2014财年FDA所有警告信的全面分析

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                                2014财年FDA所有警告信的全面分析
2014财政年的警告信的分析揭示了以下出乎意料的结果：211.113段“微生物污染的控制”再一次成为最多的缺陷__CFR的这部分内容不在去年的最常见GMP缺陷的前十位。尽管在2011和2012年，这段内容分别位列警告信最常引用内容的第二和第三，在仔细看一下这33封警告信的内容发现—不像以往警告信__它们中的一半内容是关于所谓的“配药工厂”和“配药药房”。配药机构是根据医生给出的处方而生产专门用于病人的制剂的机构。自从由于这些厂家生产的无菌产品的严重缺陷导致很多病人伤害（有些死亡）后，FDA的检查项目开始重点关注配药药房。而在2013，42封警告信中只有5封（12%）是关于配药机构的，2014，增长至33封中有20封（61%）。
在这些机构，GMP缺陷实际上在各地都一样：包括关于厂房设计和建造方面的微生物污染的控制缺陷。这意味着忽略了211.42“设计和建造的特点”被忽略了。内容很简单：厂房无法满足现代的、符合GMP要求的无菌生产的要求，污染的有限控制很难实现。因此也无需惊讶，几乎在发给所有配药机构的警告信中，生产过程中人员的有缺陷的行为被作为严重缺陷。FDA检查官也几乎同样频次的批评了稳定性测试的不足和稳定性回顾方案的缺失。
下面的清单包含了前五名的GMP缺陷（包括发给配药工厂的警告信）：
1.        211.113“微生物污染的控制”
2.        211.42“设计和建造的特点”
3.        211.28“人员职责”；211.166“稳定性测试”
4.        211.167“特别的测试要求”
5.        211.165“测试和放行”
如果不考虑发给生产病人专用药物的特别的美国机构的警告信，会得到完全不同的数据结果（基于仅有的13封警告信）。排名表里面仅有四个位置（排在第四位的CFR的段落各被引用一次）。
1.        211.25“人员确认”；211.68“自动的、机械的和电动的设备”；211.100“写好的程序，偏差”；211.113“微生物污染的控制”；211.160“一般要求（实验室控制）”；211.192“生产记录审核”
2.        211.42“设计和建造特点”；211.81“组分、药品内包材容器和盖子的测试、批准或拒绝”；211.166“稳定性测试”
3.        211.56“卫生”；211.67“设备清洁和维护”；211.94“药品内包装容器和盖子”；211.110“中间材料和药品的取样和测试”；211.125“标签的发放”；211.180“一般要求（记录和报告）”；211.188“批生产和控制记录”
4.        211.22“质量控制部门的职责”；211.28“人员职责”；211.87“批准的组分、药品的内包装容器和盖子的复测”；211.111“生产的时限”；211.137“有效期”；211.142“仓储程序”；211.170“留样”；211.182“设备清洁和使用日志”；211.194“实验室记录”；211.198“投诉资料”
“微生物控制”和“设计和建造的特点”仍然经常被引用。在这些警告信中，有6个注射药物生产厂家，其他的都是固体或者液体制剂（部分也是OTC）。这些公司坐落在以下国家：USA（5），印度（4），中国（1），墨西哥（1），澳大利亚（1）和德国（1）。
通过对警告信的分析可以明显的看出FDA的检查采用了基于风险的方法。根据这个方法，进行无菌生产的公司最优先被检查，特别像配药药房这样的机构，它们缺少适合此类生产的足够的资源—经过良好培训的人员和厂房设施。

Warning Letters in Fiscal Year 2014 - "Compounding Pharmacies" are Targets of the FDA
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 of serious 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%).
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.
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"
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).
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".
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).
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.


文章来源：http://www.gmp-compliance.org/en ... ets-of-the-FDA.html

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质管-小伟 发表于 2015-2-5 23:16
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