【技术交流】EMA公布的几个国家GMP检查不符合信息

信息截取自EMA官网，翻译仅供参考

一.印度 WOCKHARDT LIMITED  20140417

原料药产品：卡托普利、奥普布宁

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Nature of non-compliance : 1. A critical deficiency was cited with regards to data integrity of GMP records, entries were seen to be made when personnel were not present on site, documentation was seen that was not completed contemporaneously despite appearing to be completed in this manner. 2. A second critical deficiency was cited regarding potential product contamination, this included the use of inappropriate materials close to product e.g. asbestos coated PTFE seals for centrifuge manways. 3. A major deficiency was cited with regards to equipment and facility, maintenance, design and qualification. Examples included, inappropriate pressure differentials that were not in line with the original design but had not been changed using change control, cleaning validation that was not sufficiently robust to confirm cleaning practices and maintenance issues, such as the failure to spark test glass lined reactor vessels for integrity especially following maintenance.

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不符合情况：

1. 一个关键缺陷，关于GMP记录的数据完整性，人员不在场时却有该员工的数据输入，看到文件记录并非在同时完成，而显示却是在同时完成。

2. 第二个关键缺陷，关于潜在产品污染，包括在产品附近使用了不适当的物料，例如，离心机人孔处采用石棉包覆PTFE密封

3. 一个主要缺陷，关于设备和设施、维护、设计和确认。例子包括，压差不适当，与原始设计不一致，该变更未通过变更控制程序。清洁验证耐用性不够，不能确认清洁操作和维护问题，例如未能检查衬塑料搪玻璃反应釜完整性，特别是之后的维护。

二.沙特TABUK PHARMACEUTICAL MANUFACTURING CO . – TABUK 20140408

Nature of non-compliance : One critical deficiency dealing with the documentation management system and the quality management system has been raised during the inspection performed by ANSM, leading inspectorate and MPA, supporting inspectorate. Indeed the documents provided by the site have been found by the inspectors unreliable and evidences of manipulation of data have been found.

不符合情况：ANSM检查中，发现关于文件管理体系和质量管理体系的一个关键缺陷。工厂提供的文件被发现是不可靠的，发现伪造数据的证据。

As an illustration:

-          In an "In Process Control" room, located in plant A (Cephalosporine products manufacturing) – non sterile manufacturing area, the following items have been found (among others):

-          A工厂（头孢菌素产品生产）在一个“中控室”房间，非无菌生产区，发现以下情况

? Parts of original batch record (from recent and non recent batches).

一部分原始批生产记录（从最近的到不是最近的批次）

? Copies of batch records of products not manufactured on site such as Turbuhaler product (Budesonide).

非本厂区生产批生产记录副本，例如都保（布地奈德）

? Blank batch records forms.

空白批记录表格

? Original analytical data (from recent and non recent batches).

原始分析数据（最近的和非最近的批次）

? Reprocessing protocols.

返工方案

- Moreover, in a another room which is an office located in plant A, the batch record of Tabiclor MR 3BF168 has been found. According to this batch record, the batch has been entirely packed (97330 tablets) on 26th September 2013 and transferred in the Finished Goods Warehouse the same day. However, this batch has been found in the Work In Progress area, as unpacked bulk tablets, in drums.

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另外，A工厂办公区在一个房间，发现Tabiclor MR 3BF168的批记录。根据该批记录，该批次已在2013年9月26日全部包装（97330片），并在同天转移至成品库。但是，这个批号的散片被发现放在在制品区域的桶内，并未包装。

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三.日本 Seikagaku Corporation 20140402

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Nature of non-compliance : During the inspection 1 critical, 1 major and 24 other deficiencies were found. The critical deficiency concerns systematic rewriting/manipulation of documents, including QC raw data. The company has not been able to provide acceptable investigations and explanations to the differences seen in official and non-official versions of the same documents.

不符合情况：在检查过程中，发现缺陷：关键1，主要1，其它24。关键缺陷为对文件，包括QC原始数据，进行系统性重写/伪造。公司未能对同一文件具有不同的正式版本和非正式版本，提供可接受的调查和解释。

四.英国 SCM PHARMA LIMITED  20140401

Nature of non-compliance : 1. A critical deficiency was cited regarding potential product cross contamination, this deficiency was divided into two sections : A. Potential chemical contamination, it was found that the company were manufacturing a potent cytotoxic (Amsacrine) product in the non-potent suite. Processes intended to contain the product had failed and cleaning process and verification were weak with contamination of general manufacturing areas seen. B. Potential microbial contamination. There were contaminated process media simulations that were not adequately investigated and root cause explained and mitigated. VHP sanitisation of the filling isolator inadequately controlled and validated and weaknesses in the environmental monitoring program. 2. A major deficiency regarding the change control program (not all changes were controlled appropriately) and investigations, which were poor in quality with regards to root cause analysis and corrective and preventative actions and were not performed in a timely manner. 3. A second major deficiency regarding maintenance of equipment and facilities with poor controls witnessed

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不符合情况：

1、  一个关键缺陷，关于潜在产品交叉污染，该缺陷分为两部分，A、潜在化学污染，发现公司在非效价生产线上生产一种具效价细胞毒素产品（胺苯吖啶）。限制该产品扩散的处理失败，清洁过程和确认不充分，对普通生产区形成污染。B、潜在微生物污染。培养基模拟被污染，未进行充分调查，根本原因未解释和消减。充填隔离VHP灭菌控制和验证不充分，环境监控程序有缺陷。

2、  一个主要缺陷，关于变更控制程序（并非所有变更均受到恰当控制）和调查，控制和调查程序中对根本原因分析不充分，CAPA不充分，且未及时执行。

3、  第二个主要缺陷，关于设备和设施，目击控制缺失

五.印度 PUNJAB CHEMICALS AND CROP CORPORATION LIMITED 20140331

原料药：三甲氧苄二氨嘧啶

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Nature of non-compliance : Overall, 30 deficiencies were observed, including 8 major deficiencies: [Major 1] Despite its commitment following the last inspection (June 2010) to replace 4 pieces of manufacturing equipment, the company has only decided to replace 2 of them and repair the 2 others, without carrying any risk assessment or providing documented justification for this CAPA modification ; [Major 2] The tank used for the storage of crude Trimethoprim was found to be in an unacceptable condition ; [Major 3] One individual training file of an employee has been observed to be recently re-rewritten ; [Major 4] The Batch Manufacturing record was lacking details with regards to manufacturing steps and in-process controls ; [Major 5] The sample retention log-book for Trimethoprim had falsified entries ; [Major 6] The storage of raw

materials, intermediates and finished products was considered not to be compliant with GMP requirements (e.g., materials segragation, housekeeping, etc.) ; [Major 7] The company did not establish different product codes for the different Trimethoprim processes ; [Major 8] The Validation Master Plan did not contain any clear description of the policy, intentions and approach to validation.

不符合情况：总体发现30个缺陷，包括8个主要缺陷。

主要缺陷1、上次检查（2010年1月）后，公司承诺会更换4台生产设备，但后来决定只更换其中2台，另2台进行了修理，对该CAPA进行修订未进行风险评估或提供书面论述

主要缺陷2、发现用于三甲氧苄二氨嘧啶粗品存贮的贮罐状态不能接受

主要缺陷3、发现一个员工的一份培训文件最近被重新书写过

主要缺陷4、批生产记录缺乏关于生产步骤和中控的详细记录

主要缺陷5、三甲氧苄二氨嘧啶的留样记录本有篡改记录

主要缺陷6、原料、中间体和成品的存贮被认为不符合GMP要求（例如，原料隔离、库房维护等）

主要缺陷7、公司未为不同工艺的三甲氧苄二氨嘧啶建立不同产品代码

主要缺陷8、主验证计划没有对验证方针、目的、验证方法的清楚描述

六.印度 IND-SWIFT LIMITED 20140321

Nature of non-compliance : It was not possible to confirm the validity of stability testing data. Several falsified and inaccurate results had been reported in long term stability and batch testing. Discrepancies between electronic data and those results formally reported were identified. Established processes to verify data accuracy and integrity had failed and there had been no formal investigation raised by the company. The company provided commitments to address the data integrity concerns and initiated a wider review of quality critical data. Additional discrepancies were identified in process validation and release data. During on-going communications with the licensing authority regarding the data review, the company failed to disclose data integrity issues for all products. No satisfactory explanation was given for this discrepancy.

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不符合情况：无法确认稳定性数据的有效性。长期稳定性和批检测中报告了几个伪造的不精确结果。发现电子数据和正式报告数据之间不符。所建立的确认数据准确性和完整性的程序失效，公司对此未进行正式调查。公司承诺对所涉数据完整性进行说明，启动大范围的质量关键数据审核。另外发现工艺验证数据和放行数据相互不符合。公司在与发证药监当局就数据审核事宜持续沟通时，未能发现所有产品的数据完整性问题。对此不符合未给出令人满意的解释。

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七.摩纳哥SOMET 20140305

15个非无菌原料药品种

Nature of non-compliance : Overall, 31 deficiencies were observed, including 2 Critical and 12 Major deficiencies : [Critical] The manufacturing and cleaning operations during and between the campaigns of 15 APIs, whose 2 are used in injectable dosage forms and one is an ectoparasiticide (Fipronil), are not traceable. Many records are missing. [Critical] Cleaning procedures are not detailed to enable operators to clean each piece of equipment in a reproductible and effective manner. Cleaning procedures of the critical pieces of equipment used after final isolation of pure APIs are not validated. Analytical methods by TLC used for cleanliness verification are not validated. Complete records of raw data generated during cleanliness tests by thin layer chromatography are missing. Moreover, cleanliness tests are not conducted for plates of dryers used for APIs. The other major findings were mainly related to the manufacturing of an ectoparasiticide for veterinary use (Fipronil) in multi-products manufacturing area and equipment without any study based on QRM principles regarding cross-contamination and containment, highlighting the non compliance status to the GMPs.

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不符合情况：总体发现31个缺陷，包括2个关键12个主要缺陷

关键：15个原料药，其中2个用于注射剂，一个杀外寄生虫药（芬普尼），在生产周期内，和生产周期之间的生产和清洁操作不能追溯。许多记录缺失。

关键：清洁程序不详细，不能使得操作人员对每台设备进行有效可重复的清洁。在纯原料药分离后所使用的关键设备的清洁程序未经过验证。用于清洁确认的TLC分析方法未经过验证。TLC清洁测试完整原始数据记录缺失。更有甚者，原料药所用盘式烘箱未进行清洁测试。还有一个主要缺陷是关于兽用杀虫剂（芬普尼）使用多品种生产区域和设备进行生产，未进行任何基于QRM原则对交叉污染和污染进行研究，特别地暴露出其GMP不符合情况。

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8.印度 Smruthi Organics Limited 20140108

原料药：苯磺酸氨氯地平 （检查后6份CEP全部被撤销）

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Nature of non-compliance : Overall, 29 deficiencies were observed, including 2 Critical and 4 Major deficiencies : [Critical 1] Manipulation and falsification of documents and data were observed in different departments ; [Critical 2] Some Corrective and Preventive Actions, related to deficiencies raised during the previous inspection were not satisfactorily addressed ; [Major 1] An out-of-specification result obtained for an In-Process Control, performed by TLC, was considered as compliant by the analyst ; [Major 2] The documentation practices for process validation were found unacceptable ; [Major 3] The company's approach and understanding of the GMP requirements for the re-qualification of the equipment was found to be unsufficient ; [Major 4] There was no raw data available in the Quality Control laboratory for the verification of compendial analytical methods.

不符合情况：总体发现29个缺陷，包括2个关键和4个主要缺陷。

关键1：在不同部门发现伪造篡改记录和数据

关键2：在上次检查中，提出一些CAPA，其说明不满意

主要1：中控TLC方法测得一个OOS结果，被分析人员认为是符合的

主要2：工艺验证文件形式不能接受

主要3：发现公司对设备再确认的GMP要求方法和理解不充分

主要4：QC化验室没有药典分析方法确认的原始数据

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