20170809 ECA新闻：对API工厂检查后的FDA警告信和EU不符合报告-----比较
翻译：JULIA 来源： Julia法规翻译
09.08.2017
FDA Warning Letters and EU Non-Compliance Reportsafter Inspections of API Plants - a Comparison
对API工厂检查后的FDA警告信和EU不符合报告-----比较
On the legal basis of the "Freedom of InformationAct", the FDA publishes Warning Letters on their website, where they areaccessible free of charge and without further constraints like a loginprocedure. Inspection reviews by European authorities - the "Statementsof Non-Compliance with GMP" - have been publicly available in theEudraGMP database since the beginning of 2011 (EMEA Database on GMP Inspections now publicly available(EudraGMP)). It's thus possible to identify production sites whichreceived a Warning Letter as well as anon-compliance report (NCR).
依据信息自由法案，FDA会在其官网上发布警告信，该站点没有登录要求，提供免费查阅。自2011年初，欧洲官方检查之后发布的GMP不符合声明会公开发布在EUDRAGDMP数据库中。因此，很容易知道哪些工厂收到了FDA警告信以及欧盟的不符合报告（NCR）。
In the period between October 1st, 2015 and June 30th,2017, three API manufacturers (two in China and one in India) received an FDAWarning Letter as well as a NCR issued by the authority of an EU member state.The following comparison of the documents reveals interesting details.
在2015年10月1日至2017年6月30日期间，有3个API生产商（2个中国1个印度）收到FDA警告信和EU成员国签发的NCR。以下是对警告信和NCR做的对比，发现了一些有意思的细节。
1. Dongying Tiandong Pharmaceutical Co., Ltd.,Dongying City, China 东营天东制药
Inspection by GMP inspectors of the EU on December 9th, 2015, Publication of the NCR on February 25th, 2016; issuing authority: French National Agency for Medicines and Health products Safety
EU检查员在2015年12月9日进行了检查，2016年2月25日签发了NCR，签发方：法国药监
Inspection by FDA inspectors on October 12th-16th, 2016; Date of the WL: November 10th, 2016
FDA于2016年10月12-16日进行了检查，警告信签发日期2016年11月10日
Results of the EU inspection 欧盟检查结果
10 deviations, amongst which 3 are rated "critical" and 2 are rated "major".
- critical: PCR analyses of the crude heparin provided by an approved supplier confirmed the presence of foreign DNA (DNA of ruminants). The analysis results had been manipulated.
The crude heparin's journey from its supplier to the site of its processing cannot be reproduced. Relevant documents do not exist; the quality assurance shows considerable gaps.
- major: Non-GMP-compliant handling of deviations and OOS results; inappropriate qualification of new suppliers of crude heparin; insufficient assessment of NMR spektra (identity verification), an additional peak which points to a contamination is ignored.
Official measures/recommendations:
- Withdrawal of the GMP certificate
- Suggested removal of the manufacturer from the dossier of medicinal products approved in the EU (variation process)
- Recommended product recall, in consideration of the national supply situation
- Withdrawal of the CEP for enoxaparin sodium共10个缺陷，其中3个为关键，2个为主要。关键缺陷为：批准的供应商提供的粗品肝素PCR分析确认有外源DNA出现。分析结果被篡改。粗品肝素从供应商到加工工厂的运输途径不能重复。相关文件不存在，质量保证显示出重大差距。主要缺陷为：偏差和OOS结果处理不合规，粗品肝素的新供应商确认不恰当，NMR谱评估不充分（结构确证），多出一个显示污染物的峰被忽略了。
官方措施/建议：撤销其GMP证书，建议从EU批准的药品注册文件中删除该生产商，建议考虑国家供应情况的前提下召回产品，撤销依诺肝素钠的CEP。
Results of the FDA inspection FDA检查结果
Non-GMP-compliant handling of OOS results (PCR) in the analysis of crude heparin; no CAPA; PCR analysis in regards to foreign DNA (ruminants) not validated; insufficient evaluation/qualification of suppliers of crude heparin.
Official measures/recommendations:
- Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.粗品肝素分析中OOS结果处理不合规（PCR），没有CAPA，外源DNA的PCR分析未经过验证，粗品肝素供应商的评估/确认不充分。
官方措施/建议：GMP缺陷纠正之前暂停批准将该生产商列为供应商的上市许可申报。
The FDA inspectors encountered the same GMPdeficiencies as the EU GMP inspectors did 9 months ago. During that time, theChinese manufacturer apparently did nothing to correct those deficiencies.
FDA检查人员遇到了EU GMP检查员9个月之前遇到的相同的GMP缺陷。在那段时间内，中国生产商显然没有做任何努力来纠正这些缺陷。
2. Polydrug Laboratories PVT. Ltd., Ambernath (East),India 印度POLYDRUG
Inspection by GMP inspectors of the EU on February 24th, 2016, Publication of the NCR on November 11th, 2016; issuing authority: Agency for Medicinal Products and Medical Devices of Croatia
EU检查员在2016年2月24日进行了检查，2016年11月11日签发了NCR，签发方：克罗地亚
Inspection by FDA inspectors on March 16th-23rd, 2015; Date of the WL: April 14th, 2016
FDA于2015年3月16-23日进行了检查，警告信签发日期2016年4月14日
Result of the EU inspection EU检查结果
22 deviations, amongst which 4 are rated "major".
- major: deficiencies in quality management relating to the repacking of batches and their storage;inadequate validation of computerized systems; CAPA to remedy deficiencies found in earlier inspections had not been applied.
- other: reduced testing is not GMP compliant; manual integration of HPLC analyses; insufficient cleaning validation.
Official measures/recommendations:
- Suggested removal of the manufacturer from the dossier of medicinal products approved in the EU (variation process)
- Stop deliveries of API batches by the manufacturer
- Withdrawal of the CEP for 5 APIs22个缺陷，其中4个为主要缺陷。主要缺陷为与批包装和存贮有关的质量管理，计算机化系统验证不充分，之前检查发现的缺陷弥补CAPA未实施。其它缺陷为减少测试不符合GMP，HPLC手动积分，清洁验证不充分。
官方措施/建议：建议从EU批准的药品批文中删除该生产商，生产商停止发售API批次，撤销5个API的CEP。
Results from the FDA inspection FDA检查结果
Non-GMP-compliant handling of customer complaints relating to product quality; no reviews for deviations and no investigations; no access control to raw data; no adequate quality control procedures.
Official measures/recommendations:
- Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.
- Import alert与产品质量有关的客户投诉处理不符合GMP，对偏差没有审核没有调查，对原数据没有权限控制，质量控制程序不充分。
官方措施/建议：GMP缺陷纠正之前暂停批准将该生产商列为供应商的上市许可申报。进口禁令。
The EU GMP inspection was conducted almost a yearafter the inspection by the FDA. During that time, either some of the GMPdeficiencies had been corrected or the focus of the EU inspectors had been ondifferent areas. At the time of the EU inspection, the FDA Warning Letterhadn't been published yet, at least.
EU GMP检查是在FDA检查之后约1年发生的。在此期间，可能有些GMP缺陷改正了，也可能EU检查员的关注点有所不同。在EU检查期间，至少FDA警告信还没有发布。
3. Jinan Jinda Pharmaceutical Chemistry Co., Ltd.,Zhangqiu City, China 济南金达
Inspection by GMP inspectors of the EU on June 1st, 2016, Publication of the NCR on July 29th, 2016; issuing authority: Spanish Agency of Medicines and Medical Devices
EU检查员在2016年6月1日进行了检查，2016年7月29日签发了NCR，签发方：西班牙
Inspection by FDA inspectors on May 30th- June 1st, 2016; Date of the WL: February 24th, 2017
FDA于2016年5月30日至6月1日进行了检查，警告信签发日期2017年2月24日
Results of the EU inspection EU检查结果
30 deviations, amongst which 2 are rated "critical" and 8 are rated "major".
- critical: GMP violations in the area monitoring of raw data and the review/handling of OOS results
- major: GMP violations in the areas training, change control, quality assessment, process validation, cleaning validation.
Official measures/recommendations:
- Delivery stop
- Withdrawal of one CEP共30个缺陷，其中2个缺陷为关键，8个为主要。关键缺陷有：原数据监管违规，OOS结果审核/处理。主要缺陷有：培训、变更控制、质量评估、工艺验证、清洁验证方面违规。
官方措施/建议：停止发货，撤销一份CEP。
Results of the FDA inspection FDA检查结果
Non-GMP-compliant handling of OOS results, no investigation, no access control to raw data.
Official measures/recommendations:
- Approval for marketing authorisation applications listing the manufacturer as a supplier will be withheld until the GMP deficiencies are corrected.
- Import alertOOS结果处理违规，没有调查，原数据权限没有控制。
官方措施/建议：GMP缺陷纠正之前暂停批准将该生产商列为供应商的上市许可申报。进口禁令。
The FDA and GMP inspections were conducted directlyone after the other. Accordingly, the found GMP deficiencies are similar.
FDA和EU GMP检查一个紧跟着一个，所发现的GMP缺陷也就相应地类似。
A comparison of the inspection reviews shows that theinspected sites share the same GMP deficiencies in some instances. Sadly, amore thorough comparison with the elaborate Warning Letters is hardly possiblebecause of the brief descriptions - often made in keywords - in thenon-compliance reports.
对检查结果的比较显示这些受检工厂在某些方面有着相同的GMP缺陷。不幸的是，没法将两者进行更为深刻的比较，因为欧盟的NCR通常都只有关键字眼，不够详细。