公司名称：Dhanuka Laboratories Ltd.

检查方：克罗地亚

检查日期：2016-2-19

受检地址：7 km, Old Manesar Road, Village Mohammedpur,Gurgaon, Haryana, 122 001, India

产品：原料药CEFIXIME

Nature of non-compliance : 不符合情况

This inspection was performed in theframework of the CEP dossier for the manufacture of Cefixime R1-CEP2003-014-Rev 02. The inspection identified in total 32 deficiencies against EUGMP. One of them was categorized as critical and related to the Company`s weakQuality Assurance System. Seven deficiencies were categorized as majordeficiencies and were related to: Quality Assurance (2), Buildings andfacilities, Documentation, Materials Management/Storage, Laboratory controls,Qualification.

检查是根据头孢克肟的CEP文档R1-CEP 2003-014-Rev 02执行的。检查中共发现32个违反EU GMP的缺陷。其中之一被列为关键，是关于公司薄弱的质量保证体系。7个缺陷被列为主要缺陷，是关于质量保证（2），建筑与设施、文件记录、物料管理/存贮、实验室控制、确认。

[Critical] The QA system implemented onsite, which related to the workshops that were engaged in the manufacture ofCefixime, was found to be weak and not capable of proper design, planning,implementation, maintenance and continuous improvement of a system that allowsthe consistent delivery of products with appropriate quality attributes. Theseobservations are accordingly identified in the relevant sections. The GMPviolations were considered as very severe and thus bearing a risk to eitherhuman or veterinary patients.

【关键缺陷】发现工厂所实施的QA体系，与头孢克肟生产的车间相关，很薄弱，系统设计、规划、实施、维护和持续改进不恰当，这个系统是具有适当质量属性的产品持续销售所需要的。这些缺陷在相关部门有相应识别。GMP违规被认为是非常严重的，因此会对人用患者或兽用患者造成风险。

[Major] Due to a lack of control, a mix-upof CEP-grade batches of Cefixime with those derived by a different process –and their subsequent supply to EU customers – could not be excluded.

【主要缺陷】由于缺乏控制，不能排除CEP规格头孢克肟的批次与那些采用不同工艺生产的头孢克肟可能混淆，之后这些CEP规格产品被销给EU客户。

[Major] No release of individual batchestook place at the time of the inspection. That means that the requirements,such as batch production and batch analytical report review(s) were notconducted and the batches were further used for blending after testing.

【主要缺陷】在检查时没有放行单个批次。这表示未实施一些要求，例如，对批生产记录和批分析报告进行审核，批次在检测后再用于进一步混合。

[Major] A centrifugation area on thebasement of the intermediate building, the rooms hosting the fluid bed dryersas well as the dryers themselves were found as not in accordance with therequirements because a contamination of the products openly handled in thisarea could not be excluded.

【主要缺陷】在中间体建筑地下室离心机区域，房间里也有流化床干燥器，并且干燥器本身不符合要求，因为无法排除在此区域产品开放式处理产生的污染。

[Major] Batch Production Records, EquipmentCleaning Records and Lot Making Production Records (BPR, ECR, LMPR) were issuedby printing the relevant document from a pdf-file. Core principles of themanagement of electronic documentation was found not considered (ordisregarded)

【主要缺陷】批生产记录、设备清洁日志和批形成生产记录（BPR、ECR、LMPR）通过从PDF格式相关文件打印出来分发。未考虑（或者忽略了）电子文件的核心原则。

[Major] Several observations with regard tothe receipt, storage and dispensing of raw materials, key starting materials,intermediates and finished APIs were made and leading to the conclusion that anegative impact of the quality cannot be excluded.

【主要缺陷】关于原料、关键起始物料、中间体和原料药成品的接收、存贮和发放有几个缺陷，从中得出结论不能排除对质量有不良影响。

[Major] Severe violations to EU GMP weremade with regard to the IPC laboratory and the analytical operations conductedin this lab.

【主要缺陷】IPC实验室和此实验室的分析操作严重违反EU GMP，

[Major] Out of a list of 62 instruments(SMF), only four were fully qualified. A further five instruments had undergoneonly DQ, IQ and OQ steps NB: It must also be noted that the previous EDQMinspection categorized observations related to the qualification of equipmentas a major deficiency. The Company failed to implement the CAPA in a holisticway as it addressed only the equipment in question.

【主要缺陷】除了62台仪器清单以外（SMF所列），只有4台全面确认。另外5台仪器只有DQ、IQ和OQ。注：必须注意之前EDQM检查将设备确认相关缺陷分类为主要缺陷。公司未能全面实施CAPA，而只是对讨论过的仪器实施了CAPA。

吊销现有波兰颁发的GMP证书GIF-IW-N-4022/161/13

EDQM搁置CEP：

R1-CEP 2003-014-Rev02 Cefixime 头孢克肟

R0-CEP 2011-173-Rev00 Cefuroxime axetil头孢呋新酯