公司名稱：Dhanuka Laboratories Ltd.

檢查方：克羅地亞

檢查日期：2016-2-19

受檢地址：7 km, Old Manesar Road, Village Mohammedpur,Gurgaon, Haryana, 122 001, India

產品：原料藥CEFIXIME

Nature of non-compliance : 不符合情況

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.

檢查是根據頭孢克肟的CEP文檔R1-CEP 2003-014-Rev 02執行的。檢查中共發現32個違反EU GMP的缺陷。其中之一被列為關鍵，是關于公司薄弱的質量保證體系。7個缺陷被列為主要缺陷，是關于質量保證（2），建筑與設施、文件記錄、物料管理/存貯、實驗室控制、確認。

[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.

【關鍵缺陷】發現工廠所實施的QA體系，與頭孢克肟生產的車間相關，很薄弱，系統設計、規劃、實施、維護和持續改進不恰當，這個系統是具有適當質量屬性的產品持續銷售所需要的。這些缺陷在相關部門有相應識別。GMP違規被認為是非常嚴重的，因此會對人用患者或獸用患者造成風險。

[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規格頭孢克肟的批次與那些采用不同工藝生產的頭孢克肟可能混淆，之后這些CEP規格產品被銷給EU客戶。

[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】在檢查時沒有放行單個批次。這表示未實施一些要求，例如，對批生產記錄和批分析報告進行審核，批次在檢測后再用于進一步混合。

[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】在中間體建筑地下室離心機區域，房間里也有流化床干燥器，并且干燥器本身不符合要求，因為無法排除在此區域產品開放式處理產生的污染。

[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】批生產記錄、設備清潔日志和批形成生產記錄（BPR、ECR、LMPR）通過從PDF格式相關文件打印出來分發。未考慮（或者忽略了）電子文件的核心原則。

[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】關于原料、關鍵起始物料、中間體和原料藥成品的接收、存貯和發放有幾個缺陷，從中得出結論不能排除對質量有不良影響。

[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實驗室和此實驗室的分析操作嚴重違反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臺儀器清單以外（SMF所列），只有4臺全面確認。另外5臺儀器只有DQ、IQ和OQ。注：必須注意之前EDQM檢查將設備確認相關缺陷分類為主要缺陷。公司未能全面實施CAPA，而只是對討論過的儀器實施了CAPA。

吊銷現有波蘭頒發的GMP證書GIF-IW-N-4022/161/13

EDQM擱置CEP：

R1-CEP 2003-014-Rev02 Cefixime 頭孢克肟

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