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[其他] 近期2家中国公司欧盟GMP检查失败

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静悄悄 发表于 2014-11-19 22:56:07 | 只看该作者回帖奖励

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近期2家中国公司欧盟GMP检查失败

2014-11-19 20:07:10| 分类： EU GMP

信息来自：http://eudragmdp.ema.europa.eu/inspections/gmpc/index.do

http://zhuyujiao1972.blog.163.com/blog/static/98694727201410195566845/

近期2家中国公司欧盟GMP检查失败

受检公司名称：TAISHAN CITY CHEMICAL PHARMACEUTICAL CO. LTD.

检查日期：2014-09-18

检查单位：French Health Products Safety Agency（法国药监）

产品：原料药CICLOSPORIN （环孢素）

不符合项：总共发现24个缺陷，包括6个主要缺陷，

【1】质量管理体系缺陷（工艺验证数据审核、文件记录、产品质量审核），

【2】QC原始电子数据安全性不充分（没有权限限制、没有数据删除限制、没有审计追踪、追溯和存档），

【3】QC部门不能适当执行和管理HPLC检测（例如，没有关于分析程序偏差的文件记录和论述、没有发现检测错误，

【4】环孢素生产区域发现多项污染风险（例如，对清洁设备出口没有保护、“可用于生产”状态的设备在脏的情况下存贮数月、最终步骤开放部分暴露在肮脏环境下），

【5】环孢素批尾料混合没有足够的可追溯性，验证的样品不具有代表性和可追溯性，

【6】设备和区域确认不当（例如，发酵仓库、环孢素菌种中心和环孢素菌冷藏中心的自动温控仪没有确认）。

NCA措施：FIMEA之前签发了NSC NO.2723/12.01.01/2012不符合禁令，由于检查中发现的缺陷，禁令将持续有效。CEP由EDQM在2012年搁置，现在EDQM决定自2014年10月1日起撤销其CEP证书。

附加注释：本检查根据EDQM检查计划进行（EDQM索引号INSP 2008-025 P03）

受检公司名称： Fujian South Pharmaceutical

检查日期：2014-09-06

检查单位：Italian Medicines Agency（意大利药监）

产品：原料药DOCETAXEL ANHYDROUS （无水紫杉萜）

不符合项：总共发现27个缺陷，其中2个对患者有风险，因此被作为关键缺陷，与QC系统和合理的计算机化系统有关，包括数据完整性问题。另外，在厂房和设施、文件记录和化验室控制方面发现3个主要缺陷。以下为关键缺陷和主要缺陷是总结：

【关键1】检查团试图在对文件评审过程中确认一些法规信息，结果发现基本GMP和法规要求，例如数据完整缺失，结合数据管理不充分、变更控制系统、供应商确认、化验室以及提交数据的准确性，由于QA体系和法规部门的不力而未能充分实施/考虑，

【关键2】严重违反GMP，未能在QC设施内实施合理的计算机化系统，可能会导致/可能已导致伪造数据。无法确认批准原料和最终API的决定是否基于有效和准确的数据，

【主要缺陷1】在车间B-03，用于进行初次精制的房间被发现不适合于其用途，具有潜在污染风险，

【主要缺陷2】发现QA未能充分控制/保证与质量相关的文件记录发放，

【主要缺陷3】公司的无水紫杉萜生产工艺C要求对单批进行混合。由于设备产能不够，需要在混合前将一个单批分为两个批次。在最终精制步骤中进行的生产操作为四次结晶，然后干燥。在混合前单批没有检测，这种方式可能会导致单批中OOS结果被掩盖。剩下的22个缺陷也是与质量管理、建筑和设施、工艺设备、文件和记录、QC、验证、拒收和重复使用物料有关的其它问题。

NCA措施：禁止供应、EDQM搁置其CEP 2011-320 （无水紫杉萜）

其它：该检查根据EDQM检查计划进行（EDQM检查程序编号INSP2014-001 P01）。根据检查中收集到信息，截止目前为止只有样品被发给EU/US客户，公司产品的主要市场是中国。没有关于是否在EU有MAA合同生产的信息。

French Health Products Safety Agency

Report No : 14MPP078

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 :
4 { X* ]3 K! uArt. 111(7) of Directive 2001/83/EC as amended

The competent authority of France confirms the following:

The manufacturer : TAISHAN CITY CHEMICAL PHARMACEUTICAL CO. LTD.

Site address :

98 Longzhou Road, Taicheng Town, Taishan City, Guangdong Province, 529200, China

From the knowledge gained during inspection of this manufacturer, the latest of which was conducted on 2014-09-18 , it is considered that it does not comply with the Good Manufacturing Practice requirements referred to in

· The principles of GMP for active substances referred to in Article 47 of Directive 2001/83/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

1 NON-COMPLIANT MANUFACTURING OPERATIONS

1.2 Non-sterile products

1.2.1 Non-sterile products (processing operations for the following dosage forms) ; B% }5 p7 Q9 n0 @
1.2.1.17 Other: active substance(en)

Manufacture of active substance. Names of substances subject to non-compliant :

CICLOSPORIN ( en )

3. NON-COMPLIANT MANUFACTURING OPERATIONS - ACTIVE SUBSTANCES

U7 V9 K4 F8 w4 t- q" u
Active Substance : CICLOSPORIN

3.3

Manufacturing of Active Substance using Biological Processes

3.3.1 Fermentation

3.3.3 Isolation / Purification

3.5

General Finishing Steps

3.5.1 Physical processing steps :

sieving

3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)

3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)

3.6

Quality Control Testing

3.6.1 Physical / Chemical testing

Part 3

Nature of non-compliance : Overall 24 deficiencies were observed, including 6 major deficiencies related to: [Major 1] Numerous weaknesses in the quality management system (review of process validation data, documentation, product quality review); [Major 2] Insufficient securisation of the electronic raw data in the Quality Control laboratory (No limitation of access levels, no restriction on the deleting of data, no audit trail, inadequate traceability and archiving practises); [Major 3] Inability of the Quality Control unit to conduct and manage HPLC tests appropriately (e.g. no documentation and justification of deviations from analytical procedures, no detection of analysts errors); [Major 4] Multiple risks of contamination identified in the production areas of Ciclosporin (e.g. no protection of clean equipment outlets, equipment under status “to be used for production” stored dirty for several months, open parts of the final steps exposed in dirty surroundings); [Major 5] Blending of Ciclosporin batch tails without adequate traceability and validation combined with unsuitable sample representativity and traceability; [Major 6] Inappropriate equipment and area qualification (e.g. no qualification for the automatic temperature controllers at the fermentation warehouse, the strain centre for Ciclosporin and the cool storage area for Ciclosporin).

Action taken/proposed by the NCA :

Prohibition of supply
: T7 x' A, J0 r* v; ENCS No. 2723/12.01.01/2012 was previously issued by the FIMEA. Due to the nature of the findings, prohibition of supply from this site should be continued.

Suspension or voiding of CEP (action to be taken by EDQM) 5 R+ b2 ]& I/ v c7 h# v& A
The company had one CEP (Ciclosporin CEP 2006-223) which was suspended in 2012. The EDQM has decided to withdraw this CEP on 01 October 2014.

Additional comments : This inspection was performed in the frame of the EDQM programme (EDQM Reference: INSP 2008-025 P03).

Teleconference Date :

Teleconference Time (CET) :

Dial in no. :

*2014-11-05*	Name and signature of the authorised person of the Competent Authority of France
	*Confidential* % o/ Y8 F8 Q& \|2 ?" U x* v# P' U *French Health Products Safety Agency* % u! L( i- \|) i Tel : *Confidential* ( Y" T0 q. V0 A Fax : *Confidential*

Italian Medicines Agency

Report No : IT/NCR/API/3/2014

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 : 2 z( T# e: F& d) s( X, D
Art. 111(7) of Directive 2001/83/EC as amended

The competent authority of Italy confirms the following:

The manufacturer : Fujian South Pharmaceutical

Site address :

No. 98 Dongxin Road. Xuefeng Town. Mingxi, Fujian, 365200, China

From the knowledge gained during inspection of this manufacturer, the latest of which was conducted on 2014-09-06 , it is considered that it does not comply with the Good Manufacturing Practice requirements referred to in

· The principles of GMP for active substances referred to in Article 47 of Directive 2001/83/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

1 NON-COMPLIANT MANUFACTURING OPERATIONS

1.4 Other products or manufacturing activity

1.4.1 Manufacture of ( V9 G Q9 q+ P1 X, L: i
1.4.1.4 Other: Active Substances(en)

Manufacture of active substance. Names of substances subject to non-compliant :

[ 1417 ] DOCETAXEL ANIDRO ( it ) / DOCETAXEL ANHYDROUS ( en )

3. NON-COMPLIANT MANUFACTURING OPERATIONS - ACTIVE SUBSTANCES

2 _& @& ?$ p3 K8 F; v
Active Substance : DOCETAXEL ANHYDROUS

3.2

Extraction of Active Substance from Natural Sources

3.2.5 Modification of extracted substance Plant

3.2.6 Purification of extracted substance Plant

3.5

General Finishing Steps

3.5.1 Physical processing steps :

drying, milling

3.5.2 Primary Packaging (enclosing / sealing the active substance within a packaging material which is in direct contact with the substance)

3.5.3 Secondary Packaging (placing the sealed primary package within an outer packaging material or container. This also includes any labelling of the material which could be used for identification or traceability (lot numbering) of the active substance)

3.6

Quality Control Testing

3.6.1 Physical / Chemical testing

3.6.2 Microbiological testing excluding sterility testing

Part 3

Nature of non-compliance : In total 27 deficiencies were found by the inspection team, whose opinion is that two of them constitute a risk to the patient and were hence categorised as critical and related to the Quality Control System and to the implementation of sound computerised systems, including data integrity issues. Furthermore three major deficiencies were observed in the field of building and facilities, documentation and laboratory controls. Here below a brief summary of the Critical and Major deviations: [Critical] The inspection team tried to verify some regulatory information requested during the assessment of the dossier and reached the conclusion that fundamental GMP and regulatory requirements such as loss of data integrity, combined with insufficient management of data, change control system, supplier qualification, laboratory controls as well as the accuracy of data submitted, were not adequately implemented/considered because of a weakness of the QA system and regulatory affairs department; [Critical] Severe GMP violations related to the implementation of sound computerised systems in the quality control facilities were committed, that could lead/could have led to the falsification of data. It was impossible to verify that the decision to approve raw material and final API was based on valid and accurate data; [Major] In workshop B-03 the room used to perform the first purification of Docetaxel anhydrous by liquid chromatography was found not suitable for its intended use, as there was a potential risk of contamination; [Major] The issuance of quality related documentation was found inadequately controlled/secured by QA; [Major] The Company’s manufacturing process C for Docetaxel anhydrous requires the blending of individual batches. The insufficient equipment capacity requires the material previously obtained to be split into two single batches. The manufacturing operations to be conducted in the final purification step are four crystallisations followed by drying. No testing of the individual batches was required prior to the blending operation. This approach could lead to masking of Out-of-Specification results in the individual batches. The remaining 22 deficiencies identified some additional issues in the field of Quality Management, Buildings and Facilities, Process Equipment, Documentation and Records, Laboratory Controls, Validation, Rejection and Re-use of Materials.

Action taken/proposed by the NCA :

Prohibition of supply
- c0 J; O7 ]. u7 s2 H1 bDue to the nature of non-compliances, prohibition of supply is recommended.

Suspension or voiding of CEP (action to be taken by EDQM) R- x9 y2 D8 d3 k. P2 z
The EDQM Ad Hoc Committee decided to suspend the certificate of suitability CEP 2011-320 (Docetaxel anhydrous).

Additional comments : This inspection was performed in the framework of the EDQM inspection programme (EDQM inspection procedure number: INSP 2014-001 P01). According to the information gathered during the inspection, so far only samples have been supplied to EU/US customers; the main market for the Company’s products is China. No information was obtained as to whether contract manufacture for MAA in EU was concerned.

Teleconference Date :

Teleconference Time (CET) :

Dial in no. :

*2014-10-29*	Name and signature of the authorised person of the Competent Authority of Italy
	*Confidential* 0 {* Q; P4 r0 I0 p7 U+ D* V7 f *Italian Medicines Agency* 7 l9 p" S) ]) d7 ]$ p6 k Tel : *Confidential* 9 N9 m1 F& X6 f& B1 e Fax : *Confidential*