在2019.05.18日14:57，冻干机岗位人员罗兴土在Y76E冻干

At 14:57 on May 18th, 2019, Luo Xingtu, a post of freeze dryer, heard the alarm sound of D3003A freeze dryer in the Y76E freeze dryer control room. Check the main interface of D3003A freeze dryer computer. The alarm content is "AL-LSL25004-" --Low level alarm of silicone oil expansion tank ", which caused the No. 2 silicone oil pump (FP25020) to stop running; and the silicone oil temperature (PRB-TIRC25039) rose to -36.9 ° C at 15:14, and the ongoing process was 2017-190505 The fourth step of the lyophilization process of approved cilastatin sodium (-40 ° C, 1h) exceeded the process requirements (-40 ± 3 ° C). <br><br>The reason for this oil leak was that the post staff missed to check whether the connection between the inlet and outlet of the silicone oil heater (EH25035) and the screw and nut at the flange were loose. On the other hand, the screw thread part was worn and the seal was incomplete there. <br><br>1. This deviation has nothing to do with the tightness of the freeze-dried cabinet body, so it has no effect on the sterility of the batch of cilastatin sodium 2017-190505. <br>2. When alarming, the cilastatin sodium lyophilization program runs to step 4, this time is the last hour of the pre-freezing phase, the role is to ensure that the liquid is frozen (for lyophilized products, if the pre-freezing phase is not frozen, it may be There is a phenomenon of melting and collapsing after drying for a time); the alarm lasts for about 1 hour until it returns to normal, which may cause the lyophilized powder to collapse, so it may affect the product properties and moisture; the batch of cilastatin Sodium butylate was freeze-dried on May 21, 2019. No freezing or melting was found during the discharge. When the deviation occurs, the freeze-dried liquid is at a low temperature, and the possibility of the stability of the feed liquid is less affected. In addition, the entire process after step 4 runs according to the set process requirements, so there is basically no effect on the impurities of the product. <br>3. Conclusion: After the assessment of 4.1 and 4.2, the quality of sterile cilastatin sodium may be at risk in 2017-190505, and the moisture, properties and impurities of the batch of finished products need to be tracked. Later track whether the quality of the finished product meets the requirements. <br><br>1. Train “H3-TM-10235 03 version freeze dryer system maintenance operation rules” for the personnel of freeze dryer, with special emphasis on whether there is any looseness in the tightness inspection of key parts during daily maintenance. <br>2. Replace the screw and nut at the flange of the inlet and outlet of the silicone oil electric heater (EH25035) and the pipeline.<br>3.2017-190505 Before the release of sterile cilastatin sodium, perform a tightness test on the front box of the freeze dryer.

在2019.05.18日14:57，冻干机岗位人员罗兴土在Y76E冻干机控制室听到D3003A冻干机报警声，查看D3003A冻干机计算机主界面，报警内容为“AL-LSL25004---硅油膨胀罐低液位报警”，导致2号硅油泵（FP25020）停止运行；并于15时14分硅油温度（PRB-TIRC25039）上升至-36.9℃，此时正在进行的是2017-190505批西司他丁钠冻干工艺第4步（-40℃，1h），超出工艺要求（-40±3℃）。 <br><br>此次漏油的原因为岗位人员遗漏了检查硅油电加热器（EH25035）的进出口与法兰处螺丝和螺母的连接是否松动，另一方面原因为螺丝螺纹部分磨损导致该处密封不完整。 <br><br>1.此次偏差与冻干机箱体的密闭性无关，故对2017-190505批西司他丁钠无菌性无影响。<br>2.报警时，西司他丁钠冻干程序运行至第4步，此时是预冻阶段最后一个小时，作用是确保料液冻实（对于冻干产品，如果预冻阶段没冻实可能存在一次干燥出现熔融、坍塌等现象）；报警发生至恢复正常共约持续1个小时，可能会导致冻干粉的性状部分出现塌陷，故可能对产品性状和水分有影响；该批西司他丁钠于2019.05.21日冻干结束，出料时未发现冻塌或熔融现象。偏差发生时，冻干液处于低温，料液稳定性受影响的可能性较小；另外，第4步后整个过程按设定工艺要求运行，故对产品的杂质基本无影响。<br>3.结论：经过4.1和4.2的评估，2017-190505无菌西司他丁钠的质量可能存在风险，需对该批成品的水分、性状和杂质进行跟踪。后期跟踪成品质量是否符合要求。<br><br>1.对冻干机岗位人员进行“H3-TM-10235 03版冻干机系统维护操作规程”培训，特别强调日常维护时对关键部位的密闭性检查是否存在松动。<br>2.更换硅油电加热器（EH25035）进出口部位与管路连接的法兰处螺丝与螺母。<br>3.2017-190505无菌西司他丁钠放行前，对冻干机的前箱进行密闭性测试。

At 14:57 on May 18, 2019, Luo Xingtu, the freeze-drying machine operator, heard the alarm sound of d3003a freeze-drying machine in the control room of y76e freeze-drying machine, and checked the main interface of d3003a freeze-drying machine computer. The alarm content was "al-lsl25004 - low liquid level alarm of silicone oil expansion tank", which caused the No.2 silicone oil pump (fp25020) to stop running. At 15:14, the silicone oil temperature (prb-tirc25039) rose to - 36.9 ℃, which was in progress The fourth step of 2017-190505 batch of cilastatin sodium freeze-drying process (- 40 ℃, 1H), exceeding the process requirements (- 40 ± 3 ℃).<br>The reason for the oil leakage is that the post personnel missed to check whether the connection between the inlet and outlet of the silicon oil electric heater (eh25035) and the screw and nut at the flange was loose, on the other hand, the screw thread was partially worn, resulting in incomplete sealing at this place.<br>1. This deviation has nothing to do with the tightness of the lyophilizer box, so it has no effect on the sterility of 2017-190505 batch of cilastatin sodium.<br>2. During the alarm, the freeze-drying procedure of cilastatin sodium runs to step 4, which is the last hour of the pre freezing stage, to ensure the freeze-drying of the material liquid (for freeze-dried products, if there is no freeze-drying in the pre freezing stage, there may be melting, collapse and other phenomena); the alarm lasts for about 1 hour from the occurrence of the alarm to the restoration of normal, which may cause the collapse of the properties of the freeze-dried powder, so It may affect the product properties and moisture; the batch of cilastatin sodium was freeze-dried on May 21, 2019, and no freezing collapse or melting was found during discharging. When the deviation occurs, the lyophilized liquid is at low temperature, and the stability of the material liquid is less likely to be affected; in addition, the whole process after step 4 runs according to the set process requirements, so the impurities of the product are basically not affected.<br>3. Conclusion: according to the evaluation in 4.1 and 4.2, the quality of 2017-190505 sterile cilastatin sodium may be at risk, and the water content, properties and impurities of this batch of finished products need to be tracked. Follow up the quality of finished products in the later stage.<br>1. Carry out "h3-tm-10235 version 03 freeze dryer system maintenance operation procedures" training for freeze dryer post personnel, with special emphasis on whether the tightness inspection of key parts is loose during daily maintenance.<br>2. Replace the screws and nuts at the flange connecting the inlet and outlet of the silicone oil electric heater (eh25035) and the pipeline.<br>3. 2017-190505 before the release of sterile cilastatin sodium, the front box of the lyophilizer was tested for tightness.<br>