巴西抗生素生产商警告信

17.05.2017

Warning Letter for Brazilian Manufacturer of Antibiotics巴西抗生素生产商警告信

In case of serious violations of GMP requirements, the American FDA issues a Warning Letter to the company in question. The company must react to this within 15 working days and submit a corrective action plan to the FDA.

如果严重违背GMP要求，美国FDA就会签发一封警告信给有问题的公司。公司必须在15个工作日内回复此函并提交整改计划给FDA。

The FDA inspected the Brazilian Company Antibioticos Do Brasil Ltda in Sao Paulo from 18 to 27 April 2016 and the inspector witnessed serious violations of GMP requirements. Because of the company's insufficient reply to the list of deficiencies, the FDA issued a Warning Letter on 8th December 2016 focussing on three main areas. In its Warning Letters, the FDA always references the deviations to the corresponding paragraphs from the 21 CFR Part 211.

FDA于2016年4月18-27日检查了巴西公司，检查员见证其严重违背GMP要求。由于公司对缺陷清单回复不充分，FDA于2016年12月8日签发了一封警告信，主要在三个方面。在此警告信中，FDA引用了21CFR211部分里相应的段落。

1. "Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance" - 21 CFR 211.63

你公司在生产、加工、包装和保存药品过程中所使用的设备未经适当设计，不具备充分尺寸，在工厂中放置不适当于其既定用途，不适合于其清洁和维护。----21CFR211.63.

Regarding this point, the FDA criticised the lack of  unidirectional airflow in one of the ISO 5 aseptic filling zones. The airflow was considered sufficient to protect the sterile injectable product during interventions involving operator entry. Smoke studies demonstrated that the filling line design permits turbulence above and below open vials. Besides, it was observed that vials closure caused significant airflow disruptions.

关于此点，FDA批评了在一个ISO5级无菌灌装区中的单向流缺乏。在操作人员进入时，气流被认为不足以保护无菌注射剂。发烟试验证明灌装线设计使得开口安瓿瓶上面均有湍流，还发现安瓿瓶封盖导致严重的气流紊乱。

2. "Your firm failed to establish and follow appropriate procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes" - 21 CFR 211.113 (b)

你们未能建立和遵守适当的程序，这些程序应设计用以保护本应无菌的药品不受微生物污染，其中包括所有无菌和灭菌工艺的验证----21 CFR 211.113 (b)

Here, the design of smoke studies was criticised. The assertion couldn't thus be demonstrated that the unidirectional air stream was maintained for all aseptic operations. Moreover, the smoke volume was occasionally too low to demonstrate the unidirectional air stream. Additionally, the smoke was not injected in the areas affected by operator interventions.

这里，发烟试验设计受到批评。事实证明并不是在所有无菌操作中都能维持单向流。还有，发烟体积有时太低，无法证明单身气流。另外，注进烟的区域受到操作人员干涉的影响。

3. "Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas" - 21 CFR 211.42 (c)(10)

你公司未能建立充分 系统对无菌加工区域中环境条件进行监测----21 CFR 211.42 (c)(10)

Here, the insufficient documentation of environmental monitoring was criticised. By means of the records, it couldn't be demonstrated that samples had been collected from all locations designated in the SOP. Additionally, the records didn't clearly reconcile the samples taken with the results obtained. Moreover, according to the SOP only data >= 1 were recorded, 0-counts not.

这里，FDA批评了环境监测中文件记录不充分 。通过记录不能证明样品是从SOP中所指定的位置采集的。另外，记录没有清楚地将所采样品与所得到的结果平衡起来。还有，根据SOP，只有当数据>=1时才会被记录，当计数为0时则不记录。

Last but not least,  the fact that the company already received a Warning Letter in 2009 with similar deficiencies was considered particularly serious. For the FDA, this aspect shows how insufficient monitoring and control are performed by the top management.

最后一点，但也是很重要的一点，公司已经在2009年收到过警告信，其中的缺陷是类似缺陷，被认为非常严重。对于FDA来说，这种情况显示出管理层所实施的监控是不充分的。

Source: FDA Warning Letter for Antibioticos Do Brasil Ltda

来源：FDA警告信