终总结欧洲现场检查缺陷汇总中国.pdf

2013年年- 2014年欧洲年欧洲 【编者按】 2013 年到 2015 年，欧盟更新了大量的 GMP 章节，虽然几个章节 生了变化，无论是检查的广度和深度，都与 2013 年以前有所变化 出中国制药企业还没有深刻的领会 GMP 新章节含义和最近欧洲检查的特点 为了帮助医药企业厘清最近两年欧洲 GMP 的检查特点， 和简单的翻译，详见附表。 通过对欧洲检查的关键缺陷和主要缺陷进行汇总分析可以发现 共性问题，这些问题主要表现在以下几个方面： 1. 污染和交叉污染控制不良：污染和交叉污染控制不良： 污染和交叉污染问题历来是各个药监机构的检查重点 产、抗癌产品和抗生素产品。这需要制药企业不仅有防控污染和交叉污染的措施 仅是一纸文件。 2. 质量保证体系存在缺陷：质量保证体系存在缺陷： 质量保证体系的问题不是在审核文件时发现的，而是通过一系列的现场问题汇总出来的 题而没有得到有效的整改；各种程序处理表面化、文件化 有实际执行等。 1 / 12 GMP检查年终总结检查年终总结 年欧洲年欧洲GMP现场检查（中国工厂）主要问题汇总现场检查（中国工厂）主要问题汇总 虽然几个章节到 2015 年才正式实施，但是在最近的欧盟 GMP 现场中 年以前有所变化。另外，在 2014 年，中国的制药企业频繁发生国外检查不通过的情况 新章节含义和最近欧洲检查的特点。 便于企业进行自查和持续改进，我们将欧洲 2013 年-2014 年的典型的检查情况进行了汇总 进行汇总分析可以发现，欧洲 GMP 检查的方向和特点还是非常明确的，同时也暴露了中国制药存在的一些 问题历来是各个药监机构的检查重点，欧洲检查时对污染和交叉污染问题的关注也呈现一种上升的趋势 这需要制药企业不仅有防控污染和交叉污染的措施，更重要的是这些措施应该能够起到相应的防控效果 而是通过一系列的现场问题汇总出来的，比如在偏差、投诉、OOS 文件化，只是为了应付检查而做记录；人员数量不足够或者资质不相适应 康利华咨询 张磊 现场中，检查的特点已经悄然发 中国的制药企业频繁发生国外检查不通过的情况，由此可以看 年的典型的检查情况进行了汇总 同时也暴露了中国制药存在的一些 检查时对污染和交叉污染问题的关注也呈现一种上升的趋势，尤其是涉及到共线生 更重要的是这些措施应该能够起到相应的防控效果，而不仅 OOS 等程序中频繁出现类似的问 人员数量不足够或者资质不相适应；各种质量程序没 3. 实验室和检验数据管理存在问题：实验室和检验数据管理存在问题： 实验室管理和检验数据的管理成了最近欧洲检查的重灾区 确的告诉了制药企业：凭借运气和侥幸通过检查的时代已经过去了 以上只是对最近检查显著的特点进行了简要分析，后续我们还会对更新的 的汇总分析，欢迎大家持续关注我们的微信公众号。 附表： 2013 年-2014 年欧洲药监当局对中国制药企业检查缺陷汇总 数据来源：http:/eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do 2 / 12 实验室管理和检验数据的管理成了最近欧洲检查的重灾区，欧洲检察官对检验数据的真实性和完整性的关注程度不同以往 凭借运气和侥幸通过检查的时代已经过去了！ 后续我们还会对更新的 EU GMP 章节做出解读，对欧洲、FDA、日本和 年欧洲药监当局对中国制药企业检查缺陷汇总 http:/eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance.do 欧洲检察官对检验数据的真实性和完整性的关注程度不同以往。这些缺陷已经很明 日本和 TGA 的检查特点进行详细 2013年年-2014 序号序号 检查方检查方 1. Irish Medicines Board （Ireland） Nature of non- compliance : Four Critical Deficiencies were identified during the course of the inspection; these related to: (a) The management and redistribution (reselling) of batches contaminated with over sulphated chondroitin sulphate (OSCS) and, separately, with ruminant DNA; (b) The management and investigation of the OSCS and ruminant contamination incidents; (c) The lack of quality assurance oversight for the entire supply chain, from abattoirs to the mixing plant; (d) The lack of quality assurance in the supply chain in place at the Chongqing Huhao workshop where Raw Heparin Sodium is manufactured. Eleven Major Deficiencies were identified during the course of the inspection; these related to a number of areas with quality system. 译文：译文： 在检查期间发现了 4 个关键缺陷，分别是： (a) 批次的管理和再分销（再销售）分别污染了过量的硫酸化硫酸软骨素 (b) 对 OSCS 和反刍类动物 DNA 污染问题的处理和调查存在严重缺陷 (c) 对于从屠宰场到生产工厂的整个供应链缺乏质量保证监管 (d) 供应链中重庆 Huhao 工厂（生产粗品肝素钠 另外在现场检查中发现的 11 项主要缺陷与一系列的质量 2. French Health Products Safety Agency Nature of non- compliance : Twenty seven deficiencies were found, out of which 4 were classified as major deficiencies in the Equipment (2 major), Materials Management (1 major), Production and In preventative action plan provided by the company in response to the initial inspection report was not found satis many of the findings and in particular regarding some of the major deficiencies. 译文：译文： 在检查中发现了 27 个缺陷，其中 4 个主要缺陷 个是生产和工艺控制方面。公司针对检查报告中的缺陷制定的整改计划中有很多是不令人满意的 定的整改措施。 3 / 12 2014年欧洲药监当局对中国制药企业检查缺陷汇总年欧洲药监当局对中国制药企业检查缺陷汇总 缺陷详细描述缺陷详细描述 Four Critical Deficiencies were identified during the course of the inspection; these related to: The management and redistribution (reselling) of batches contaminated with over sulphated chondroitin sulphate (OSCS) (b) The management and investigation of the OSCS and ruminant contamination incidents; (c) The lack of quality assurance oversight for the entire supply chain, from abattoirs to the mixing plant; (d) The lack of quality assurance in the supply chain in place at the Chongqing Huhao workshop where Raw Heparin Sodium is Eleven Major Deficiencies were identified during the course of the inspection; these related to a number of areas within the 了过量的硫酸化硫酸软骨素（OSCS）和反刍类动物 DNA。 问题的处理和调查存在严重缺陷。 对于从屠宰场到生产工厂的整个供应链缺乏质量保证监管。 生产粗品肝素钠的车间）缺乏质量保证。 项主要缺陷与一系列的质量体系相关。 Twenty seven deficiencies were found, out of which 4 were classified as major deficiencies in the following areas: Process Equipment (2 major), Materials Management (1 major), Production and In- Process Controls (1 major). The corrective and preventative action plan provided by the company in response to the initial inspection report was not found satisfactory for many of the findings and in particular regarding some of the major deficiencies. 个主要缺陷，这些主要缺陷分布在：2 个是工艺设备方面的，1 个是物料管理方面 公司针对检查报告中的缺陷制定的整改计划中有很多是不令人满意的，特别是针对主要缺陷制 报告编号报告编号 关键词关键词 The management and redistribution (reselling) of batches contaminated with over sulphated chondroitin sulphate (OSCS) (d) The lack of quality assurance in the supply chain in place at the Chongqing Huhao workshop where Raw Heparin Sodium is in the 2012/5767 2012/5768 污染污染 交叉污染交叉污染 质量保证质量保证 监管监管 following areas: Process Process Controls (1 major). The corrective and factory for 物料管理方面，1 特别是针对主要缺陷制 12MPP063 工艺设备工艺设备 物料管理物料管理 生产与生产与IPC 序号序号 检查方检查方 3. French Health Products Safety Agency Nature of non- compliance : Forty- eight deficiencies were found, of which one was considered Critical deficiency and eight were considered Major deficiencies, in the areas of: Critical deficiency Quality management: due to a global lack of understanding of Good Manufacturing Prac major deficiencies. Major deficiencies Quality management: deficient management of the Annual Product Quality Reviews. Documentation and records: deficient management of the batch manufacturing report (BMR) of numerous mistakes, insufficiently detailed production instructions, lack of indication of the production equipment). Materials management: deficient approach for the qualification of a supplier of crude Mefenamic Acid API (e.g. no G requirement, no quality agreement, no follow- up on the implementation of the supplier CAPA action plan) Laboratory control: lack of management of the reference standards (e.g. recommended storage conditions not followed, use of a chemical grade substance as working standard for impurity A) Validation: lack of understanding of the validation process management and deficient review of the Mefenamic Acid validatio protocol/report by the quality unit. Qualification: deficient management for the qual performed after the purchase of equipment, IQ/OQ/PQ protocols not provided, IQ/OQ/PQ reports not signed). Change Control: deficient management of the change control procedure (e.g. implementation of a new analytical method for Mefenamic Acid without a CC). Complaints: deficient investigation of a complaint regarding Mefenamic Acid 译文：译文： 现场检查时发现了 48 条缺陷，其中 1 条关键缺陷和 关键缺陷：关键缺陷： ? 质量管理：质量管理：由于缺乏对 GMP 的全面理解， 主要缺陷：主要缺陷： 4 / 12 缺陷详细描述缺陷详细描述 eight deficiencies were found, of which one was considered Critical deficiency and eight were considered Major Quality management: due to a global lack of understanding of Good Manufacturing Practice, underlined by the combination of Quality management: deficient management of the Annual Product Quality Reviews. Documentation and records: deficient management of the batch manufacturing report (BMR) of Mefenamic Acid (e.g. numerous mistakes, insufficiently detailed production instructions, lack of indication of the production equipment). Materials management: deficient approach for the qualification of a supplier of crude Mefenamic Acid API (e.g. no G up on the implementation of the supplier CAPA action plan) Laboratory control: lack of management of the reference standards (e.g. recommended storage conditions not followed, use ance as working standard for impurity A) Validation: lack of understanding of the validation process management and deficient review of the Mefenamic Acid validatio Qualification: deficient management for the qualification of the controlled area for Mefenamic Acid production (e.g. DQ performed after the purchase of equipment, IQ/OQ/PQ protocols not provided, IQ/OQ/PQ reports not signed). Change Control: deficient management of the change control procedure (e.g. CC initiated after completion of the DQ, implementation of a new analytical method for Mefenamic Acid without a CC). Complaints: deficient investigation of a complaint regarding Mefenamic Acid 条关键缺陷和 8 条主要缺陷，分别为： 多项主要缺陷组合在一起构成了关键缺陷。 报告编号报告编号 关键词关键词 eight deficiencies were found, of which one was considered Critical deficiency and eight were considered Major tice, underlined by the combination of Mefenamic Acid (e.g. Materials management: deficient approach for the qualification of a supplier of crude Mefenamic Acid API (e.g. no GMP Laboratory control: lack of management of the reference standards (e.g. recommended storage conditions not followed, use Validation: lack of understanding of the validation process management and deficient review of the Mefenamic Acid validation ification of the controlled area for Mefenamic Acid production (e.g. DQ CC initiated after completion of the DQ, INS 2008- 027 P03 质量管理质量管理 文件和记录文件和记录 物料管理物料管理 实验室控制实验室控制 验证验证 确认确认 变更变更 投诉投诉 ? 质量管理：质量管理：年度质量回顾缺乏有效管理。 ? 文件和记录：文件和记录：Mefenamic Acid 的批制造报告缺少有效的管理 备缺少参数的显示等） 。 ? 物料管理：物料管理：Mefenamic Acid API 粗品的供应商没有进行确认 供应商 CAPA 计划的跟踪确认） 。 ? 实验室控制：实验室控制：缺乏对标准品的管理（比如： ? 验证：验证：缺少对验证程序管理的理解，Mefenamic Acid ? 确认：确认：缺少对 Mefenamic Acid 生产控制区域的确认 确认方案，IQ/OQ/PQ 没有签名） 。 ? 变更控制：变更控制：变更控制程序缺少管理（例如： 就使用了新的分析方法） 。 ? 投诉：投诉：Mefenamic Acid 相关的投诉缺少调查 4. Italian Medicines Agency Nature of non- compliance : The inspection identified 10 major deficiencies to EU Good Manufacturing Practice Guide Part II. They were found in the areas of: building and facilities (4), process equipment (1), documentation and records (1), materials manag controls (1), validation (2). The combination of 6 of the major deficiencies (the ones regarding Buildings and Facilities, Process Equipment and Materials Management) constitutes a critical departure from GMP, which induces risk of c and cleaning status and inadequate material handling, hence leading to a significant risk of manufacturing a product that is harmful to human or veterinary patients. 译文：译文： 在检查中发现了 10 条主要缺陷，这些主要缺陷主要有以下几类 和记录方面，1 条为物料管理方面，1 条为实验室控制方面 主要缺陷中的六条（分别为建筑设施、工艺设备和物料管理方面 态以及不恰当的物料管理存在有污染的风险，从而会导致产品对患者有严重的 5 / 12 的批制造报告缺少有效的管理（比如：有许多错误，没有详细的描述生产操作，生产设 粗品的供应商没有进行确认（例如：没有提出 GMP 要求，没有签署质量协议，没有 储存条件不符合要求，使用了化学级的物质作为杂质 A 的工作标准品） Mefenamic Acid 的验证方案和报告没有经过质量部门的审核。 生产控制区域的确认（比如购买了设备后才进行的设计确认，没有提供 IQ/OQ/PQ 完成 DQ 后才开始启动变更程序，Mefenamic Acid 没有执行变更控制程序 相关的投诉缺少调查。 The inspection identified 10 major deficiencies to EU Good Manufacturing Practice Guide Part II. They were found in the areas of: building and facilities (4), process equipment (1), documentation and records (1), materials management (1), laboratory The combination of 6 of the major deficiencies (the ones regarding Buildings and Facilities, Process Equipment and Materials Management) constitutes a critical departure from GMP, which induces risk of contamination due to inappropriate maintenance and cleaning status and inadequate material handling, hence leading to a significant risk of manufacturing a product that is 这些主要缺陷主要有以下几类：4 条为建筑设施方面，1 条为工艺设备方面，1 条为文件 条为实验室控制方面，2 条为验证方面。 工艺设备和物料管理方面）构成了 1 条关键缺陷，设施设备不合适的维护和清洁状 从而会导致产品对患者有严重的使用风险。 生产设 没有 ） 。 IQ/OQ/PQ 的 没有执行变更控制程序 The inspection identified 10 major deficiencies to EU Good Manufacturing Practice Guide Part II. They were found in the areas ement (1), laboratory The combination of 6 of the major deficiencies (the ones regarding Buildings and Facilities, Process Equipment and Materials ontamination due to inappropriate maintenance and cleaning status and inadequate material handling, hence leading to a significant risk of manufacturing a product that is 条为文件 设施设备不合适的维护和清洁状 IT/API/NC/ 01- 2013 建筑设施建筑设施 工艺设备工艺设备 文件和记录文件和记录 物料管理物料管理 实验室控制实验室控制 验证验证 序号序号 检查方检查方 5. French Health Products Safety Agency Nature of non- compliance : 16 deficiencies were found, out of which 2 were classified as critical deficiencies and 9 as major deficiencies in the follow areas: Quality Management (2 critical, 2 major), Buildings and Facilities (1 Major), Process Equipm Management (2 major) and Laboratory Controls (1 major). The 2 critical deficiencies were due to 1 Analyses of related substances by HPLC not performed on each batch of Paracetamol EP grade and 2 Most batches (92%) manufactured and marketed in 2012 without issuing a batch record. 译文：译文： 在检查中发现了 16 条缺陷，其中包括 2 个关键缺陷和 2 条主要缺陷，建筑和设施方面存在 1 条主要缺陷 实验室控制存在 1 条主要缺陷。 2 条主要缺陷分别为： 1 EP 标准的扑热息痛没有每批检验有关物质。 22012 年生产和销售的大部分批次（92%）没有批生产记录 6. National Agency for Medicines and Medical Devices （ Romania ） Nature of non- compliance : A total of 35 deficiencies were found, of which two were characterised as critical, four as major and 29 as other. One of the critical deficiencies consisted of three major findings. The inspection revealed a low GMP awareness i especially regarding management of the Quality System, inadequate qualifications of key personnel, and potential risks of product contamination. It also identified discrepancies, both in terms of actual data and applied manufacturing pract approved CEP dossier. 译文：译文： 在检查中发现了 35 条缺陷，其中 2 条关键缺陷 成的。检查显示出，企业在很多地方都存在比较低的 当的资质，产品有潜在的污染风险。另外，实际执行的参数和数据与 6 / 12 缺陷详细描述缺陷详细描述 16 deficiencies were found, out of which 2 were classified as critical deficiencies and 9 as major deficiencies in the follow areas: Quality Management (2 critical, 2 major), Buildings and Facilities (1 Major), Process Equipment (3 major), Materials Management (2 major) and Laboratory Controls (1 major). 1 Analyses of related substances by HPLC not performed on each batch of Paracetamol EP grade and d and marketed in 2012 without issuing a batch record. 个关键缺陷和 9 个主要缺陷，主要分布如下：质量管理方面存在 2 条关键缺陷和 条主要缺陷，工艺设备方面存在 3 条主要缺陷，物料管理方面存在 2 条主要缺陷 没有批生产记录。 A total of 35 deficiencies were found, of which two were characterised as critical, four as major and 29 as other. One of the critical deficiencies consisted of three major findings. The inspection revealed a low GMP awareness in several areas, especially regarding management of the Quality System, inadequate qualifications of key personnel, and potential risks of product contamination. It also identified discrepancies, both in terms of actual data and applied manufacturing practices, to the 条关键缺陷，4 条主要缺陷和 29 条一般缺陷。其中 1 条关键缺陷是由 3 条主要缺陷组 企业在很多地方都存在比较低的 GMP 管理意识，比如：在质量管理方面薄弱，关键人员没有充分 实际执行的参数和数据与 CEP 证书有差异。 报告编号报告编号 关键词关键词 16 deficiencies were found, out of which 2 were classified as critical deficiencies and 9 as major deficiencies in the following ent (3 major), Materials 条关键缺陷和 条主要缺陷， 13MMP019 实验室控制实验室控制 批生产记录批生产记录 A total of 35 deficiencies were found, of which two were characterised as critical, four as major and 29 as other. One of the n several areas, especially regarding management of the Quality System, inadequate qualifications of key personnel, and potential risks of ices, to the 条主要缺陷组 关键人员没有充分适 NCF/009/R O GMP管理管理 质量管理质量管理 人员资质人员资质 污染污染 注册注册一致性一致性 序号序号 检查方检查方 7. French Health Products Safety Agency Nature of non- compliance : Overall, 31 deficiencies were observed, including 2 Critical and 9 Major deficiencies. Critical1 4 deficiencies (out of them 2 critical) related to the previous inspections not satisfactory corrected; Critical 2 Repeated critical deficiency related to the cross Major 1 Inadequate cleaning and maintenance of the production equipment; Major 2 Incomplete Annual Product Quality Reviews; Major 3 Inadequate control and storage of quality documents; Major 4 Risk of contamination by reusable plastic containers of raw materials; Major 5 Cross contamination issues between Phenoxymethylpenicillin potassium and Penicillin G Potassium; Major 6 Repeated major deficiency related to the cleaning and ma Major 7 Risk of contamination in the filtration and washing area for inadequate cleaning of the production equipment and tools; Major 8 Risk of microbial, particle and chemical contamination of startin Major 9 Inadequate review and control of computerized laboratory results and systems. 译文：译文： 在检查中发现了 31 条缺陷，其中包括 2 个关键缺陷和 Critical1 之前检查中出现的 4 项缺陷（其中 2 Critical2 设备被 - 内酰胺交叉污染的重要缺陷反复出现 Major 1 生产设备的清洁维护不充分。 Major 2 年度产品质量回顾不充分。 Major 3 质量文件的受控和储存不当。 Major 4 盛放原料的塑料容器反复使用有污染的风险 Major 5 青霉素 V 钾和青霉素 G 钾之间存在交叉污染情况 Major 6 与盛放溶剂的容器的清洁和维护相关的主要缺陷反复出现 Major 7 在过滤和清洗区，生产设备和器具清洁不彻底存在污染风险 Major 8 起始原料存在微生物、粉尘和化学污染的风险 Major 9 电子实验结果和系统的审核和控制不充分 7 / 12 缺陷详细描述缺陷详细描述 Overall, 31 deficiencies were observed, including 2 Critical and 9 Major deficiencies. Critical1 4 deficiencies (out of them 2 critical) related to the previous inspections not satisfactory corrected; to the cross- contamination of the facility with beta- lactam. Major 1 Inadequate cleaning and maintenance of the production equipment; Major 2 Incomplete Annual Product Quality Reviews; Major 3 Inadequate control and storage of quality documents; Major 4 Risk of contamination by reusable plastic containers of raw materials; 5 Cross contamination issues between Phenoxymethylpenicillin potassium and Penicillin G Potassium; Major 6 Repeated major deficiency related to the cleaning and maintenance of the utensils used for the solvents; Major 7 Risk of contamination in the filtration and washing area for inadequate cleaning of the production equipment and Major 8 Risk of microbial, particle and chemical contamination of starting materials; Major 9 Inadequate review and control of computerized laboratory results and systems. 个关键缺陷和 9 个主要缺陷。 项为严重缺陷）整改不合格。 内酰胺交叉污染的重要缺陷反复出现。 盛放原料的塑料容器反复使用有污染的风险。 钾之间存在交叉污染情况。 维护相关的主要缺陷反复出现。 生产设备和器具清洁不彻底存在污染风险。 粉尘和化学污染的风险。 电子实验结果和系统的审核和控制不充分。 报告编号报告编号 关键词关键词 Major 7 Risk of contamination in the filtration and washing area for inadequate cleaning of the production equipment and 13MPP049 整改整改不不合格合格 交叉污染交叉污染 设备设备清洁清洁 质量质量回顾回顾 文件管理文件管理 实验室数据实验室数据 序号序号 检查方检查方 8. French Health Products Safety Agency Nature of non- compliance : Overall, 14 deficiencies were observed, including 2 major and 1 critical deficiencies. Major 1 Inadequate control and storage of quality documents such as certificates of analysis o