日本无菌生产商的警告信

Warning Letter for Japanese Sterile Manufacturer

日本无菌生产商的警告信

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. In its Warning Letter, the FDA always references the deviations to the corresponding paragraphs from the 21 CFR Part 211.

如果严重违反了GMP要求，USFDA会签发一份警告信给该公司。公司必须在15个工作日内进行反馈，提交一份CAPA给FDA。在警告信中，FDA一般会在缺陷中引用21CFR第211部分的条款。

The FDA inspected the Japanese company Sato Pharmaceutical Co. Ltd from 8 to 12 February, 2016  and the inspector (investigator) witnessed serious violations of GMP requirements. Because of insufficient answers from the company, a Warning Letter was issued.

FDA于2016年2月8-12日检查了日本的SATO制药公司，检查人员发现了严重违反GMP要求的问题。因由公司的回复不充分，FDA签发了警告信。

Deviation 1 "Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42 (c)(10)(iv))"

偏差1“贵公司未能建立足够的体系来监测无菌工艺区域的环境条件（21 CFR 211.42 (c)(10)(iv)）”。

Here, the inspector criticised the lack of routine personnel monitoring. This was the state before a successful renovation. In the draft of a new SOP on that topic too, the inspector considered that not all the aspects had been addressed. For example, there was no description of appropriate measures to be taken when personnel monitoring yields results outside of action and alert limits. Regarding the action and alert limits, the lack of a scientific rationale was also criticised.

这里，检查人员批评了公司缺乏日常的人员监测，这是改善前的情形。在一份关于此问题的新SOP草案中，检查人员认为并没有解决所有方面的问题。例如，没有说明当人员监测结果超出行动限和警戒限时要采取的适当措施的描述。关于行动限和警戒限，缺乏科学合理性也受到了批评。

Furthermore, routine surface sampling of the cleanroom environment as well as data about the air quality were inexistent. From the FDA's point of view, the monitoring frequencies and the sampling locations weren't sufficiently described.

还有日常洁净区环境表面取样以及空气质量数据不存在的问题。从FDA的角度来说，监测频次和取样点没有进行充分描述。

In the response to this Warning Letter, the FDA is expecting a reassessment and CAPA measures with regard to the monitoring programme, including:

在回复此警告信时，FDA期望对监测计划进行重新评估，并采取CAPA措施，包括：

• an assessment of the sampling locations including related action and alert limits
• 评估取样点，包括行动限和警戒限
• ensuring that all locations are sampled at appropriate frequencies, in particular with regard to the routine sampling of aseptic processing room surfaces
• 确保所有位置均以适当的频次取样，尤其是无菌工艺间表面取样
• a description of the circumstances under which investigation of adverse trends and out-of-limit results are triggered, as well as appropriate responses to such occurrences in order to promptly address contamination hazards
• 描述在何情形下，不良趋势和超出限度结果调查会被触发，以及对此类事件的恰当反应以立即解决污染危害
  

Deviation 2 "Your firm failed to establish and follow appropriate written 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))"

偏差2“贵公司未能建立和遵守适当的书面程序，以防止理应为无菌药品的微生物污染，其中包括所有无菌和灭菌工艺的验证（21 CFR 211.113 (b)）”。

The main critic here was that no smoke studies under "at rest" and "dynamic" conditions had been performed to evaluate air flow characteristics of an open RABS. In the meantime, the RABS has been renovated and a closed design established. Nevertheless, the FDA expected in the company's response an assessment of the deficits observed with regard to the quality of the products manufactured for the U.S. market on the "old" open RABS design. In the response to this Warning Letter, the FDA is also expecting a risk assessment including all the possible process failures and the sterility history (sterility testing, media fills). Furthermore, all measures taken should be described addressing the acceptability of the products manufactured on the open RABS that were distributed to the U.S. market.

这里的主要问题是一个开放式RABS没有进行静态和动态条件下进行发烟试验来评估气流特性。同时，RABS已经进行了改善，做了封闭设计。但是，FDA期望公司在回复中对检查中所发现的在“旧”的开放式RABS设计中生产的美国市场的药品质量的缺陷进行评估。在回复此警告信时，FDA还期望提交一份风险评估，包括所有可能的工艺失败，以及无菌历史（无菌检测、培养基灌装）。还有，需要描述所采取的所有措施，说明在开放式RABS中生产的已销售至美国市场的药品的可接受性。

Source: FDA Warning Letter for Sato Pharmaceutical Co. Ltd

来源：FDA警告信SATO制药公司

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