ECA新闻：过去21个月API警告信----事实与趋势分析

翻译：JULIA  来源： Julia法规翻译

26.07.2017

The API warning letters of the last 21 months -facts and trends

过去21个月API警告信----事实与趋势分析

The number of warning letters addressed to API (ActivePharmaceutical Ingredient) manufacturers has increased considerably over thepast three years. 22 were issued in 2016; that is more than twice as much as inthe year before, when 10 manufacturers of active substances received theunpopular FDA letter.

在过去3年中，对原料药生产商签发的警告信数量大幅增加。在2016年签发了22封，这是前一年度数量的2倍还要多，而其中有10家原料药生产商收到此令人沮丧的FDA信函。

While the warning letters for pharmaceuticalmanufacturers are based on chapters of the "Code of Federal Regulations, 21 CFR, Part211", the citations in APIwarning letters refer to regulations in the chapters of guideline ICH Q7. Onthe contrary to the 21 CFR 211 chapters in pharmaceutical warning letters,those are not specified explicitly; however, the wording of main deficiencies(usually in bold print) in API warning letters literally reflects thecorresponding passages of guideline ICH Q7 most of the time, so that a clear allocation ispossible in most cases. This also facilitates a simple statistical assessmentin regards to frequency distribution of deficiencies and the trends over aspecific period of time.

给药品生产商的警告信是基于联邦法典21CFR第211部分的，在API警告信中的引用则是来自ICH Q7指南。与21CFR211章节相反，在药品警告信中，这些写的并不是很清楚，但原料药警告信中主要缺陷的用词（通常是黑体显示）大多数时候反映的就是ICH Q7指南的对应段落。因此，在大多数案例中可以清楚锁定对应条款。这也有助于对频繁出现缺陷进行频次分布统计评估，并对指定时间段内的趋势进行分析。

Hereafter, some facts about the warning letters issuedto API manufacturers during the period of fiscal year 2016 (Oct. 15-Sept. 16)and the nine months of fiscal year 2017 (Oct. 16-Jun. 17) are listed.

下面列出了2016财年（10月15日至9月16日）以及2017财年9个月（10月16日至7月17日）签发给原料药生产商的警告信的一些情况。

Inspected Sites 受检地区

The share of production sites located in India orChina which received a warning letter is high in both considered periods.

印度和中国生产场所拿到的警告信在所统计时间段时占了很高比例。

The numbers for the previous fiscal years are similar; this is a stable trendwhich will probably continue in the future.

之前财年的数字也是类似的，未来此趋势可能也会保持稳定。

It's interesting to take a look at the findingsdescribed in the warning letters of both periods.

看一下在两个时间段内的警告信中所述缺陷也是很意思的。

Frequencydistribution of quotes所引用的缺陷条款分布频次

Frontrunners in FY 2016 are deficiencies whichrefer to chapter 5 Process Equipment, subsection 5.4ComputerizedSystems, paragraph 5.43 of guideline ICH Q7. This paragraph states:

在2016财年缺陷中领跑者是ICH Q7的第5章，工艺设备第5.4节计算机化系统，第5.43段。此段要求如下：

"Computerized systems should have sufficientcontrols to prevent unauthorized access or changes to data. There should becontrols to prevent omissions in data (e.g. system turned off and data not captured).There should be a record of any data change made, the previous entry, who madethe change, and when the change was made."

计算机化系统应具备足够的控制以防止未经授权进入或修改数据。应有控制防止数据遗漏（例如，系统关闭时未捕获到数据）。应记录所有对数据所做的修改，记录之前录入的内容、由何人做的修改以及何时做的修改。

In total, there are 12 citations in the warningletter which refer to the unregulated access to raw electronic data.Most cases describe fraud and data manipulation, e.g. deleting of"bad" analyses (HPLC) after choosing the ones with specificationcompliant results, manipulation of metadata in audit trail, changing the dateof analyses etc. These deficiencies are described in warning letters issued to6 Indian, 5 Chinese and one German manufacturer.

警告信中总计有12次引用了“未经授权进入原始电子数据”。大部分案例描述了数据造假，例如，在选择了一个合格结果之后删除“不好的”分析（HPLC）、捏造审计追踪中元数据、修改分析日期等。这些缺陷出现在6家印度生产商、5家中国生产商和1家德国生产商警告信中中。

The second most frequent GMP violations the inspectorsfound were in quality management, relating to the ICH Q7 chapter 2 QualityManagement. Particularly common with 6 citations were violations of the requirementfor prompt recording of quality relevant activities as stated in paragraph2.15:

排在第二位的是质量管理，与ICH Q7第2章质量管理有关。尤其多的是对“质量相关活动进行及时记录的要求”违规情况有6次，该段落内容如下：

"All quality related activities should berecorded at the time they are performed."

所有与质量有关的活动应在执行时即行记录。

Here, the FDA inspectors observed incompletelyfilled-in batch protocols as well as the frequently practiced later transfer ofmeasured values from memos to the official protocol (partly even "frommemory", i.e. without memo). The corresponding warning letters wereaddressed to 4 sites in China and 2 in India.

这里，FDA检查人员发现填写不完整的批记录，以及频繁地在操作完成之后将所测得值从备忘本中写入正式方案中（有一部分甚至是“凭借记忆”，也就是说没有备忘单）。这一条在中国生产商警告信中出现4次，印度生产商中出现2次。

The frequency distribution in FY 2017 looks alittle different. With 11 citations referring to GMP violations of chapter 5Process Equipment in total, the number of findings in this area is stillrelatively high. The number of citations directly referring to unauthoriseddata access as per subsection 5.4 Computerized Systems, paragraph 5.43however has significantly decreased with only 5 citations (warning lettersissued to 2 Indian, 2 Chinese and one Japanese manufacturer). 5 more citationsrefer to regulations concerning an entirely different issue: cleaning andmaintenance. Subsection 5.2 Euipment Maintenance and Cleaning, paragraph5.21 states:

2017年财年的缺陷分布看起来有点不太一样。总计有11次引用了第5章工艺设备的GMP违规，在此领域来说是相对比较高的。所引用的条款直接指向第5.4节计算机化系统第5.43段“未经授权的数据进入”，但数量已明显下降至5次（2家印度，2家中国，1家日本生产商）。还有5个缺陷引用的是5.2节“设备维护和清洁”中5.21条款，其中要求如下：

"Written procedures should be established forcleaning of equipment and its subsequent release for use in the manufacture ofintermediates and APIs. Cleaning procedures should contain sufficient detailsto enable operators to clean each type of equipment in a reproducible andeffective manner. ..."

应为原料药和中间体生产所用设备建立清洁和清洁后放行使用程序。清洁程序应包括有足够的详细内容使得操作人员可以能重复的有效方式对每类设备进行清洁……

Warning letters that listed deficiencies in this areawere issued to 3 companies in India, one in the USA and one in Spain. Thewarning letter issued to the Spanish manufacturer also described a GMPviolation in relation to unsuitable Production equipment with reference tosubsection 5.1 Design and Construction, paragraph 5.11 ("Equipmentshould be constructed so that surfaces that contact raw materials,intermediates, or APIs do not alter the quality of the intermediates and APIsbeyond the official or other established specifications").

有该类缺陷的警告信是签发给3家印度、1家美国以及1 家西班牙生产商的。签发给西班牙生产商的警告信还描述了与生产设备不适当有关的GMP违规情况，引用的是5.1“设计和构造”第5.11段（设备构造应使其与原料、中间体和原料药接触的表面不会改变中间体和原料药的质量，使其超出官方或其它既定标准之外）。

The actual peak in frequency distribution of findingsin FY 2017 are citations related to chapter 2 Quality Management. Overall, the warning letters described 12 GMP violations of the principlesof quality assurance and relating to the areas of responsibility in QualityUnits (subsection 2.1 Principles, 2.2 Responsibilities of theQuality Unit(s) and 2.3 Responsibilities for Production Activities);twice as much as in FY 2016. Scenarios vary from complete lack of a QualityUnit (e.g.: "Your firm has no Quality Unit. ... Your salespeople signedyour CoA under the title "QC Director". Without performing tests,your salespeople also signed under "Tested By"") to the lack offundamental GMP documents (e.g.: "Your firm had no written procedures forsupplier qualification, relabeling and repackaging operations, sampling,production release, stability, and document retention. ...").

2017财年的缺陷中真正最频繁的缺陷是与第2章“质量管理”有关。总体来说，警告信描述了12个GMP违规情况是违反“质量保证原则和质量部门职责相关”（2.1原则，2.2质量部门职责和2.3生产活动职责），是2016财年的2倍。具体情形从完全没有质量部门（例如，你公司没有质量部门……你们的销售人员在COA中“QC主管”下签名。在没有实施检测的情况下，你们销售部门人员还在“检测人”下面签名）到缺乏基本的GMP文件（例如，你公司没有书面的供应商确认、重新标签和重新包装操作、取样、生产放行、稳定性和文件保存程序……）。

12 more GMP deficiencies were found in the area quality control andlaboratory. The incomplete or not at all conducted investigation intothe reasons for OOS results especially caused the FDA inspectors reprimandsin the warning letters. Recipients of the warning letters with GMP violationsin the areas quality management and lab controls were - apart from a USAmerican company - exclusively API manufacturers from India and China.

还有12个GMP缺陷是关于QC和化验室的。尤其引起FDA检查人员申斥的是对OOS结果的原因所进行的调查不完整，或完全没有进行调查。在质量管理和化验室控制这方面GMP违规的警告信接收者---除了1家美国公司外-----无一例外都是印度和中国的API生产商。

Taking a look at the complaints phrased in the warningletters shows a slight trend away from the GMP violation "non-existentregulation of access to electronical data and its manipulation" andtowards "inadequately performed responsibility of Quality Unit andmistakes in the quality control laboratory". Still, the violation ofdata integrity will very likely remain a problem for the time being, especiallyat Far Eastern production sites. An analysis of warning letters when FY 2017 isover at the end of the year will show whether this prognosis proves to be true.

看看警告信里的这些幽怨的用词，“对电子数据及其修改权限没有制订制度”到“质量部门未尽到其职责以及QC化验室的错误”，显示出有点偏出GMP违规的趋势了。而数据完整性违规情况貌似仍是目前最大的问题，对于远东生产场所来说尤其如此。让我们拭目以待2017财年结束时的警告信分析，看看是否会不幸言中。