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 Information Act", 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 the EudraGMP 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