偏差管理方案计划案例解析分析.doc

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1、/.Causal Analysis Report /因果分析报告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.希罗达周期性清洁再验证中，Glatt制粒干燥系统的清洁剂结果（样品编号37.2）超出接受标准。Discrepancy ID number / 差异ID号码TW1079413Causal Analysis T

2、eam Participants / 因果分析小组成员Function / 职能Name / 姓名QALily Zhou/周玲洁QVLily Li/李志珍Prod-SMEZhao Bin/赵斌Prod-SMEXu Feng/徐锋Prod-SMEAlex Yu/郁昊MSAT-SMEChen Jie/陈洁Documentation of all information/data available from the initial Investigation /初步调查中获取的所有信息/数据的记录1. RCA/因果分析Fishbone diagram /因果分析鱼骨图1.1 Material/物料

3、方面：l Possible cause 1: Citric Acid可能原因1：柠檬酸The supplier for citric acid is not changed since last cleaning validation(2013.01)自从上次清洁验证（2013.01）至今，柠檬酸的供应商未发生过变更。The quantity of citric acid was weighed by two operators and formulation of citric acid solution was performed by two operators. Citric acid

4、 solution 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.柠檬酸

5、由双人称量，柠檬酸溶液由双人配制。使用前，柠檬酸溶液被吸入清洁剂储罐中待用。员工检查计量泵的设定值正确。在WIP期间，员工始终在清洁剂储罐旁边并确保所有柠檬酸溶液用尽。查看相关日志，没有发现异常情况。Outcome: No.结果：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)自从上次清洁验证（2013.01）至今，CIP100的供应商未发生过变更。Two whole drums of CIP100

6、 are 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.两

7、整桶CIP100用于WIP。CIP100被吸入清洁剂储罐中待用。员工检查计量泵的设定值正确。在WIP期间，员工始终在清洁剂储罐旁边并确保所有CIP100用尽。查看相关日志，没有发现异常情况。Outcome: No.结果：不是可能原因。l Possible cause 3: Glove (for cleaning)可能原因3：手套（用于清洁）The supplier for rubber glove is not changed since last cleaning validation (2013.01)自从上次清洁验证（2013.01）至今，手套的供应商未发生过变更。Rubber glov

8、e is single used. 70% Ethanol is only used during gowning before entering granulation room. No 70% ethanol is used during manual cleaning.乳胶手套为一次性使用。只在进入制粒间前的更衣时使用过70% 乙醇。在手工清洁期间没有使用过70% 乙醇。According to current sampling procedure (sop0105674 v2.0), the Sterile glove is used during CV visual inspecti

9、on 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.依据现行版取样程序（sop0105674 v2.0），自2015.06.12起，清洁验证目检时使用无菌手套。在2015.06.12前，清洁验证目检时使用乳胶手套。无菌手套和乳胶手套均为一次性使用，戴手套时不使用70%乙醇

10、。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. 在清场后的目检核清洁验证取样期间使用无菌手套。无菌手套为一次性使用。在清洁验证前的目检期间，戴无菌手套时不使用酒精。According to current sampling proced

11、ure (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.依据现行版取样程序（sop0105674

12、 v2.0），自2015.06.12起，生产部在目检样时使用无菌手套。在2015.06.12前，生产部目检时使用乳胶手套。无菌手套和乳胶手套均为一次性使用，戴手套时不使用70% 乙醇。 Above all, interference of 70% ethanol to the detergent result can be excluded. 综上，70%乙醇对酒精对清洁剂结果的干扰可以被排除。Outcome: No.结果：不是可能原因。l Possible cause 4: Glove (for Sampling)可能原因4：手套（用于取样）The supplier for glove is

13、 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 Sterile gl

14、ove and rubber glove is single used, and no 70% ethanol is used when wearing glove.自从上次清洁验证（2013.01）至今，手套的供应商未发生过变更。自2015.06.12起，依据现行版取样程序（sop0105674 v2.0），在目检和TOC取样时使用无菌手套。在2015.06.12前，目检和TOC取样时使用乳胶手套。无菌手套和乳胶手套均为一次性使用，戴手套时不使用70% 乙醇。Outcome: No.结果：不是可能原因。l Possible cause 5: Low fibre wiper可能原因5：低纤维抹

15、布Low fibre wiper is used during manual cleaning for machine and parts. Visual inspection before sampling met the acceptance criteria.低纤维抹布用于设备和部件的手工清洁。取样前的目检结果符合可接受标准。Outcome: No.结果：不是可能原因。l Possible cause 6: Drinking water可能原因6：饮用水The quality monitoring parameters (hardness, chlorine and conductivi

16、ty) 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.根据SRD-0101917 SHiP饮用水系统运行记录表”，清场期间的水质监测参数（硬度、余氯和电导率）均在可接受标准内。且没有发现数据有不良趋势。Outcome: No.结果：不是可能原因。l Possible cause 7: Purifi

17、ed water可能原因7：纯水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根据SHiP纯水系统的打印记录，清场期间的水质监测参数（臭氧和电导率）均在可接受范围内。且没有发现数据有不良趋势。Outcome: No.结果：不是可能原因。l Possibl

18、e cause 8: TX761 sampling swab 可能原因8：TX761取样棉签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.取样棉签的型号是Texwipe TX761，

19、在分析方法验证和清洁验证过程中所有的清洁剂取样中均使用该棉签进行取样，同时，进行使用空白棉签作为空白对照样品，至今未发现异常结果。Outcome: No.结果：不是可能原因。1.2 Man/人员方面l Possible cause 1: Qualification for Operator (Cleaning)可能原因1：操作员工的清洁资质All operators participated in the clearance are trained of current SOP-0102731”Cleaning procedure for Glatt granulation train in

20、HP plant”. They are all qualified for manual cleaning with qualification certificate.所有参与清场的员工都被培训过现行版SOP-0102731“高致敏车间Glatt 制粒干燥系统的清洁程序”。他们均有手工清洁的资质认证证书。Outcome: No.结果：不是可能原因。l Possible cause 2: Qualification for sampling staff 可能原因2：取样员工的资质Sampling person is trained and qualified, and have taken C

21、V samples for almost 3 years.取样员工受过培训过，是有资质的，且已进行近3年的清洁验证取样。Outcome: No.结果：不是可能原因。1.3 Measure/测量方面l Possible cause 1: alarms during WIP可能原因1：WIP期间的报警Checking printout of WIP process, it was found that at 10:16 2015.08.31, alarm 5452-1”Tank loop water flow-actual valuemin” occurred in “WIP STOP” step

22、. 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 and 3 ste

23、ps 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，确认一下！was not performed. And, steps for drinking water washing/rinse were after CIP100 washing.查看WIP程序的打印报告，发现在2015.08.31 上午10：16，5452-1报警”Tank loop water flow-actual valuemin”发生在“生在“暂停”步

24、骤。在“骤。在暂停”步骤，对Glatt的清洗暂停，饮用水储罐正在补水。饮用水补水流量太小导致了5452-1报警的发生。在“警的发暂停”步骤前，7步饮用水清洗/淋洗（4步VG，3步FBD）已完成，剩余3步饮用水清洗/淋洗（21步VG，12步FBD）还未进行。饮用水清洗步骤是在CIP100清洗步骤后进行的。During stopping period of machine, alarm 138-3 “Product container seal-leak” occurred and caused the upper seal of FBD deflated. At that time, drink

25、ing 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 FBD bowl rim

26、.在设备停止期间，138-3报警“Product container seal-leak”发生并导致FBD上上密封圈泄气，这里是否只写FBD密封圈泄气更合适啊？密封圈放气。此时，饮用水可能进入上密封圈和FBD碗形腔体边缘的间隙中。该报警是由于压缩空气管道漏气导致的。报警发生16分钟后，管道被更换，报警消除，上密封圈FBD密封圈重新充气。重新充气。一些饮用水可能残留在上密封圈和FBD碗壁间的空隙中。Alarm 138-3 will occur when the seal pressure of FBD lower seal is min. Confirmed by supplier, this

27、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 compressed air sup

28、ply 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报警为FBD碗形腔体的下密封圈的压力最小值时发生的报警。经供应商确认，该报警会导致上密封圈和下

29、密封圈同时泄气。供应商对138-3报警原理的解释见附件-01。此外，在该偏差发生后，进行了模拟运行及支持性测试：人为中断下密封圈的压缩空气供应，出现报警138-3，同时观察到上密封圈也泄气了；人为中断上密封圈的压缩空气供应，出现报警139-3，同时观察到下密封圈也泄气了。When the alarms occurred, WIP process was during drinking water washing/rinse after CIP100 washing. There might be some CIP100 residue in drinking water in the spac

30、e between the upper seal and FBD bowl rim.报警发生时，WIP程序处于CIP100清洗后的饮用水清洗/淋洗步骤中。残留在上密封圈和FBD碗形腔体边缘之间的空隙中的饮用水中可能有CIP100残留。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 and FBD bowl rim.WI

31、P程序的最后一步为干燥。所以，在上密封圈和FBD碗形腔体边缘之间的空隙中的饮用水蒸发了，但是CIP100 可能残留在上密封圈和FBD碗形腔体边缘上。Outcome: YES结果：是可能的原因。l Possible cause 2: Visual inspection before sampling 可能原因2：取样前的目检MSAT, QV and Prod person have performed visual inspection before sampling, and confirmed the equipment was visual clean (no residue and fo

32、reign objects) and dry.MSAT, QV和生产部员工在取样前进行了目检，并确认设备目视清洁（无残留和异物）并干燥。Outcome: No.结果：不是可能原因。1.4 Machine/设备方面l Possible cause 1: Glatt granulation and FBD system可能原因1：Glatt制粒干燥系统The Glatt granulation and FBD system is within revalidation due date. Maintenance is performed according to maintenance plan.

33、Glatt制粒干燥系统在再在验证有效期内。维护行动按照维护计划进行。Outcome: No.结果：不是可能原因。1.5 Environment/环境方面l Possible cause 1: Temperature, humidity and differential pressure可能原因1：温湿度及压差The temperature, humidity and differential pressure of granulation room is within acceptance criteria during clearance according to printout of B

34、MS system.根据BMS系统打印记录，在清场期间制粒间的温湿度和压差均在可接受标准内。Outcome: No.结果：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处方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 steps and parameters ar

35、e all correct.从上次清洁验证（2013.01）至今，WIP处方没有变更。查看本次清场的WIP打印记录，WIP程序完整。所有步骤和参数正确。Outcome: No.结果：不是可能原因。l Possible cause 2: Manual cleaning可能原因2：手工清洁There is no change for manual cleaning procedure since last cleaning validation (2013.01). Manual cleaning for the FBD bowl rim and upper seal is performed a

36、fter 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 double checked after

37、manual cleaning, and there is no visible powder and water trace on FBD bowl rim and upper seal.从上次清洁验证（2013.01）至今，手工清洁程序没有变更。根据现行版SOP-0102731有高致敏车间Glatt 制粒干燥系统的清洁程序”，FBD碗的边缘和上密封圈在柠檬酸清洗后和整个WIP程序后进行。所有参与清场的员工均有手工清洁的资质认证证书。在手工清洁后，清洁状态经双人复核，在FBD碗边缘和上密封圈没有发现可见粉尘和水迹。Outcome: No.结果：不是可能原因。l Possible cause

38、3: Sampling method 可能原因3：取样方法The sampling procedure is according to current SOP-0105674v2.0, “Sampling for Cleaning Validation”, and the recovery of sampling method was validated.取样程序是依据现行版SOP-0105674v2.0，“清洁验证的取样”进行的，且取样方法的回收率已经过验证。Outcome: No.结果：不是可能原因。2. RCA5 Whys /因果分析5 Whys1st-Why detergent tes

39、t result of Sampling No. 37.2 was out of acceptance criteria?为什么样品37.2的清洁剂测试结果超出接受标准？CIP100 residue contaminated the FBD bowl rim and was collected by sampling.CIP100残留污染了FBD碗形腔体的边缘，被取样收集到。2nd-Why CIP100 residue contaminated the rim? 为什么CIP100残留污染了FBD碗形腔体的边缘？Drinking water with CIP100 residue entere

40、d the gap between upper seal and rim when upper seal deflated; and remained and couldnt be cleaned after upper seal re-inflated.上密封圈泄气时，带有CIP100残留的饮用水进入上密封圈和FBD碗形腔体边缘的间隙中；上密封圈重新充气后留在间隙中，且无法被清洗干净。3rd-Why the CIP100 residue in the gap couldnt be cleaned?为什么留在间隙中的CIP100残留无法被清洗干净？Alarm 138-1 occurred du

41、e 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 taken. 由于下密封圈压缩空气管道漏气，

42、发生了138-1报警。机修更换了管道，上、下密封圈重新充气。上密封圈重新充气后，清洁用水无法冲洗密封圈和碗沿之间的间隙。机修解决了引起报警的问题，但没有做额外的清洁行动。4th-Why no additional cleaning action was taken?为什么没有做额外的清洁行动？Current alarm handling focuses on solving the problem, not requires assessing potential risk to relevant process. 目前的报警处理流程关注解决问题本身，不要求评估对相关流程的潜在风险。5th-

43、Why current alarm handling doesnt assess potential risk to relevant process?为什么目前的报警处理流程不要求评估对相关流程的潜在风险？Improper/Inadequate handling process for critical GMP alarms 3. 关键GMP报警的处理流程不当/不足Conclusion/结论Possible contamination pathway based on root cause analysis/根本原因分析得出的可能的污染途径Alarm 138-3 occurred and u

44、pper 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 resid

45、ue remained on FBD bowl rim Detergent test result out of acceptance criteria出现报警138-3，FBD碗形腔体的上密封圈泄气 饮用水及CIP100进入上密封圈和腔体边缘的缝隙 报警138-3 解除，上密封圈重新充气 饮用水及CIP100留在上密封圈和腔体边缘的空隙中 干燥过程中饮用水蒸发，但CIP100残留在腔体边缘上 清洁剂样品结果超出接受标准Cause conclusion/原因结论Abnormal deflate and re-inflate of upper seal during drinking water

46、 washing/rinse process due to compressed air duct leakage由于压缩空气管道漏气，上密封圈在饮用水清洗/淋洗过程中发生了不正常的泄气并重新充气Improper/Inadequate handling process for critical GMP alarmsl 关键GMP报警处理流程不当/不足Root Cause/根本原因:During WIP process, alarm 138-3 occurred and upper seal of FBD bowl deflated, then drinking water with CIP10

47、0 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过程中，出现138-3报警，导致这样修改是否更合适？FBD碗形腔体的上密封圈泄气，使导致含

48、CIP100的饮用水进入上密封圈和腔体边缘的空隙中。经过报警138-3解除（上密封圈重新充气）和干燥步骤后，CIP100 残留在腔体边缘上，最终导致该取样点的清洁剂样品结果超出接受标准。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