鐘后，管道被更換，報警消除，上密封圈FBD密封圈重新充氣。重新充氣。一些飲用水可能殘留在上密封圈和FBD碗壁間的空隙中。Alarm 138-3 will occur when the seal pressure of FBD lower seal is <min. Confirmed by

27、 supplier, this alarm will cause upper seal and lower seal deflate together. Pls. see attachment-01 for Explanation for the principle of alarm 138-3 provided by the supplier. Moreover, Simulation run and supporting test was performed after the discrepancy occurred: When intentionally stopping the co

28、mpressed air supply to lower seal, Alarm 138-3 occurred, and the upper seal was found deflated at the same time. When intentionally stopping the compressed air supply to upper seal, Alarm 139-3 occurred, and the lower seal was also found deflated at the same time.138-3報警為FBD碗形腔體的下密封圈的壓力<最小值時發(fā)生的報警

29、。經(jīng)供應(yīng)商確認，該報警會導(dǎo)致上密封圈和下密封圈同時泄氣。供應(yīng)商對138-3報警原理的解釋見附件-01。此外，在該偏差發(fā)生后，進行了模擬運行及支持性測試：人為中斷下密封圈的壓縮空氣供應(yīng)，出現(xiàn)報警138-3，同時觀察到上密封圈也泄氣了；人為中斷上密封圈的壓縮空氣供應(yīng)，出現(xiàn)報警139-3，同時觀察到下密封圈也泄氣了。When the alarms occurred, WIP process was during drinking water washing/rinse after CIP100 washing. There might be some CIP100 residue in drinki

30、ng water in the space between the upper seal and FBD bowl rim.報警發(fā)生時，WIP程序處于CIP100清洗后的飲用水清洗/淋洗步驟中。殘留在上密封圈和FBD碗形腔體邊緣之間的空隙中的飲用水中可能有CIP100殘留。The last step of WIP process is drying. So, drinking water in space between the upper seal and FBD bowl rim was evaporated, but residue of CIP100 was on upper seal

31、 and FBD bowl rim.WIP程序的最后一步為干燥。所以，在上密封圈和FBD碗形腔體邊緣之間的空隙中的飲用水蒸發(fā)了，但是CIP100 可能殘留在上密封圈和FBD碗形腔體邊緣上。Outcome: YES結(jié)果：是可能的原因。l Possible cause 2: Visual inspection before sampling 可能原因2：取樣前的目檢MSAT, QV and Prod person have performed visual inspection before sampling, and confirmed the equipment was visual clea

32、n (no residue and foreign objects) and dry.MSAT, QV和生產(chǎn)部員工在取樣前進行了目檢，并確認設(shè)備目視清潔（無殘留和異物）并干燥。Outcome: No.結(jié)果：不是可能原因。1.4 Machine/設(shè)備方面l Possible cause 1: Glatt granulation and FBD system可能原因1：Glatt制粒干燥系統(tǒng)The Glatt granulation and FBD system is within revalidation due date. Maintenance is performed according

33、to maintenance plan.Glatt制粒干燥系統(tǒng)在再在驗證有效期內(nèi)。維護行動按照維護計劃進行。Outcome: No.結(jié)果：不是可能原因。1.5 Environment/環(huán)境方面l Possible cause 1: Temperature, humidity and differential pressure可能原因1：溫濕度及壓差The temperature, humidity and differential pressure of granulation room is within acceptance criteria during clearance accord

34、ing to printout of BMS system.根據(jù)BMS系統(tǒng)打印記錄，在清場期間制粒間的溫濕度和壓差均在可接受標準內(nèi)。Outcome: No.結(jié)果：不是可能原因。1.6 Method /方法方面l Possible cause 1: WIP recipe可能原因1：WIP處方There is no change for WIP recipe since last cleaning validation (2013.01). Checking printout of WIP for this clearance, WIP process is integrated. The ste

35、ps and parameters are all correct.從上次清潔驗證（2013.01）至今，WIP處方?jīng)]有變更。查看本次清場的WIP打印記錄，WIP程序完整。所有步驟和參數(shù)正確。Outcome: No.結(jié)果：不是可能原因。l Possible cause 2: Manual cleaning可能原因2：手工清潔There is no change for manual cleaning procedure since last cleaning validation (2013.01). Manual cleaning for the FBD bowl rim and upper

36、 seal is performed after citric acid washing and after the whole WIP recipe according to current SOP-0102731” Cleaning procedure for Glatt granulation train in HP plant”. All operator participated in the clearance are qualified for manual cleaning with qualified certificate. The cleaning status is d

37、ouble checked after manual cleaning, and there is no visible powder and water trace on FBD bowl rim and upper seal.從上次清潔驗證（2013.01）至今，手工清潔程序沒有變更。根據(jù)現(xiàn)行版SOP-0102731有高致敏車間Glatt 制粒干燥系統(tǒng)的清潔程序”，F(xiàn)BD碗的邊緣和上密封圈在檸檬酸清洗后和整個WIP程序后進行。所有參與清場的員工均有手工清潔的資質(zhì)認證證書。在手工清潔后，清潔狀態(tài)經(jīng)雙人復(fù)核，在FBD碗邊緣和上密封圈沒有發(fā)現(xiàn)可見粉塵和水跡。Outcome: No.結(jié)果：不是可能

38、原因。l Possible cause 3: Sampling method 可能原因3：取樣方法The sampling procedure is according to current SOP-0105674v2.0, “Sampling for Cleaning Validation”, and the recovery of sampling method was validated.取樣程序是依據(jù)現(xiàn)行版SOP-0105674v2.0，“清潔驗證的取樣”進行的，且取樣方法的回收率已經(jīng)過驗證。Outcome: No.結(jié)果：不是可能原因。2. RCA5 Whys /因果分析5 Whys1

39、st-Why detergent test result of Sampling No. 37.2 was out of acceptance criteria?為什么樣品37.2的清潔劑測試結(jié)果超出接受標準？CIP100 residue contaminated the FBD bowl rim and was collected by sampling.CIP100殘留污染了FBD碗形腔體的邊緣，被取樣收集到。2nd-Why CIP100 residue contaminated the rim? 為什么CIP100殘留污染了FBD碗形腔體的邊緣？Drinking water with C

40、IP100 residue entered the gap between upper seal and rim when upper seal deflated; and remained and couldnt be cleaned after upper seal re-inflated.上密封圈泄氣時，帶有CIP100殘留的飲用水進入上密封圈和FBD碗形腔體邊緣的間隙中；上密封圈重新充氣后留在間隙中，且無法被清洗干凈。3rd-Why the CIP100 residue in the gap couldnt be cleaned?為什么留在間隙中的CIP100殘留無法被清洗干凈？Ala

41、rm 138-1 occurred due to the compressed air duct of the lower seal was leakage. Mechanics replaced the duct, then both seals were re-inflated. Cleaning water couldnt rinse the gap after the upper seal re-inflated. Mechanics fixed the problem caused the alarm, but no additional cleaning action was ta

42、ken. 由于下密封圈壓縮空氣管道漏氣，發(fā)生了138-1報警。機修更換了管道，上、下密封圈重新充氣。上密封圈重新充氣后，清潔用水無法沖洗密封圈和碗沿之間的間隙。機修解決了引起報警的問題，但沒有做額外的清潔行動。4th-Why no additional cleaning action was taken?為什么沒有做額外的清潔行動？Current alarm handling focuses on solving the problem, not requires assessing potential risk to relevant process. 目前的報警處理流程關(guān)注解決問題本身，不

43、要求評估對相關(guān)流程的潛在風(fēng)險。5th- Why current alarm handling doesnt assess potential risk to relevant process?為什么目前的報警處理流程不要求評估對相關(guān)流程的潛在風(fēng)險？Improper/Inadequate handling process for critical GMP alarms 3. 關(guān)鍵GMP報警的處理流程不當(dāng)/不足Conclusion/結(jié)論Possible contamination pathway based on root cause analysis/根本原因分析得出的可能的污染途徑Alarm

44、138-3 occurred and upper seal of FBD bowl deflated Drinking water with CIP100 entered the gap between seal and FBD bowl rim Alarm 138-3 removed and upper seal re-inflated Drinking water with CIP100 remained in the space between upper seal and FBD bowl rim Drinking water was evaporated after drying s

45、tep but CIP100 residue remained on FBD bowl rim Detergent test result out of acceptance criteria出現(xiàn)報警138-3，F(xiàn)BD碗形腔體的上密封圈泄氣 飲用水及CIP100進入上密封圈和腔體邊緣的縫隙 報警138-3 解除，上密封圈重新充氣 飲用水及CIP100留在上密封圈和腔體邊緣的空隙中 干燥過程中飲用水蒸發(fā)，但CIP100殘留在腔體邊緣上 清潔劑樣品結(jié)果超出接受標準Cause conclusion/原因結(jié)論Abnormal deflate and re-inflate of upper seal d

46、uring drinking water washing/rinse process due to compressed air duct leakage由于壓縮空氣管道漏氣，上密封圈在飲用水清洗/淋洗過程中發(fā)生了不正常的泄氣并重新充氣Improper/Inadequate handling process for critical GMP alarmsl 關(guān)鍵GMP報警處理流程不當(dāng)/不足Root Cause/根本原因:During WIP process, alarm 138-3 occurred and upper seal of FBD bowl deflated, then drink

47、ing water with CIP100 entered the gap between seal and FBD bowl rim. After Alarm 138-3 removed (upper seal re-inflated) and drying step, CIP100 remained on FBD bowl rim, which finally caused that detergent test result of this sampling point was out of acceptance criteria.WIP過程中，出現(xiàn)138-3報警，導(dǎo)致這樣修改是否更合適

48、？FBD碗形腔體的上密封圈泄氣，使導(dǎo)致含CIP100的飲用水進入上密封圈和腔體邊緣的空隙中。經(jīng)過報警138-3解除（上密封圈重新充氣）和干燥步驟后，CIP100 殘留在腔體邊緣上，最終導(dǎo)致該取樣點的清潔劑樣品結(jié)果超出接受標準。l Causal Analysis/因果分析: Alarm 138-3 occurred and upper seal of FBD bowl deflated Drinking water with CIP100 entered the gap between seal and FBD bowl rim Alarm 138-3 removed and upper seal re-inflated Drinking water with CIP100 remained in the space between upper seal and FBD bowl rim Drinking water was evaporated after drying step but CIP100 residue remained on FBD bowl rim Detergent test result out of acceptance criteria出現(xiàn)報警138-3，F(xiàn)BD碗形腔體的上密封圈泄氣 含CIP100的飲用水進入上密封圈和腔體邊緣