2019年06月29日03时22分，看罐人员黄莉发现替考拉宁2121-

At 03:22 on June 29, 2019, Huang Li, a tank watcher, found that the dissolved oxygen of 208 cans for koilanin 2121-190602 was 27.2%, which was lower than the process range (process requirement ≥30%), at 03:31 The dissolved oxygen rises back into the process range for a total of 9 minutes. Afterwards, there were two similar situations where the dissolved oxygen was lower than the process range. At 05:32, the dissolved oxygen rose back into the process range, and the three times lasted a total of 29 minutes. <br><br>The root cause of this deviation is that there are few production batches for kolanin, the lack of actual operation experience by tank personnel, and the relevant SOP does not specifically describe the mid-early dissolved oxygen adjustment method, and cannot effectively guide the post operation, resulting in the operation process. The adjustment range of the medium dissolved oxygen flow rate is too large, and the pressure of the tank cannot be kept stable when the pressure is adjusted, which eventually causes the deviation. <br><br>The deviation occurred during 41-43h of the fermentation culture period, during which the oxygen demand of the cells began to weaken, and the stirring was running normally, the air flow rate was still within the process range (process range 200 ~ 700m3 / h), which could provide a certain amount of solvent Oxygen, short-term low dissolved oxygen causes less damage to the bacteria. 1) The results of the fermentation broth before and after the deviation (listed in the preliminary investigation) all meet the quality standards of teicoplanin intermediates; 2) The final result of the tank is: the culture period is 166h, the fermentation broth is brownish yellow, and the mycelium Aging, tending to autolysis, fermentation unit 7144.5μg / ml, reached the standard of the tank (period 130h-170h, tank conditions: fermentation broth is brownish yellow, mycelia aging, tend to autolysis, fermentation unit is not increasing or growing Slow, fermentation unit ≥6000μg / ml), so the deviation here has basically no effect on the product. <br><br>1. The conclusion obtained after a comprehensive investigation, revision H3-MPD-10325-02 "Operation Regulations of Teicoplanin Fermentation Posts" 03 edition, adding the method of adjusting dissolved oxygen in the early and middle stage of dissolved oxygen recovery of teicoplanin 1) .Once the dissolved oxygen rises to more than 60%, then adjust; 2). The flow rate of each adjustment is small (recommended not to exceed 50m3 / h); 3). When adjusting the flow rate, ensure that there is no obvious fluctuation in pressure (open the air valve while closing Exhaust valve).<br>2. Train all personnel in Building Y10 of Workshop 109 in the revised H3-MPD-10325-02 "Operation Regulations for Tiicoplanin Fermentation Posts", emphasizing the operating methods for the adjustment of dissolved oxygen in the early and mid-stage dissolved oxygen recovery of tiicoplanin, And use this deviated air flow operation as a counterexample to improve employees' awareness.

2019年06月29日03时22分，看罐人员黄莉发现替考拉宁2121-190602批次208罐溶氧为27.2%，低于工艺范围（工艺要求≥30%），在03时31分溶氧升回工艺范围内，共持续9分钟。后又发生了两次类似溶氧低于工艺范围的情况，于05时32分溶氧升回工艺范围内，三次一共持续29分钟。 <br><br>此次偏差发生的根本原因是替考拉宁生产批次少，看罐人员缺乏实际操作经验，且相关SOP对中前期溶氧调节方法未做具体描述、不能有效指导岗位操作，导致在操作过程中溶氧流量调节幅度过大、调节压力时也未能保持罐压稳定，最终导致该次偏差发生。 <br><br>此次偏差发生在发酵培养周期的41-43h时，期间菌体耗氧需求开始减弱，且搅拌正常运转、空气流量仍在工艺范围内（工艺范围200~700m3/h），能提供一定的溶氧，短暂的低溶氧对菌体造成的伤害较小。1）偏差发生前后的发酵液检测结果（初步调查中已列出），皆符合替考拉宁中间体质量标准；2）最终放罐结果为：培养周期166h，发酵液呈棕黄色，菌丝衰老，趋于自溶，发酵单位 7144.5μg/ml，达到了放罐标准（周期130h-170h ，放罐条件：发酵液呈棕黄色，菌丝衰老，趋于自溶，发酵单位不在增加或增长缓慢，发酵单位≥6000μg/ml），故此处偏差对产品基本无影响。 <br><br>1.经过全面调查后得到的结论，修订H3-MPD-10325-02《替考拉宁发酵岗位操作规程》03版，加入替考拉宁中前期溶氧回升阶段调节溶氧的操作方法1）.待溶氧回升至60%以上再进行调节；2）.每次调节流量幅度小（建议不超过50m3/h）；3）.调节流量时应保证压力无明显波动（边开进空气阀门边关排气阀门）。<br>2.对109车间Y10幢所有人员进行修订后H3-MPD-10325-02《替考拉宁发酵岗位操作规程》的培训，强调替考拉宁中前期溶氧回升阶段调节溶氧的操作方法，并以此偏差的空气流量操作作为反例，提高员工的认识。

On June 29, 2019, at 03:22, tank inspector Huang Li found that the dissolved oxygen in 208 tanks of teicoplanin 2121-190602 batch was 27.2%, lower than the process range (process requirements ≥ 30%), and the dissolved oxygen rose back to the process range at 03:31, lasting for 9 minutes. After that, two times of similar dissolved oxygen lower than the process scope happened. At 05:32, dissolved oxygen rose back to the process scope, three times lasting for 29 minutes.<br>The root cause of this deviation is that the production batch of teicoplanin is small, the tank watchers lack of practical operation experience, and the relevant SOP does not make a specific description of the dissolved oxygen regulation method in the early stage, and cannot effectively guide the post operation, resulting in the large adjustment range of dissolved oxygen flow in the operation process, and the failure to maintain the tank pressure stability when regulating the pressure, resulting in this deviation finally.<br>The deviation occurred in 41-43h of the fermentation culture cycle, during which the oxygen consumption of the bacteria began to weaken, and the stirring was in normal operation, the air flow was still within the process range (process range 200-700m3 / h), which could provide a certain amount of dissolved oxygen, and the short-term low dissolved oxygen caused little damage to the bacteria. 1） The results of fermentation liquid test before and after the deviation (listed in the preliminary investigation) were all in line with the intermediate quality standard of teicoplanin; 2) the final results were as follows: the culture cycle was 166h, the fermentation liquid was brown yellow, the mycelium was aging and tended to autolysis, and the fermentation unit was 7144.5 μ g/ml, which reached the standard of putting in the tank (cycle was 130h-170h) The fermentation liquid is brown yellow, the mycelium is aging and tends to autolysis, the fermentation unit is not increasing or growing slowly, and the fermentation unit is ≥ 6000 μ g / ml), so the deviation has no effect on the product.<br>1. According to the conclusion after comprehensive investigation, revision h 3-mpd-10325-02 operation rules of teicoplanin fermentation post (version 03) and adding the operation method of regulating dissolved oxygen in the recovery stage of dissolved oxygen in the middle and early stage of teicoplanin 1). Adjust after the dissolved oxygen rises to more than 60%; 2) adjust the flow rate in a small range (no more than 50m3 / h is recommended); 3) ensure that there is no obvious pressure fluctuation when regulating the flow rate（ Open the air inlet valve and close the exhaust valve).<br>2. Train all personnel in building Y10 of workshop 109 in the revised h3-mpd-10325-02 operation procedures for fermentation posts of teicoplanin, emphasize the operation method of regulating dissolved oxygen in the recovery stage of dissolved oxygen in the middle and early stage of teicoplanin, and take the deviated air flow operation as an example to improve the awareness of employees.