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)).

药厂没有建立并遵守合适的关于控制无菌药品微生物污染的书面规程，包括无菌操作的验证。

A. Your procedures did not include a requirement for smoke studies to be performed in dynamic conditions in classified critical areas. There have been no smoke studies to determine whether the “(b)(4) LAF [laminar air flow]” can provide appropriate unidirectional air during dynamic activities, such as loading of the (b)(4) into the (b)(4) restricted access barrier systems ((b)(4)RABS). The mobile LAF was not evaluated during the smoke studies under dynamic conditions. For example, the operator removes the (b)(4) tub from the mobile LAF and carries them under the “(b)(4) LAF” (which is classified as an ISO 7 area) and then into the (b)(4)RABS.

检查官认为规程没有明确规定核心区域动态条件下的气流模式测试怎么做。没有对某层流车和RABS对接以及将某盒子传递至RABS内的无菌操作进行气流模型研究。

Thorough smoke studies are essential to evaluate and qualify your aseptic processing operations and ensure appropriate implementation of needed design remediations.

严谨的气流模型测试对于评估和确认无菌操作至关重要，通过气流模型可以发现一些需要改进的无菌操作设计。

In your response, you indicate your procedures were revised to include instructions for conducting smoke studies under dynamic conditions. You state you have now performed smoke studies under dynamic conditions for the (b)(4) tub loading process including the mobile LAF and “(b)(4) LAF.” You commit to an assessment for all filling lines of parenteral drug products to evaluate execution of smoke studies in static and dynamic conditions.

药厂在回复中说已经升级了相关规程，增加了动态条件下气流模型测试的实施步骤，并声称已经对层流对接以及小盒传递的操作进行了气流模式测试。药厂承诺将对所有注射剂灌装线的静态和动态条件下的气流模式进行评估。

Your response is inadequate. You do not provide the smoke study video and report evaluating unidirectional airflow patterns under dynamic conditions for the (b)(4) tub loading process, including mobile LAF and “(b)(4) LAF.”

FDA不接受药厂的回复，因为药厂在回复中并没有提供层流对接以及小盒传递操作的气流模型测试视频和报告。

B. The qualification of the (b)(4) cycle of the (b)(4) equipped with transport ports failed to ensure adequate decontamination and worst-case locations in the (b)(4) used in manufacturing. Specifically, the (b)(4) transport port (b)(4) used to transport components to the (b)(4) was not assessed with biological indicators at the (b)(4) of the (b)(4). In addition, the investigator observed an overlap and fold in the (b)(4) of the (b)(4) near the area where the (b)(4) attaches to the (b)(4) for which the qualification failed to address if this area can be reproducibly decontaminated by (b)(4).

检察官认为某一带有传递口的设备的灭菌程序验证不充分，没有覆盖最差点。尤其是用于 部件传递的通道内没有BI的布点，并且检查官发现了设备内待灭菌的区域有出现重叠、褶皱等灭菌死角的问题。

In your response, you acknowledge the observation that chemical and biological indicators were not placed at the (b)(4) of the (b)(4) transfer port and (b)(4) for (b)(4). We note a requalification was performed on the (b)(4) cited during the inspection and a report was provided. You commit to evaluating all (b)(4) and (b)(4) for appropriate sample locations. You commit to reviewing the qualification protocols and reports for all remaining (b)(4) to ensure the (b)(4) are adequately sampled. As a result of this inspection, you conducted a retrospective review and discovered five other (b)(4) that did not have chemical and biological indicators at the (b)(4) of the (b)(4) for (b)(4)-decontamination.

药厂承认在做灭菌确认时没有在部件传递口布置化学和生物指示剂，检查官注意到药厂在接受检查期间进行了灭菌程序的再确认，并且药厂也提供了再确认的报告，药厂承诺将重新评估取样点，重新审核所有相关设备灭菌程序的方案和报告以确保取样点具有代表性。结果药厂识别出5个类似的问题点。

As acknowledged in your response, further evaluations are needed to identify and assess the potential weak spots in your (b)(4) decontamination process. Your strategy appears to emphasize use of chemical indicators. However, biological indicators are essential to any evaluation to identify and evaluate locations that may lack assurance of sufficient (b)(4) exposure.

FDA认为药厂强调化学指示剂在灭菌程序验证中的使用，而忽视了生物指示剂的重要性。

In response to this letter, provide:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:

    o All human interactions within the ISO 5 area
    o Equipment placement and ergonomics
    o Air quality in the ISO 5 area and surrounding room
    o Facility layout
    o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)

FDA要求药厂对所有关于无菌工艺、设备及设备的污染危害进行综合评估，包括但不限于：

在A/B级区的人员干预操作；

设备布置和人体力学；

A/B级区域及其背景区域的空气质量；

设施布局；

无菌操作所涉及房间的人流及物流。

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

  FDA要求药厂在完成污染风险评估后制定详细的并有时间节点的整改计划，描述针对无菌操作的设计及控制相关的具体改进措施。

总结：从部件无菌传递操作为切入点，检查气流模型测试和灭菌程序验证，评估药厂无菌保证的能力。从检查发现的问题来看，药厂对无菌操作和灭菌验证的理解是很薄弱的，重点看文中提到的几个点：

1.检查官认为规程没有明确规定核心区域动态条件下的气流模式测试怎么做。——这个可能是不少企业存在的问题，有的人起草一份规程只要个把小时，把其他企业的规程拿过来简单改一改，内容大多是空话套话，一点不切合企业自身的情况（产品剂型、生产工艺、产线设备、所要遵守的GMP法规等）。然后日常工作时基本不去看规程，员工也不熟悉规程，想怎么干怎么干。

2.没有对某层流车和RABS对接以及将某盒子传递至RABS内的无菌操作进行气流模型研究。——任何无菌操作都应该评估其对单向流的影响以及无菌风险，层流车和RABS对接以及将层流车内的物品取出转移的全过程没有做气流模型测试，实在让人对药厂人员的能力水平产生质疑。

3.FDA认为严谨的气流模型测试对于评估和确认无菌操作至关重要，通过气流模型可以发现一些需要改进的无菌操作设计。——这里面有一个逻辑关系：气流模型支撑无菌操作的动作规范，所以先有气流模型的研究测试，再有无菌操作的SOP，并且往往某一比较复杂的无菌操作会有多次的气流模型测试以确定最终无菌操作的细节要求（即最终版的SOP）。所以从审计角度来说，从气流模型测试的时间、修改次数、无菌操作SOP的版本更新这几点之间的逻辑，也能看出一些端倪。

4.FDA不接受药厂的回复，因为药厂在回复中并没有提供层流对接以及小盒传递操作的气流模型测试视频和报告。——不能理解为何药厂在回复缺陷时没有提交气流模型测试视频和报告，不需要听你说什么，需要看你做了什么，难怪FDA很生气。

5.检查官发现了设备内待灭菌的区域有出现重叠、褶皱等灭菌死角的问题。——这种细节是容易被忽略的，比如隔离器或者RABS使用过氧化氢进行灭菌时，需要严格评估这类灭菌死角问题，尤其是一些局部区域（部件）在灭菌后的使用过程中可能会出现移动从而导致暴露的问题。还有一些和产品直接接触的关键部件（比如胶塞锅等）最好可以在安装前先进行湿热灭菌，然后再随设备整体进行过氧化氢灭菌。

撰稿人 | 言语 解读FDA483和警告信

责任编辑 | 胡静

审核人 | 何发