Warning Letters in Fiscal Year 2014 - "Compounding Pharmacies" are Targets of the FDA
2014财年警告信—“药房”成为FDA的目标
The analysis of the Warning Letters of FY (Fiscal Year) 2014 has revealed an unexpected result: again, paragraph 211.113"Control of microbiological contamination" was at the top of the most observed deficiencies - the section from the Code of Federal Regulations (CFR) which was absent from the top 10 of the ranking list of the most frequent GMP deviations the year before. Although this paragraph appeared as the second and respectively the third most frequent quote in the Warning Letters of the fiscal years 2011 and 2012, a closer look at the addressees of the total 33 Warning Letters from FY 2014 shows yet that - unlike the Warning Letters of the past years - over half of them were addressed to so-called "compounding facilities" and "compounding pharmacies". "Compounders" are establishments which manufacture patient-specific preparations according to a prescription issued by a doctor. Compounders are mostly large pharmacies or establishments emerged from pharmacies and manufacture also sterile dosage forms among other things. "Compounding pharmacies" are in the focus of FDA's inspection programme since many patients have been harmed (in some cases death) because ofserious deficiencies in the sterile production of these facilities. Whereas in FY 2013 only 5 out of 42 Warning Letters (12%) were sent to "compounders", the number of Warning Letters in FY 2014 increased to 20 out of 33 (61%). 对2014财年的警告信的分析发现一个意外的结果：211.113“微生物污染控制”再一次成为排名第一的缺陷项，该项刚刚在去年从前10缺陷清单中消失。尽管该段落在2011和2012财年警告信分别排名第2和第3。对2014财年共33封缺陷信仔细分析显示—不象前几年的警告信—近半警告信是签发给所谓“药房”和“药房代工场所”。“药房”是根据医生处方生产患者专用制剂的场所。药房也生产无菌制剂。由于这些设施中的无菌生产具有严重缺陷，因而引发了多起患者伤害事件（有些案例致患者死亡），此后FDA检查计划开始关注药房。而在2013财年，共42封缺陷信中仅5专卖店（12%）是签发给“药房”的，在2014年该数据增加至33封中有20封签发给“药房”（61%）。
In these establishments, the GMP deviations are practically everywhere all the same: beside insufficient control of microbiological contamination (211.113) deficiencies in design and construction of premises were observed. This means that the requirements from 211.42 "Design and Construction Features" were disregarded. The context is simple: in premises which fulfil in no way the requirements for a modern, GMP-compliant sterile production, adequate control of contamination is difficult to realise. It is therefore hardly surprising that deficient behaviour of the staff during production (211.28 "Personnel responsibilities") appeared in almost all the Warning Letters issued to the "compounders" as severe criticism. FDA investigators also criticised nearly as often the insufficient performance of stability testing and the absence of a stability review program. 在这些工厂里，GMP偏差随处可见，且都是一样的：除了对微生物污染（211.113）控制不充分外，还发现厂房设施的设计和建造缺陷。这表示211.42“设计和建设属性”的要求被忽视了。用词很简单：设施无法满足现代化要求，很难实现无菌生产的GMP符合性，很难实现对污染的充分控制。因此，毫不意外地，员工在生产过程中其行为具有缺陷（211.28“人员职责”）这样的出现在签发给“药房”的几乎所有的警告信中作为严重批评的问题。FDA检查员还批评了稳定性试验实施不充分以及缺乏稳定性审核计划。
The hit list containing the top five GMP deviations (incl. Warning Letters to the "compounding facilities") is now as follows:
1. 211.113 "Control of microbiological contamination"
2. 211.42 "Design and construction features"
3. 211.28 "Personnel responsibilities"; 211.166 "Stability Testing"
4. 211.167 "Special testing requirements"
5. 211.165 "Testing and realease for distribution"
排序榜包括了前5位的GMP偏差（包括给药房的警告信），列出如下：
1. 211.113“微生物污染的控制”
2. 211.42“设计和建设属性”
3. 211.28“人员职责”，211.166“稳定性测试”
4. 211.167“特殊检测要求”
5. 211.165“检测和放行销售”
If one doesn't consider the Warning Letters issued to these specific US American establishments manufacturing patient-specific drugs, a completely different statistic arises (based on 13 Warning Letters only). The ranking list consists of only 4 positions (the CRF paragraphs indicated under position 4 have been respectively quoted once).
如果不考虑签发给美国本土的生产特定患者用药的设施的警告信，则统计数据显示出完全不同的趋势（仅基于13封警告信）。提名清单只包括前4位（CFR段落分别在相应的引用中给出一次）
1. 211.25 "Personnel qualifications"; 211.68 "Automatic, mechanical, and electronic equipment"; 211.100 "Written procedures, deviations"; 211.113 "Control of microbiological contamination"; 211.160: "General requirements" (Laboratory Controls); 211.192 "Production record review"
2. 211.42 "Design and construction features"; 211.84 "Testing and approval or rejection of components, drug product containers, and closures"; 211.166 "Stability Testing"
3. 211.56 "Sanitation"; 211.67 "Equipment cleaning and maintenance"; 211.94 "Drug product containers and closures";211.110 "Sampling and testing of in-process materials and drug products"; 211.125 "Labeling
issuance"; 211.180 "General requirements" (Records and Reports); 211.188 "Batch production and control records"
4. 211.22 "Responsibilities of quality control unit"; 211.28 "Personnel responsibilities"; 211.87 "Retesting of approved components, drug product containers, and closures"; 211.111 "Time limitations on production";
211.137 "Expiration dating"; 211.142 "Warehousing procedures"; 211.170 "Reserve samples"; 211.182 "Equipment cleaning and use log"; 211.194 "Laboratory records"; 211.198 "Complaint files".
1. 211.25“人员资质”，211.68“自动化、机械和电子设备”，211.100“书面程序，偏差”，211.113“微生物污染控制”，211.160“一般要求”（化验室控制），211.192“生产记录审核”
2. 211.42“设计和建设属性”，211.84“组分、药品容器和密闭器的检测和批准及拒收”，211.166“稳定性检测”
3. 211.56“消毒”，211.110“中控原料和药品的取样和检测”，211.125“标签发放”，211.180“通则要求”（记录和报告），211.188“批生产和检验记录”
4. 211.22“质量控制部门的职责”，211.28“人员职责”，211.87“已批准组分、药品容器和密闭器的复测”，211.111“生产时间限制”，211.137“有效期”，211.142“仓库管理程序”，211.170“留样”，211.182“设备清洁和使用台帐”，211.194“化验室记录”，211.198“客诉文件”
The topics "Microbiological control" and "Design and Construction Features" are still frequently quoted but they appear along with quotations to quite a number of other CFR paragraphs. Among the addressees of the Warning Letters, there are 6 manufacturers of parenteral drugs, the other ones are producers of solid and liquid dosage forms (partly also OTC). The companies are located in the following countries: USA (5), India (4), China (1), Mexico (1), Australia (1) and Germany (1).
“微生物控制”和“设计和建设属性”仍被频繁引用，但被同时引用还有很多其它的CFR段落。在警告信中，有6个注射剂生产商，另一个生产固体和液体制剂（有一部分也是OTC）。这些公司分别位于以下国家：美国（5）、印度（4）。中国（1）、墨西哥（1）、澳大利亚（1）和德国（1）。
The analysis of the Warning Letters clearly demonstrates the risk-oriented approach which the FDA uses for the inspections. According to this approach, companies running a sterile production have top priority and this particularly applies to such establishments like "compounding pharmacies" which have inadequate resources for this kind of production - with regard to well-trained personnel and premises.
对警告信的分析清楚说明FDA现在用于检查的基于风险的方法。根据该方法，进行无菌生产的公司最可能被检查，尤其适用于像“药房”这样的场所，他们没有充分的资源来进行这类生产—没有受过良好培训的人员和设施。
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