EU-GMP欧盟药品生产质量管理规范PPT幻灯片

1、1,GMP,Good Manufacturing Practice （优良的生产实践）药品生产质量管理规范 Seminar for the whole Workforce 职工整体培训,2,Shanghai Jinji Business Consulting 上海金冀商务咨询有限公司,General Manager 中国地区总经理 Dr. Hartmut Steinel 石泰牛 博士 B.Sc. you have to register the product first. Then, after your sponsor has received the registration, he h

2、as to call the GMP inspectors. 在美国情况也是一样的，您必须先注册产品。然后，在您的主办人得到注册后，他必须申请GMP检查。,28,General Preparations (1)常规准备(1),Most of you have experience with the Inspections by the Chinese State Food and Drug Administration, which are similar to the Swiss inspections. However, this time the inspectors do not sp

3、eak Chinese and cannot read Chinese. 你们中的大多数都经历过中国国家食品药品监督管理局的检查,这和欧洲的检查很相似.但是,这次检查员不会讲中文,也看不懂中文.,29,General Preparations (2) 常规准备(2),This time, the inspectors will come from the Swiss SFDA. Therefore, everything has to be according to the Swiss regulations (most regulations are the same as the Chin

4、ese one) and the European Pharmacopoeia. However, you have to state that this time I manufacture according to the Swiss regulations or according to the European Pharmacopoeia (even if they are the same as the Chinese ones). 这次，检查员不是来自中国SFDA，而是来自欧洲SFDA。因此，每件事必须符合欧洲法规（大多数法规和中国的是一样的）。然而，您必须声明这次我是按照欧洲的法

5、规进行生产的（即使是和中国的法规一样）。,30,General Preparations (3) 常规准备(3),During the inspection we will be in your factory, together with the inspectors. We will also supply you with suitable interpreters, if required. 在检查期间,我们也将在你们厂陪同检察官.随行人员还有GMP翻译.如果需要，我们也将提供适当的翻译员。,31,General Preparations (4) 常规准备(4),As it is de

6、scribed in the GMP requirements, we have to show “that we are in control”. We are in control regarding English documents, regarding production, regarding validations etc. and we want to be better than any Swiss company. This requires smart thinking and hard work. 正像GMP要求中描述的，我们必须显示出“一切都在我们的掌握当中”。关于英

7、文的文件、生产和验证等等都已经准备充分。我们可以做的比任何一家欧洲公司做的更好。这就需要开放的思维和勤奋的工作。,32,Very Important,The most important is Clean. All room and equipment in the workshop should be extremely clean during the inspection. 清洁是最重要的。在检查期间车间内的房间和设备要彻底清洁。,33,Official Welcome正式的欢迎仪式,The first working day in the factory, they usually s

8、tart with a formal welcome with the General Manager and the Vice-Managers or Directors and all key personnel. There the auditors usually introduce themselves, give you a short GMP introduction and tell you their schedule, based on the “Site Master File”. In general, they prefer to start with the ins

9、pection of the ware house for raw material, followed by the packaging materials. 由总裁、副总裁或董事出席的一个正式的欢迎仪式，是检查工作的一个良好开端。在管理层会议后，召开所有主要工作人员会议。会议上,审计员通常先自我介绍，然后做一个简短的GMP介绍,描述他们的时间表，这取决于“场地主要文件”。通常情况下，他们希望从检查原材料仓库开始，然后是包装材料库。,34,After the inspection has been completed, the inspectors will hold a meeting a

10、nd tell you all their complains, which are called deficiencies. They will give you a timeline for changing these deficiencies. They will also tell you that you have passed the inspection, after changing these deficiencies. That means, that you will hold the GMP license in your hands between 6 10 wee

11、ks after this meeting. 检查结束后，检查员将召开会议，告诉您他们所有的意见，也就是贵工厂的不足。他们将给您一个时间范围来弥补这些不足。整改之后，他们也同样会告诉您，您已经通过了检查。也就是说，您将在会议后的610周内得到GMP证书。,35,Another step 下一步,The inspectors always find a number of deficiencies. Some 15 45. That is the normal procedure. Small changes in some SOPs, a log book table, minor chang

12、es of the production etc. Additionally, they give you suggestions how to improve the running of the workshops. On rare occasions, this suggestions can even save you money. Dont hesitate to ask for advise. 检查员通常寻找一些小问题。一般1035个。那是常规的程序。一些SOP文件、台帐表和生产上等等需要一些小的改变。此外，他们会建议您如何改进车间的运行。很少的情况下，这些建议可以帮助您节约成本。

13、您可以要求检查员提供建议。,36,GMP Part III,Good Manufacturing Practice （优良的生产实践）药品生产质量管理规范 The Inspection 检查,37,Entering the Workshop (1)进入车间,It is very important to treat the auditors as described in the Standard Operation Procedures for visitors (they have to sign all forms required and the relevant officers o

14、f your company have to countersign). Then we suggest that you address the auditors and ask: “Usually our visitors will receive instruction how to behave in the workshops. This will take about 30 min. Because you are very familiar with GMP regulations and workshops, and have only a limited time to sp

15、end, we suggest to skip this introduction. Is this acceptable with you?” Very likely they will answer with “yes”, but it is important that you ask this question. 像针对来访者的标准操作程序中描述的一样接待审查员是非常重要的（他们必须签署所有要求的表格，贵公司的相关官员必须副署。)然后我们建议您询问审查员：“通常我们的来访者将收到在车间的正确行为说明。这需要大约30分钟。因为您非常熟悉GMP法规和车间，并且时间有限，我们建议省略这张说明

16、。您认为可以吗？”他们非常有可能回答“好的”,但是您的这个问题是非常重要的。,38,Inside the Workshop (2)车间内,The auditors prefer very much to see all your staff and all the machines in action. However, they understand that this is not always possible and they also understand that they are usually disturbing your production. If possible, y

17、ou should manufacture these days something very simple or do a test run. 审查员愿意看到所有的职员和机器都在运作。然而，他们理解这种情况不是持续发生的，他们也同样理解他们的到来会打扰职员的工作。如果有可能，这几天您应该生产一些非常简单的产品或者做一个测试性的运作。,39,Inside the Workshop (3)车间内,The designated staff has to be next to each machine (even if the machine is not used this day). They

18、have the production process for a particular product near them in the designated place. The auditors will ask some of the staff regarding details of the production process and they will definitely ask questions regarding the cleaning procedures. They use an interpreter for this questioning and they

19、will also ask for translations of one or the other SOP involved. 相关的人员必须站在每台机器旁（即使这台机器当天没有使用）。在靠近他们的指定地点要有一份产品的生产程序。审查员将会询问一些员工关于生产程序的细节问题，很明显他们将会问一些关于清洁程序的问题。他们请一位翻译员来问这些问题，他们也会要求查看一个或多个标准操作程序的翻译文件。,40,Inside the Workshop (4)车间内,All workers have to be prepared for questions regarding the SOPs of th

20、e 所有的员工必须准备关于标准操作规程的问题 machinery机器 cleaning of machinery and room机器和房间的清洁 exchange of status labels状态标签的更换 and the particular step in production which is just running in their room. 正在运行的生产步骤,41,Inside the Workshop (5)车间内,The will ask questions about the in-process-control of this particular product

21、 and they want to see the records. They will also ask the QA officer how to test the balances each morning and where the records for all temperatures and humidity results are stored. 他们会提问关于某种产品的中间程序控制的问题,他们还会问QA官员每天早晨如何测试天平,所有的温湿度记录放在哪里.,42,Inside the Workshop (6)车间内,The auditors will go through al

22、l rooms, look at each single machine and ask one or two questions via the interpreter. “All rooms” includes every cabinet, closet and laundry. 审查员将检查所有的房间，查看每一台机器，并且通过口译官提出一或二个问题。”所有的房间”包括柜子,壁柜和洗衣房.,43,Inside the Workshop (7)车间内,They will check the SOPs and are very happy, if they have an English ve

23、rsion of the production process of this particular product in hand, this includes starting material, in process controls and end control specification. 他们将核查标准操作程序，如果是某种产品的英文操作程序，他们会非常高兴，这包括原辅料预处理,中间过程控制和最终控制指标。,44,Inside the Workshop (8)车间内,The auditors will follow the flowchart of the material and

24、 also the flowchart of the staff. It is a nice gesture, if you can provide them with a bound copy of the “Site Master File” and the floor plans of the workshops. Double locks are tested and special attention is paid to all balances and weighing stations. The auditors will always check the log books

25、next to the balances. 审查员将实地考察人流物流走向。您应该提供他们“场地主要文件” 的副本和车间楼层平面图,这对检查很有帮助。他们会检查车间的气闸，以及特别注意所有的天平和称量站。审查员通常还要检查天平旁边的工作记录。,45,Inside the Workshop (9)车间内,In the Intermediate Storage Area they will ask to see the log books for incoming and outgoing intermediates and incoming and outgoing final products.

26、 Different intermediates and products have to be separated clearly and labeled clearly. 在中间体存放区域,他们会要求检查中间体和成品（未包装成品）的进出记录.不同的中间体和成品必须清楚的分开,并且贴上标签.,46,Inside the Workshop (10)车间内,Everything which is moved, whatever it is, need one inside and one outside label. 任何需移动的物料,其桶内外都必须有标签.,47,In process cont

27、rol testing station在中间控制检测站内,The auditors will look at the log books and will ask for the calibration and validation of the equipment. 审查员将要求检查工作记录并要求设备校准和验证。,48,Inside the Storage Areas (1)在储藏区域内,The auditors appreciate if they receive a copy of each single label for a particular product, including

28、 starting material and in process and end controls (tracking document) with the expected Chinese signatures on it. A few explanatory words in English on each of these papers will make them very happy. 审查员会非常高兴，如果他们看到某一个产品的各个标签的复印件，包括原辅料的预处理和中间控制和最终控制（跟踪性）,这些标签上都应有中文签名。在这些标签上有一些英文注释会令审计员非常高兴。,49,Insi

29、de the Storage Areas (2)在储藏区内,Although the coloured ribbons are very handy, each intermediate or product needs an additional label attached to one of the boxes. They will read selected labels and ask you to find the products in your computer system. 尽管用不同颜色的绳子分隔是非常容易的，但是每一个中间体或产品的盒子上需要额外贴上标签。他们会检查几个

30、标签,然后在您的电脑系统中查找该产品.,50,Inside the Storage Areas (3)在储藏区内,They check the thermometers and inquire about the “temperature range” of each room and why you selected a particular place at the wall for the thermometer. Each room need a defined range (e.g.: 5 30 oC), the definitions “cold” room, “cool” roo

31、m, “shades” or “room temperature” are not accepted. 他们会检查温度计并且询问每一间房间的“温度范围”，以及您选择墙上的位置安放温度计的原因。每一间房间需要明确温度范围（例如5-30），不能仅仅定义为“冷藏”室、“阴凉”室或“室温”。,51,Inside the Storage Areas (4)在储藏区内,All workers have to be prepared for questions regarding the SOPs of the 所有的员工必须准备关于标准操作规程的问题 acceptance of material物料的接收

32、 cleaning 清洁 exchange of status labels 状态标签的更换 and transfer of material 物料的传递,52,Inside the Storage Areas (5)在储藏区域内,They will ask for the exact procedure how incoming raw material is treated, and they want to see the SOP. A clear division between released (green), quarantined (yellow) and rejected (

33、red) products is required. “Reds” have to be in a locked room or in a locked cage. 他们会要求准确的程序，原辅料进来后的预处理，他们希望看到SOP文件。要求严格的区分放行（绿色），待验（黄色）和不合格（红色）的产品。“红色”的产品必须要锁在房间里或铁丝网笼里。,53,Inside the Laboratory (1) 在化验室内(1),The auditors will have a quick look at every piece of equipment. A quick check of log book

34、s of selected items is usual. Calibration records and validation records are required (if they are stored some where else, they will be checked later). Validation of the HPLC injection volume might be a question. 审查员将简短的查看设备的每个部件。通常还要选出一些项目对工作记录台帐进行一个简短的检查。还需要检查校准报告和验证报告（如果报告被放在其他什么地方，检查员会晚些检查）。HPLC

35、的注射量的验证可能会成为一个问题。,54,Inside the Laboratory (2) 在化验室内(2),Storage room for reagents has to be completely renovated. Holes in wall covered with cement, white paint on the wall, new shelves, all reagents need label and all reagents have to be cleaned. When reagents are stored in boxes, the boxes have to

36、 be labeled. Organise a system and may be store cards. 试剂储存室必须完全更新。墙上的洞要用水泥封好，粉刷墙面，新货架，所有试剂要贴标签以及清洁。如果试剂存放在盒子里，盒子必须贴标签。做好储存货位卡。,55,Inside the Laboratory (3)在化验室内 (3),They also expect that the validations of the equipment has been done with the APIs and the excipients which are used for the European

37、products. They will ask for the validation of all used APIs with HPLC, IR and/or GC. 检察官要看到检测设备以相关产品所做的验证。他们将要求看到所有用HPLC, IR 或 GC检测的相关API的验证,56,Inside the Laboratory (4)在化验室内 (4),All workers have to be prepared for questions regarding the SOPs of the 所有的员工必须准备关于标准操作规程的问题 acceptance of material物料（样品）

38、的接受 cleaning 清洁 usage and maintenance of equipment 设备的使用和维护 and transfer of material 物料（样品）的传递,57,Sampling (1)取样 (1),检察官通常从取样程序开始 Who takes samples? 谁取样？检察官会要求看取样SOP。 Who fill in the sampling application form? 谁填写请验单？ Sampling application form should be filled properly. 样品请验单要按照要求填写。 Samples should

39、be identified with different numbers. 样品要有相应的编号系统以确保每个样品都能够被区别。,58,验证批COA,If you declare that your validation batches will only for doing validation ,not for selling, it can avoid many problems. But you must put “Batches only for validation” on the COA and emphasize these batches will not be release

40、d. 如果你们将验证批产品定义为“ 只用于验 证 ”，因为不牵涉到销售，可能会回避掉一些问题。但是在COA上必须明确强调这是“验证用批次”，从而不作放行处理，避免混淆。,59,Purified Water Unit (1)纯化水系统 (1),There is no difference between the machines for water purification between Europe and China. It looks good when the machines and filters are labeled in English and Chinese. The in

41、spectors want to see the sampling points (important that they have a label/number system throughout the whole factory), conductivity testing and the log books. No conductivity testing with out the temperature is accepted. Always state the water temperature. If you test the pH remember 3 calibration

42、solutions are required in the European Pharmacopoeia. 欧洲和中国的纯化水设备是相同的.最好设备和滤头上贴上中英文标签.检查官会检查取样点(在整个工厂内有统一标签和编号系统很重要), 电导率测试和台帐.要注明水温,没有水温的电导测试不被接受.测试PH时,要依照欧洲药典用3种缓冲液进行测试.,60,Purified Water Unit (2)纯化水系统 (2),All ingredients and solutions for water testing have to be labeled as in the laboratory. Tha

43、t means preparation date, expiry date and name (s) of the operator (s). If they are purchased reagents or solutions, receiving date, opening date and expiry date plus the signatures. If burettes are used, they have to be calibrated and need a maintenance/calibration sticker. Important are the cleani

44、ng SOPs for the water plant and logbooks of the purification unit and the filters. 实验室中所有做纯水测试的试剂和溶液都要贴上标签.上面注明制备日期,有效期和配制人的名字.如果是购买的试剂和溶液,要注明接收日期,开瓶日期,有效期和签名.如果用到量管,量管上要贴校验和维护标签.制水车间的清洁SOP和纯化水系统及过滤器的台帐非常重要.,61,Floor plans 房间平面图,The inspectors require the floor plans for the complete ventilation sys

45、tem. The large original plans. They check which areas have recycled air, because there is the possibility that only one product is permitted to be manufactured in such an area. Furthermore, they want to see the corresponding SMP which defines these areas and says that only manufacturing one product

46、in this area is permitted. It is advisable to have as many direct exhausts as possible. 检查官会要求看通风系统的房间平面图.他们会检查哪些区域有回风.因为有可能在这个区域内只允许生产一种产品.他们还会看相应的SMP上是否说明了这个区域只能生产一种产品。最好尽可能多的使用直排.,62,Air-conditioning空调系统,The inspectors will inspect the air-cleaning unit and check pressures and SOPs. The computer

47、print-outs have to be glued into a logbook. They might ask to see one of each different filters (that means inside the package). They want to know from the staff under which pressure the filters are changed, see the logbooks and the SOPs. 检查员会检查空气净化系统和压力系统及SOPs。电脑打印必须做记录。他们可能要求查看每一种不同的过滤器（这表示新的过滤器）。

48、 他们会问工作人员在什么压力条件下应该更换过滤器，查看记录和SOP。,63,Sample Storage Area样品储藏区域,The auditors want to see the samples and the records. They might pick one to find it again in your computer records. They will ask you to show them the stability data of one or more of the products, which you will manufacture for Europe

49、a. 审查员希望看到样品和报告。他们可能会随意挑选一个样品重新在电脑中查看报告。他们会要求您提供一种或更多产品的稳定性数据，这些产品是您将为欧洲加工的产品。,64,Documentation (1)文件,The auditors usually start with a list of the headings of all your relevant SMPs and SOPs and tell you what documents they want to see. They start with the ones in English and very likely will take

50、some of the English ones in the evening to their hotel. It is always a good idea to ask them to sign for the documents, because they are company confidential. 审查员通常从阅读您所有的相关SOP和SMP文件标题的列表开始。然后告诉您他们希望看那些文件。他们从英文文件开始，并且很有可能把一部分带到宾馆在晚间阅读。可以要求他们在文件上签名，因为他们都是公司机密。,65,Documentation (2) 文件,Furthermore, if

51、the key documents in English, you show that you are a professional, ready to manufacture internationally. 此外，如果您呈递他们英文的关键文件， 您表现出您是一个专业的制造商，并且为国际化的生产做好准备。,66,Documentation (3)文件,It is advisable to use the conference room and transfer the required folders to this room. All senior QA/QC persons should

52、 be there plus one or more “runners” who has to get additional documents, samples or people from elsewhere. The auditors will use the interpreter to read particular documents to them. 使用会议室并将需要的文件转移到会议室是明智的。所有的高级QA/QC人员及机动人员应该在场，机动人员必须随时到其他地方拿一些文件，样品或叫一些人员。审查员会要求翻译官口译他们需要的文件。,67,Documentation (4)文件,

53、They are required by law to see each production process from Europea. They will compare it with your production process for China or your test runs, if it is a “new” product. They want to see the analytical test of the APIs and the analytical tests of the retained samples. 法规要求他们查看每一个来自欧洲的生产程序。他们将它和您的中国的生产程序进行比较，如果是一个“新的”产品，就和您的测试运作进行比较。他们希望看到APIs的分析测试，和留样的分析测试。,68,Validation 验证,They will ask for one or more of the following group: Validation master file, cleaning validation, a validation of each product you will manufacture for Eu