FDA警告信：霉菌偏差调查

FDA警告信

霉菌偏差调查

美国食品药品监督管理局

2023.10.16

FDA美国食品药品监督管理局对印度太阳制药发放了一份警告信，其中就包含了霉菌偏差调查的内容。

部分原文如下

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

Your investigations into water leaks in your cleanroom were inadequate because they lacked appropriate CAPA and failed to extend to other potentially affected batches.

For example, water leaked from the service floor through the heating, ventilation, and air conditioning (HVAC) duct floor and into the ceiling directly above the ISO 5 filling area. Your investigation report noted water accumulated on the service floor due to a leak from an old, punctured(b)(4). Water then collected over the(b)(4)partition ceiling prior to entering the aseptic filling room where medroxyprogesterone acetate injectable suspension USP, was manufactured. Your personnel confirmed there was substantial water accumulation on the service floor.

Although you sealed gaps in the ceiling, you did not sufficiently inspect the service floor,(b)(4)LAF ceiling, and HVAC duct floor for mold growth and water damage after the repairs were made. You also failed to extend the scope of your investigation to potentially impacted batches of medroxyprogesterone acetate injectable suspension USP manufactured in this room since the last preventive maintenance of the(b)(4), approximately two months before the leak was observed.

In your response, you state the leak was isolated to the day it was observed. You acknowledge that your investigation did not evaluate the impact of the leak to other batches. You initiated a recall on May 17, 2022, for all marketed batches of medroxyprogesterone acetate injectable suspension USP, 150 mg/mL, 1 mL vials manufactured on this line, for events unrelated to this investigation.

Your response is inadequate. While we acknowledge you initiated actions to address this specific leak, your investigation failed to sufficiently address facility damage and the potential for microbial (i.e., particularly fungal) contamination that could persist in the facility due to water leaks and moisture. In response to this letter, provide a comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

#重点总结

01.

在该药厂注射剂车间，生产醋酸甲羟孕酮注射混悬液。在灌装间日常监测中发现霉菌。

02.

发现霉菌后开始偏差调查，发现是灌装间技术夹层漏水，正好进入了灌装间，造成了霉菌发生。

03.

该药厂采取了措施：密封了天花板上的缝隙。

但FDA认为：密封了天花板上的缝隙这种措施，远远不够。比如对技术夹层的全面检查，漏水的带来的其他房间及夹层的处理都没有做到。

04.

空调系统是否在存在霉菌的污染，没有做过调研和处理。空调系统若受到污染会成为严重隐患，而且空调系统的污染处理难度较大。

05.

FDA要求：对整个系统进行全面、独立的评估，以调查偏差、差异、投诉、OOS 结果和故障。提供详细的行动计划来修正此系统。您的行动计划应包括但不限于调查能力、范围确定、根本原因评估、CAPA 有效性、质量保证单位监督和书面程序的重大改进。说明您的公司将如何确保所有阶段的调查都得到适当进行。

对于洁净室来说霉菌是非常可怕的。

在药厂洁净室内最常见的霉菌（青霉属）。

菌丝通常无色，分生孢子呈蓝绿色

分生孢子是该菌主要的扩散方式，

但是并非所有的青霉菌都为蓝绿色，

也有白色或者绿色。

该属菌喜欢潮湿，阴凉的环境

青霉菌也是室内空气和灰尘中能分离到常见环境菌

甚至能在天花板上存活。

也较易在药品原料-乳糖中检出。

根据一项研究报道，洁净室中透明真菌总和的检出率51%。‍

霉菌在事宜的条件下，湿度和营养中，3天就可以在空调系统的回风管道中监测到。

梵通工程师可以做到

发现霉菌的溯源：利用分子生物技术，判定污染是来自技术夹层还是原料。

其他房间（包括技术夹层）霉菌监测、分型。

空调系统中污染情况的评估。

洁净区域包括技术夹层全面的消毒处理。