一家印度企业被吊销EU GMP证书 - 药群论坛

来源：http://zhuyujiao1972.blog.163.com/blog/static/98694727201411250155521/

一家印度企业被吊销EU GMP证书

检查单位：意大利药监

受检企业：SRI KRISHNA Pharmaceuticals Ltd.

受检地址：Unit II - A-35, IDA, Nacharam, Hyderabad, Andhra Pradesh, 500 076, India

检查日期：2014-12-04

不符合事项：检查期间共发现10个重大缺陷。主要关注的有：

1. 药品未能符合质量控制标准，但没有拒收。特别是：1）化验员日常使用计算机管理员权限来设定控制时间和日期，通过倒置日期来覆盖之前采集的不合格和/或非预期样品结果，一直重复该做法直到样品检测通过和/或获得想要的结果；2）化验员日常都在正式/报告检测操作前进行样品溶液“试针”进样。这些试分析并没有样品制备记录，这些试针结果没有进行报告，且发现与后续的报告结果有显著差异；3）化验员日常都在正式/报告检测操作前进行样品溶液“试针”进样，所得的原始数据图谱文件被发现经常是被删除了，无法获取来做审核；4）化验员删除不想要的和/或不合格结果（整个样品序列），重新检测样品直到获得想要的结果。

2. 没有遵守已建立的化验室控制机制。使用了电子记录，但并不符合系统验证要求，不能保证其值得信任，及可靠和等同于纸质记录。

3. 质量协议缺失或很差

4. 书面生产和工艺控制程序没有在进行时被记录。特别是，在对生产设施现场检查的过程中发现，由质量部门发放的不同产品的受控批生产记录被撕毁和丢弃的太多，无法计数（TNTC）。5本批生产记录被拿来与存档的生产记录进行比较，确认选来审核的这5本没有根据SOP QA/SOP/DOC/001的要求再次发放。值得注意的是，在后续的调查中，还发现母版批记录（版本号为0）被大多数质量和生产部门的负责人倒签日期。在检查期间，上述倒签日期的人员确认了该情况。

备注：吊销现行GMP证书N° IT/E/GMP/8/2013 （2013年3月19日签发）和IT/E/GMP/15/2013 （2013年11月6日签发）。建议撤销其GMP证书DE_BW_01_GMP_2014_0105 （2014年8月4日由Baden – Württemberg (德国)签发）。根据检查期间获得的信息，目前没有理由关注成品的质量，原因如下：受检单位只生产颗粒中间体，这些中间体将在其它制剂生产工厂进行进一步加工；成品在放行销售前要由成品批放行场所进行进一步检验。如果在放行前没有对成品进行全检（包括杂质），国家药监局要考虑立即召回已经放行的批次，并禁止该公司的颗粒销售。作为国家药监部门，应考虑要求上市许可持有人进行风险评估，基于上述已发现的问题，评估产品质量和患者的风险。

Italian Medicines Agency

Report No : IT/ GMP/NCR/INT/1-2014

STATEMENT OF NON-COMPLIANCE WITH GMP

Exchange of information between National Competent Authorities (NCAs) of the EEA following the discovery of serious GMP non-compliance at a manufacturer (1)

Part 1

Issued following an inspection in accordance with :
Art. 111(7) of Directive 2001/83/EC as amended

The competent authority of Italy confirms the following:

The manufacturer : SRI KRISHNA Pharmaceuticals Ltd.

Site address :

Unit II - A-35, IDA, Nacharam, Hyderabad, Andhra Pradesh, 500 076, India

From the knowledge gained during inspection of this manufacturer, the latest of which was conducted on 2014-12-04 , it is considered that it does not comply with the Good Manufacturing Practice requirements referred to in

· The principles and guidelines of Good Manufacturing Practice laid down in Directive 2003/94/EC

__________________________________________________________________________________________________________________________

(1) The statement of non-compliance referred to in paragraph 111(7) of Directive 2001/83/EC and 80(7) of Directive 2001/82/EC, as amended, shall also be required for imports coming from third countries into a Member State.

Part 2

Human Medicinal Products

1 NON-COMPLIANT MANUFACTURING OPERATIONS

1.2 Non-sterile products

1.2.1 Non-sterile products (processing operations for the following dosage forms)
1.2.1.8 Other solid dosage forms: granules in bulk(en)

1.6 Quality control testing

1.6.2 Microbiological: non-sterility
1.6.3 Chemical/Physical

Part 3

Nature of non-compliance : During the inspection 10 Major deviations from EU GMP have been found. In particular, main concerns were: 1. Drug products failing to meet established quality control criteria are not rejected. In particular: a) analysts routinely use the PC administrator privileges to set the controlling time and date settings back to over-write previously collected failing and/or undesirable sample results. This practice is performed until passing and/or desirable results are achieved; b) Analysts routinely perform “trial” injections of sample aliquots prior to performing the official/reported analysis. There are no documented sample preparation details for these trial analyses. The results of these trial injections are not reported, and were found to differ significantly from the subsequent reported results; c) Analysts routinely perform “trial” injections of sample aliquots prior to performing the official/reported analysis. The resulting raw data chromatogram files were often found to have been deleted and unavailable for review; d) Analysts delete undesirable and/or failing results (entire sample sequences) and retest samples until desirable results are achieved. 2. Established laboratory control mechanisms are not followed. Electronic records are used, but they do not meet systems validation requirements to ensure that they are trustworthy, reliable and generally equivalent to paper records; 3. Missing or poor quality agreement; 4. Written production and process control procedures are not documented at the time of performance. Specifically, Too Numerous to Count (TNTC) torn and discarded controlled manufacturing batch records for a variety of different products issued by the Quality Unit were found during a walk-through inspection of the facility. Five batch records were compared with the archived manufacturing one and it was ascertained that no records had been made for duplicate issuance of these five batches chosen for review, as required per SOP QA/SOP/DOC/001. Notably, after subsequent investigation it was found that the Master Batch Record (version 0) had been back-dated by the most responsible persons within your firm’s Quality and Manufacturing departments, which was confirmed by these persons during our inspection.

Action taken/proposed by the NCA :

Requested Variation of the marketing authorisation(s)
In case of non-critical products Marketing Authorization Holders should be required to remove the site from applicable Authorization by variation.

Prohibition of supply
Due to the nature of non-compliances prohibition of supply is recommended

Additional comments : The current GMP certificates N° IT/E/GMP/8/2013 issued on 19 March 2013 and IT/E/GMP/15/2013 issued on 6 November 2013 are invalid. It is proposed to withdraw also the GMP Certificate DE_BW_01_GMP_2014_0105 issued by Baden – Württemberg (Germany) on 04 August 2014. Based of the information gained during the inspection, at the moment there is no reason of concern regarding the quality of the batches of finished products for the following reasons: - only intermediates granules to be further processed by other manufacturing plants of finished products are manufactured in the inspected units; - the finished product is further tested by the batch release site before the release on the market. If no full testing (including impurities) of the finished product has been performed before the release, National Competent Authorities should consider immediate recall of the already released batches and prohibition of supply of further batches using Sri Krishna sourced granules. As an alternative National Competent Authorities should consider to request Marketing Authorisation Holders to conduct a risk assessment in order to evaluate the risk to product quality and patients from the issues identified.

Teleconference Date :

Teleconference Time (CET) :

Dial in no. :

*2014-12-23*	Name and signature of the authorised person of the Competent Authority of Italy
	*Confidential* *Italian Medicines Agency* Tel : *Confidential* Fax : *Confidential*