2019.11.18日，洪燕在检查盐酸多奈哌齐生产计划表时发现，902

On November 18th, 2019, Hong Yan discovered that the batch of donepezil hydrochloride intermediate 9027-191002 was completed on October 31st, 2019 (tested on January 11, 2019) according to the production plan of donepezil hydrochloride. Until use, the intermediate DH-5 will be stored in the intermediate storage room for 27 days after completion of production. Does not meet the H3-MPD-10195 Donepezil Hydrochloride Process Regulations (Version 05), the requirements for Donepezil Hydrochloride DH-5 intermediate storage at room temperature for 20 days. <br><br>Due to the need for dynamic verification of donepezil hydrochloride, the workshop updated the production plan many times. During the preparation of the production plan, the planners did not notice that the storage time of DH-5 has been adjusted from 30 days to 20 days, resulting in deviations in the production plan. , DH-5 storage time will exceed the prescribed period. This deviation was the cause of personnel and occurred for the first time in two years. <br><br>According to the Donepezil Hydrochloride Intermediate Stability Evaluation Report (H3-EV-9027-008R), staying the intermediate DH-5 for 20 days does not affect the product quality. According to historical data and trend analysis, DH-5 is basically stable within 30 days of storage. There is basically no quality risk during this 27-day stay, and there are still multiple steps such as hydrogenation, extraction, salt formation, and crystallization that can effectively remove impurities. This deviation does not affect the quality of the finished product or the validity of the verification. In order to increase the risk identification, it is planned to sample the DH-5 stayed before production, and the sample can be put into production after passing the test. <br><br>1. Re-sampling and testing the staying DH-5 before production. If it is qualified, it can continue to be put into production; if it fails, the batch of DH-5 is destroyed. <br>2. Organize the retraining of H3-MPD-10195 donepezil hydrochloride process specification version 05 for scheduling and production related personnel to clarify the storage period of donepezil hydrochloride intermediate DH-5.

2019.11.18日，洪燕在检查盐酸多奈哌齐生产计划表时发现，9027-191002批盐酸多奈哌齐中间体于2019.10.31日完成生产（2019.11.01完成检测），根据生产计划安排，到2019.11.26开始使用时为止，中间体DH-5在完成生产后，将在中间体存放室存储27天。不符合H3-MPD-10195盐酸多奈哌齐工艺规程（05版），关于盐酸多奈哌齐DH-5中间体常温20天存放的要求。 <br><br>由于盐酸多奈哌齐动态核查需要，车间多次更新生产计划，计划制定人员在制定生产计划期间未注意DH-5贮存时间已由30天调整为20天，从而导致生产计划出现偏差，根据最新的生产计划，DH-5的贮存时间将超过规定期限。此次偏差为人员原因，且为尽两年来首次发生。 <br><br>根据盐酸多奈哌齐中间体稳定性评估报告（H3-EV-9027-008R），中间体DH-5停留20天不对产品质量产生影响。而根据历史数据和趋势分析，DH-5贮存30天内基本稳定，此次停留27天基本不存在质量风险，而且后续仍有氢化、提取、成盐、结晶等多个步骤可以有效去除杂质，评估此次偏差不对成品质量造成影响、不影响验证有效性。为增加风险辨识，计划在生产前对停留的DH-5进行取样检测，样品合格后方可投料生产。 <br><br>1.在生产前对停留的DH-5重新进行取样检测，合格后方可继续投料生产；如不合格，对该批DH-5进行销毁处理。<br>2.组织对排产及生产相关人员进行H3-MPD-10195盐酸多奈哌齐工艺规程05版的再培训，明确盐酸多奈哌齐中间体DH-5的存储期限。

On November 18, 2019, when Hong Yan checked the production schedule of donepezil hydrochloride, he found that the 9027-191002 batch of donepezil hydrochloride intermediates finished production on October 31, 2019 (detection completed on November 1, 2019). According to the production schedule, by November 26, 2019, the intermediate dh-5 will be stored in the intermediate storage room for 27 days after the completion of production. It does not meet the requirements of h3-mpd-10195 technical specification for donepezil hydrochloride (version 05) on the storage of donepezil dh-5 intermediate at room temperature for 20 days.<br>Due to the need of dynamic verification of donepezil hydrochloride, the workshop has updated the production plan for many times, and the planners did not notice that the storage time of dh-5 has been adjusted from 30 days to 20 days during the preparation of the production plan, resulting in deviation of the production plan. According to the latest production plan, the storage time of dh-5 will exceed the specified period. The deviation was due to personnel and was the first in two years.<br>According to the stability evaluation report of donepezil hydrochloride intermediate (h3-ev-9027-008r), if the intermediate dh-5 stays for 20 days, the product quality will not be affected. According to the historical data and trend analysis, dh-5 is basically stable within 30 days of storage, and there is no quality risk in this stay for 27 days, and there are still many steps such as hydrogenation, extraction, salification, crystallization, etc. which can effectively remove impurities, so it is estimated that the deviation will not affect the quality of the finished product and the validation effectiveness. In order to increase risk identification, it is planned to sample and test the dh-5 staying before production, and only after the sample is qualified can it be put into production.<br>1. Before production, sampling and testing shall be carried out again for the dh-5 staying, and the production can be continued only after it is qualified; if it is unqualified, the batch of dh-5 shall be destroyed.<br>2. Organize the retraining of production scheduling and production related personnel on h3-mpd-10195 donepezil hydrochloride process specification version 05, and define the storage period of intermediate dh-5 of donepezil hydrochloride.<br>