WHO-GMP检查缺陷与整改计划CAPA for WHO-GMP Inspection

To be initiated Not initiated WHO Inspectors: WIP WIP < 75% WIP WIP > 75% Completed Closed Inspection Organization 审计机构 Inspection Date 审计日期 Item 项目 Report Code 报告编号 WHO OBSERVATIONS 缺陷 WHO Ref. 参考指引 CAPA 整改与预防措施 Remark 备注 Responsible Person 负责人 Team Member 1 相关人员1 Target Date 实现目标期 Current Status 现状 Current Progress 进展 1st Report Date 首次报告时间 2nd Report Date 二次报告时间 WHO-GMP检查缺陷与整改 计划 项目进度计划表范例计划下载计划下载计划下载课程教学计划下载 CAPA for WHO-GMP Inspection 钟健 Zhong Jian 段石凤 Duan Shifeng 侯军 Hou Jun CAPA-ZJ-100201-01Our Ref. 2010.4.23 CAPA approved by: Pan Yong Indicator 针对无菌分装程序所存在的缺陷，桂林南药将投入大量的人力、物力及财力进行改造，包括生产设备的更换、监测仪器的购买以及其他一些相 应的改进措施，详细的整改措施如下： For the observations concerning aseptic filling procedrue, Guilin will introduce great human, material and financial investment in the reconstruction, including the replacement of manufacturing equipments, the procurement of monitoring instruments and take other relevant corrective actions, the details are as follows: 1、启动变更程序，对分装机进行更换。更换后的分装机具有单向流保护、自动取样、自动下料、装量控制稳定等功能，且有较好的物理隔离 系统，能够限制人员进入分装关键区域，从而避免对环境产生影响。此外，使用新的分装机在生产一个批次的产品时，无需进行加料操作，可 有效避免人员加料操作对A级层流的影响，更加保证产品质量。 Initiate a change control procedure for the replacement of filling machine.The new machine will be protected by UDAF and have the functions such as automatic sampling, automatic charging and filling quantity controling. The advanced physical isolation system can restrict personnel's access into critical filling areas, so as to reduce risks of interrupting the environment. In addition, by employing the new filling machine, batch production will not be interrupted by charging of powders, which could sufficiently reduce the manual interference towards laminar airflow of Class A so as to further guarantee the product quality. 2、按照 规范 编程规范下载gsp规范下载钢格栅规范下载警徽规范下载建设厅规范下载 的变更流程进行分装机URS的起草、设备的采购以及设备的确认，合格后投入生产使用。 Draft the URS for filling machine, purchase the equipment and conduct equipment qualification and finally put the qualified equipment into practical use by following the established change control procedure. 3、在新工厂的设计时，我们将充分考虑分装核心区域的各项风险，在对厂房设备设计、选型、建造时尽可能地考虑自动化生产 或是选择隔离器（Isolator）生产设施，避免人工操作带来的影响，并确保有足够大的空间进行生产操作，以确保产品质量。 For the design of new plant, Guilin will sufficiently take various risks in the core filling area into account. Automatic devices or isolators will be introduced in the premises design, pattern selection and plant construction as far as possible, so as to reduce the manual interference and to ensure adequate operating space to further guarantee the quality of product. 4、对洁净区环境监测管理规程及记录进行修订，要求沉降碟摆放时间必须覆盖整个生产过程 Revise the SMP and record for environmental monitoring of clean areas to require that the exposure of settle plates cover the entire manufacturing period. 5、在洁净区内关键操作区域增加尘埃粒子在线监测装置，在线监测点包括分装间层流、隧道烘箱冷却段层流、西林瓶转盘层流、 析晶间层流、胶塞出料层流，确保青蒿琥酯无菌粉及注射用青蒿琥酯分装过程的关键操作区域环境能够符合要求 Guilin will introduce online device for monitoring of non-viable particles in the critical operational area in clean room. The online monitoring points will include the laminar airflow (LAF) in filling room,LAF in the cooling section of tunnel drying oven, LAF of vials turntable, LAF in crystallization room and LAF for unloading of rubber stoppers, to ensure that the enviroment in critical operational areas for packaging of Artesunate Sterile Powder and filling of Artesunate for Injection could comply with requirements. 6、我们查阅了WHO-GMP、EU-GMP及FDA-GMP，其中规定在进行模拟灌封试验时，模拟灌封批量可以为3000瓶、5000~10000、大于 10000瓶，若是批量较小的话，则模拟灌封数量则应与实际生产数量一致。目前注射用青蒿琥酯实际生产批量约为48000支，因此，结合GMP 规范及桂林南药的实际情况，为了保证模拟分装试验批量能够反映出实际生产时的无菌控制情况，我们将对模拟分装试验 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 进行修订，提高 模拟分装的批量，由原来的5500瓶提高到12000瓶，即根据正常生产批量的四分之一来确定模拟分装批量，同时，在模拟分装方案的设计及实 施时，我们将充分考虑模拟各类干预操作以及最差工况。桂林南药将在分装机完成更换后（2010年8月）按照新的方案进行一次MFT。 By referring to WHO-GMP, EU-GMP and FDA-GMP, the quantity for Media Fill Test (MFT) could be 3,000 vials, 5,000 to 10,000 vials,or above 10,000 vials, and the quantity used for MFT should be in line with practical batch size if the batch size is reletively small.At present, the practical batch size for Artesuante for Injection is approximately 48,000 vials. By combining the GMPpractices with Guilin's actual situation, in order to ensure that the MFT quantity could reflect the practical aseptic control,Guilin will revise the MFT study protocol to increase the MFT quantity from 5,500 vials to 12,000 vials, i.e. one fourth of the normal production batch size. Meanwhile, during the design and implementation of MFT testing protocol, Guilin will adequately consider the simulation of various interferences and the worst case. The MFT testing will be conducted as per newly prepared protocol after the replacement of filling machine, which is expected to be Mr. Deus MUBANGIZI (WHO) Ms. Dr. Chan Wai Yee (for WHO) 备注栏中绿色字体为已经完成的项目 The completed items are highlighted in green under the Remark column. WIP < 75% 附件1：分装机变更控制表 Annex1: change control form of filling machine 附件2：分装机URS Annex2: URS of filling machine 附件3：分装机确认报告 Annex3: qualification record of filling machine 附件4：分装机购买 合同 劳动合同范本免费下载装修合同范本免费下载租赁合同免费下载房屋买卖合同下载劳务合同范本下载 Annex4: purchase contract of filling machine 附件5：修订后的环境监测管理规程及记 录实例 Annex5: revised SMP and record for environmental monitoring 附件6：青蒿琥酯环境检测方法变更控制 表 Annex6: change control form of environmental monitoring method for Artesunate workshop 附件7：尘埃粒子在线监测购买 协议 离婚协议模板下载合伙人协议 下载渠道分销协议免费下载敬业协议下载授课协议下载 Annex7: purchase contract of on-line monitoring device for non-viable particles 附件8：在线监测仪确认方案、报告 Annex8: qualification protocol and report of on-line monitoring device 附件9：修订后的MFT方案 Annex9:Revised MFT testing protocol 无菌分装与监 控 Aseptic filling and monitoring 分装机变更 Change of filling machine： 变更控制表制定 preparation of change control form：2010.4.7 分装机URS制定 preparation of URS of filling machine：2010.4.10 分装机采购 procurement of filling machine：2010.6.25 分装机安装调试 installation and commission of filling machine：2010.6.30 分装机IQ/OQ/PQ IQ/OQ/PQ of filling machine：2010.7.10 分装机操作培训 training on operation of filling machine：2010.7.12 分装机投入使用 put the filling machine into use：2010.7.15 环境监测管理规程及记录修订 revision of SMP for environmental monitoring and the record：2010.4.7 环境监测方法变更 change of environmental monitoring method： 变更控制表制定 preparation of change control form：2010.4.7 尘埃粒子在线监测仪采购 purchase of on line monitoring device for non-viable particles：2010.5.20 尘埃粒子在线监测仪安装调试 installation and commission of monitoring device for non-viable particles：2010.5.30 尘埃粒子在线监测装置确认qualification of monitoring device for non-viable particles：2010.6.5 尘埃粒子在线监测装置投入使用 put the monitoring device for non-viable particles into use：2010.6.8 MFT方案修订 revision of MFT protocol： WIP Type of Inspection: Routine inspection and Follow-up inspection Ms. Jeanette Ann Twell (WHO) Date(s) of Inspection: 22, 23 and 24 February 2010 22, 23 and 24 February 2010 WHO Major1 Monitoring aseptic filling procedure: Aseptic techniques within the aseptic filing area were still inadequate in as far as: 1.1 There were still many manual interventions in the Grade A zone during the aseptic filling process involving scooping of freeze dried powder from a container into filling hoppers. The space for the operation was too small for comfortable operation. 1.2 The monitoring of the environment by settle plate did not cover the entire filling period. 1.3 There was no continuous monitoring of non-viable particles during aseptic procedures (loading sterile powders into the lyophiliser, filling lyophilised sterile powder into the SS container and vial filling). 1.4 There was no documented justification why only approximately 5500 vials were used during the media fill tests to simulate a batch size of 48,000 - 60,000 vials. 无菌分装程序监控： 无菌分装区内的无菌技术仍然不足，表现在： 1.1 无菌分装的过程中，仍然存在很多对A级区的人为干扰，例如将冻干粉从容器铲入 进料斗。操作的空间太小，不能很方便地进行操作。 1.2 环境监控采用沉降碟，但沉降碟的摆放没有覆盖整个分装过程。 1.3 分装过程中未持续监控尘埃粒子（没有包括无菌粉进冻干箱，将冻干粉装入不锈钢 容器，以及冻干粉分装入西林瓶中这些过程）。 1.4 没有文件证据合理证明，模拟得48,000至60,000瓶的批量，仅用约5,500瓶产品进 行培养基灌封试验即可。 Name of Manufacturer: Guilin Pharmaceutical Co. Ltd. CAPA prepared by: Hou Jun CAPA reviewed by: Xing Liping 4.15 , 4.20 , 9.12，3.3， 2.2, 4.1 , 4.2 , 4.12 , 4.17 , 7.3 . 附件10：T080302批碳酸氢钠注射液销毁 记录 Annex10: record for destruction of sodium bicarbonate injection, batch T080302 附件11：工艺验证后生产产品批量列表 Annex11: list for product batch sizes after the process validation 2010.4.23 1、为了解决取样区及非无菌物料（碳酸氢钠原料、乙醇、胶塞、西林瓶、安瓿）取样与无菌原料（头孢/青霉素原料）取样交叉污染的问题， 我们计划对两种物料的取样区域进行彻底的分离，即非无菌物料于仓库现场使用移动取样车进行取样，无菌原料于QC无菌取样间进行取样， 从而避免交叉污染的发生，并解决了物料传递不便的问题。具体措施如下： In order to resolve the problem regarding sampling areas and the potential corss-contamination between non-sterile raw materials (sodium bicarbonate API, ethanol, rubber stoppers, vials and ampoules) and sterile raw materials (Cephalosporins/penicillins) during sampling, Guilin plans to thoroughly isolate the sampling areas for these two categories of materials, i.e. use a mobile sampling booth for the sampling of non-sterile materials in the warehouse, and sample the sterile raw materials in QC sterile sampling room to avoid the occurrence of cross-comtamination. This method also solves the problem concerning inconvenience of material tranferrring. The detailed measures are as follows: *启动变更控制程序，将非无菌物料的取样地点由非无菌取样间变更为仓库移动取样车，避免与无菌原料（头孢菌素和青霉素类）产品的取样 在同一地点进行，从而产生交叉污染 Initiate a change control procedure to change the sampling place for non-sterile materials from sampling room in QC lab to the mobile sampling booth in the warehouse, which is different from the sampling place of sterile materials (Cephalosporins and penicillins) to avoid cross-contamination. *起草移动式取样车URS，并根据URS进行移动式取样车的采购。移动式取样车洁净级别符合C级标准，与产品生产级别保持一致 Prepare URS for the mobile sampling booth, and purchase the sampling booth accordingly. The cleanliness of mobile sampling booth will comply with requirements of Class C area, which is in line with that of manufacturing area. *对移动式取样车进行运行及洁净度确认后，将其放置于青蒿琥酯专用仓库内（原辅料库、内包材库），用于非无菌物料（碳酸氢钠原料、乙 醇、胶塞、西林瓶、安瓿）的取样 Place the mobile sampling booth in the dedicated Artesunate warehouse (raw material and excipient warehouse, primary packaging materials warehouse) for the sampling of non-sterile materials (sodium bicarbonate API,ethanol, rubber stoppers, vials and amploues)after performing qualification on performance and cleanliness. *QC对取样SOP进行修订，规定今后非无菌物料在仓库新购的移动取样车内进行，同时对QC取样人员进行培训 QC will revise the sampling SOP to state that in the future the sampling of non-sterile material should be performed in the newly purchaced mobile sampling booth in the warehouse, meanwhile, QC staff of sampling should be trained on the revised SOP. 附件12：取样地点变更控制表 Annex12: change control form for change of sampling place 附件13：移动取样车URS及确认报 告 Annex13: URS and qualification report for mobile sampling booth 附件14：修订后的取样SOP Annex14: revised sampling SOP 附件15：取样SOP培训记录 Annex15: training record for revised sampling SOP 在通常情况下，桂林南药会按照标准批量进行产品的生产（注射用青蒿琥酯批量为48000瓶，碳酸氢钠注射液为120000支），但是有时会出 现产品批与批之间批量变化大的情况，这是由于桂林南药偶尔会根据特殊订单情况进行产品的生产，这些特殊订单通常是一个较小的批量，与 标准批量会有较大的差异。而T080302批注射用碳酸氢钠注射液是一批小试产品，该批产品主要用于产品贴签试验考察，使用的小试的生产设 备，并没有使用正常的生产设备，因此，该批产品最后并未用于市场销售，而是进行了报废处理。 Under normal conditions, products are manufactured as per established standard batch sizes (48,000 vials for Artesunate for Injection, 120,000 ampoules for Sodium Bicarbonate Injection). However, Guilin may occasionally adjust the production as per specific purchase order. The size of specific batch may be relatively small and quite different from standard one, leading to various sizes from batch to batch. Sodium Bicarbonate Injection batch T080302 is a laboratory scale batch product, which was mainly used for study of labelling process. This batch was manufactured by applying the equipments for laboratory scale but not production scale products. Therefore, the products of that batch were destroyed rather than distributed on the market. 桂林南药于2009年10～12月分别完成了青蒿琥酯无菌粉、注射用青蒿琥酯、碳酸氢钠注射液工艺验证，工艺验证完成后，桂林南药即开始按 照验证的标准批量（青蒿琥酯无菌粉投料量10kg，注射用青蒿琥酯48000瓶，碳酸氢钠注射液120000支）进行产品的生产。 Guilin had completed the process validations on Artesunate Sterile Powder, Artesunate for Injection and Sodium Bicarbonate Injection between October and December 2009. The above products have been being manufactured in accordance with validated standard batch sizes, i.e. 10kg of feeding quantity for Artesunate Sterile Powder,48,000 vials for Artesunate for Injection and 120,000 ampoules for Sodium Bicarbonate Injection. 桂林南药已经意识到若是未按标准批量进行生产，将会给批与批之间产品质量的一致性、稳定性带来风险，因此，桂林南药从2010年1月开始 纠正了批量不固定的做法，严格按照固定的验证批量进行生产，以确保批与批之间产品质量的一致性、稳定性。若是标准批量发生较大变化， 桂林南药将更新PQIF并按照程序通知WHO，在得到WHO的批准后才按照新的批量进行产品生产；若是标准批量在±10%范围内波动，属于计 划内偏差，则桂林南药将按照计划性偏差处理程序进行处理，在得到批准后才进行产品生产，以确保产品质量。 Guilin had realized that inconsistent batch sizes will bring risks to the manufacturing consistency and product stability from batch to batch. Therefore, in January 2010, Guilin rectified the previous practice that the batch size was not fixed and thereafter conducts the manufacturing by strictly following the validated fixed batch size to ensure the batch product consistency and stability.If it is necessary to make relatively great change to the standard batch size, Guilin will update the PQIF and notify WHO by following established procedure, and conduct the product manufacturing as per new batch size on WHO's approval. If the standard batch size varied within the range of ± 10%, or the change could be regarded as a planned deviation, then Guilin will initiate an deviation handling procedure for review and approval of planned deviation. In order to ensure the product quality, the change on batch size will not be implemented until the planned deviation is approved. 陆漓滨 Lu Libin Closed 移动取样车变更 change of sampling booth: 变更控制表制定 preparation of change control form：2010.3.24 移动取样车URS制定 preparation of URS for sampling booth:2010.3.24 移动取样车采购 procurement of sampling booth：2010.4.25 移动取样车安装调试 commission of sampling booth：2010.4.30 移动取样车确认 qualification of sampling booth：2010.5.5 移动取样车使用培训 training on application of mobile sampling booth： 2010 5 7 WIP WIP < 75% 2010.4.20 case. The MFT testing will be conducted as per newly prepared protocol after the replacement of filling machine, which is expected to be completed in August 2010. Production practices: Routine manufacturing was not limited to the validated batch size as the size varied from batch to batch for both Artesunate powder for injection and Sodium bicarbonate injection. Some batches could not match the operational capacities of some of the equipment on site. For example, Batch No. T080302 of NaHCO3 (11 litres) could not have been effectively manufactured using the mixing tank on site as it was below the validated minimum capacity (60L) that could be effectively mixed in the mixing tank. 生产活动： 正常生产的注射用青蒿琥酯以及碳酸氢钠注射液批与批之间批量变化大，且并未在经 过验证的批量限度范围内。其中某些批次的批量与现场设备的产能不一致。例如：现 场的配料罐不能有效地混合批号为T080302的碳酸氢钠（11L），因为该批的量低于 经验证的该配料罐的最小有效混合量（60L）。 22, 23 and 24 February 2010 Major2 Completed 2010.4.20 15.22, 15,23(b), 15.23(e), 2.2 , 4.28 , 4.172. WHO 侯军Hou Jun 生产活动 Production practices WHO Sampling area and risk of cross-contamination: The area used for sampling non-sterile raw materials was not suitable for the sampling activities in as far as: 3.1 It was located in a room in the microbiology laboratory whose entrance airlock and pass-box were too small for the containers of some of the materials claimed to be sampled there, e.g. NaHCO3 bags and Ethanol drums. 3.2 The room (Room 8) used for holding materials awaiting sampling was also used for holding both sterile and non-sterile raw materials in transit for sampling including cephalosporins and penicillins, raising a risk of cross contamination for the materials being sampled and/or tested. 3.3 The UV lamp used to disinfect the materials in pass box leading to the room within the microbiology laboratory used for sampling non-sterile materials was not working, raising the chances of contaminating the microbiology laboratory. 3.4 There were no dust extraction facilities in the room. 取样区和交叉污染的风险： 目前的取样活动不适合在非无菌原料的取样区进行，表现在： 3.1 该取样间位于微生物实验室，其入口处的气闸和传递窗太小，难以传递某些待取样 12.2, 12.22, 12.24, 12.26, 3.1, 12.3. Major3取样区Sampling area 22, 23 and 24 February 2010 2010.4.23 GuilinPharma 1 / 7 2010/4/24 15:56 Inspection Organization 审计机构 Inspection Date 审计日期 Item 项目 Report Code 报告编号 WHO OBSERVATIONS 缺陷 WHO Ref. 参考指引 CAPA 整改与预防措施 Remark 备注 Responsible Person 负责人 Team Member 1 相关人员1 Target Date 实现目标期 Current Status 现状 Current Progress 进展 1st Report Date 首次报告时间 2nd Report Date 二次报告时间 附件17：USP培训协议及培训图片 Annex17: photos of USP trainings and contract 附件18：微生物岗位培训SOP清单、 培训计划 Annex18: list of SOPs to be trained for microbiology stations/posts and training schedule 附件19：QC培训记录 Annex19: QC training record 附件20：QC人员考核记录、结果 Annex20: exam records and results for QC persons 附件21：微生物人员招聘证书 Annex21: letter of appointment of microbiology lab staff 附件22：修订后的SOP（菌种管理规 程、菌种传代与使用SOP、菌种鉴定 与鉴别SOP/SOR、培养基质控 SOP/SOR、灭菌SOP） Annex22: revised SOP (bacterial strains/species management procedure, SOP for species generation and usage, SOP/SOR for identification of species, SOP/SOR for quality control of culture media, and sterilization SOP) 附件23：菌种保存期限考察方案 Annex23: bacterial species hold time p g , , p g 2、由于今后非无菌物料均在移动取样车内进行取样操作，不再使用QC非无菌取样间，因此无需再配备除尘系统。同时，也不再需要通过目 前的传递窗进行非无菌原料的传递，因此，我们决定不再对目前的传递窗及除尘系统进行改造 Because in the future all of the non-sterile materials will be sampled in the mobile sampling booth, rather than in the QC sampling room, it is not necessary to install dust extraction facilities in the sampling room. Meanwhile,since the non-sterile materials will not be transferred through the current transferring hatch anymore, Guilin decided not to modify the current transferring hatch and dust extraction system. 3、桂林南药目前已有紫外灯使用记录，并会按照记录要求每次在使用紫外灯之前对其完好性进行检查，在检查现场检察官发现紫外灯不能正 常工作，我们认为这是一次异常情况。为此，桂林南药立即启动了偏差调查程序，并根据流程对此次异常情况进行了处理，即对紫外灯进行了 更换。为防止今后出现类似的情况，桂林南药在今后将继续严格执行使用前检查紫外灯完好性的制度，同时进行累积使用时间的记录，并在紫 外灯每使用500小时进行一次紫外强度检查，以确保紫外灯消毒效果。 Currently, Guilin has a UV light logbook, according to which the integrity of UV light is required to be checked before every time of use.We considered the failure of UV light found during on site inspection as an abnormal condition and immediately initiated an investigation procedure of a deviation. The abnormal condition has been handled according to the procudure and the UV light has been changed. In order to prevent the reoccurrence of similar case in the future, Guilin will continue the light integrity checking before use,meanwhile,record the cumulative duration and conduct light intensity checking once per 500 hours of use, so as to ensure the performance of UV light disinfection. g 附件16：紫外灯偏差登记表 Annex16: deviation register of UV light Microbiology laboratory: The microbiology laboratory, related procedures and staff qualifications were not comprehensive enough to support and instil confidence in the quality control of aseptic and sterile procedures: 4.1 The staff in-charge of the microbiology laboratory did not have adequate basic qualification in microbiology and adequate working experience in microbiology procedures. 4.2 There was inadequate information on the purchase and generation of the reference cultures used in the microbiology laboratory. 4.3 The staff indicated that the reference cultures were kept at 2℃ - 8℃ for a year while repeatedly being used for the regeneration of culture species for routine tests, which was considered inappropriate conditions for long storage of reference cultures. 4.4 There was no quality control done to monitor the microbiology species in the reference cultures, e.g. gram staining for gram positive or negative species, purity plates or biochemical testing to ensure the integrity of the reference organisms. 4.5 Turbidity results were not presented in detail but recorded as only one "+". 4.6 There was no method on the media bottle to distinguish sterilized media from that not yet sterilized. Autoclave tape was not used. 4.7 Although bio-indicators were used to monitor the autoclave during validation, they were not used frequently to verify autoclaving integrity. 4.8 The door to the autoclave room was tilting and required repair and the effectiv