Your firm failed to 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)).

贵公司未能遵循旨在防止无菌药品发生微生物污染的适当书面规程，并且未包括对所有无菌和灭菌过程的验证（21 CFR 211.113(b)）Poor Aseptic Practices。

During the inspection of your facility, we observed poor practices and behaviors in ISO 5 areas during the manufacturing of sterile (b)(4) drug products. These poor practices included, but were not limited to:

• Operators blocked first air by placing their gloved hands directly over open sterilized bottles without clearing them from the aseptic filling line.
• 操作人员将戴手套的手直接放在打开的已灭菌瓶上，阻挡了初始气流，而未将其从无菌灌装线上移除。
• Operators used their gloved hands instead of using appropriate sterile tools to remove jammed bottles.
• 操作人员使用戴手套的手而不是使用适当的无菌工具来移除卡住的瓶子。
• Operator movements in the critical areas were not always slow and deliberate.
• 操作人员在关键区域的移动并不总是缓慢而谨慎。
• Operators used goggles that had numerous open holes and therefore had exposed skin during line set-up and aseptic processing.
• 操作人员使用了有许多开放孔的护目镜，因此在部件组装和无菌生产过程中暴露了皮肤。

In 2022, your firm identified contamination in two media fill batches one on the “(b)(4)” aseptic filling line and another on the “(b)(4)” aseptic filling line. You identified the root cause as poor aseptic behavior. These contamination events along with the poor aseptic practices observed during our inspection indicate your aseptic manufacturing operations may lack adequate control. Your firm did not perform a sufficiently comprehensive evaluation of aseptic behavior of operators as part of this recurrent trend.

We also note that open door interventions required a large door to be opened. On numerous occasions, the door remained opened for extended periods of time while the line was still in-operation. When opened, the door was exposed to the ISO 7 area, and when being closed, there was a significant risk of the lower quality room air sweeping into the ISO 5 aseptic processing area. Empty sterile containers were located extremely close to the door. In addition, operators did not adequately disinfect the open door. While spraying disinfectant on the (b)(4), operators failed to consider open sterilized bottles on the line, exposing them to potential contamination.

Inadequate Smoke Studies and Cleanroom Design

不充分的烟雾研究和洁净室设计

Your smoke studies did not adequately demonstrate unidirectional air flow in the ISO 5 classified areas used for the aseptic filling of ophthalmic drug products on the “(b)(4)” and “(b)(4)” aseptic filling lines. For example:

• Your smoke studies lacked simulation of aseptic line set-up, dynamic operations, and interventions that occur during aseptic manufacturing operations.
• 气流模型研究缺乏对无菌生产线组装、动态操作以及在无菌生产操作过程中发生的干预措施的模拟。
• Generation of smoke was not sufficient to demonstrate unidirectional air flow.
• 产生的烟雾不足以证明单向气流。

We also note that there were multiple aspects of your cleanroom and aseptic processing line design which represented fundamental contamination risks:

我们还注意到，您的洁净室和无菌生产线设计中存在多个方面的基本污染风险：

• There was no physical barrier between the operator and the open  (b)(4)-sterilized bottles on the conveyor. Your production operator remained inside the ISO 5 aseptic processing area, sitting or standing next to the conveyor line where open, exposed bottles pass.
• 操作人员与出瓶轨道上敞口的(b)(4)灭菌瓶之间没有物理隔离屏障。
    生产操作人员留在ISO 5无菌工艺区内，坐着或站在出瓶轨道旁边，有敞口的瓶子经过。
• There were extensive manual interactions with the aseptic processing line and its exposed sterile drug product and containers/closures.
• 人员与无菌生产线及其暴露的无菌药品和容器/密封件存在广泛的交叉。
• Operators performed multiple manual interventions during filling by  (b)(4) or  (b)(4) due to  (b)(4) not being installed on these  (b)(4). These interventions may pose inherent risks to your aseptic processes.
• 操作人员在灌装过程中通过(b)(4)或(b)(4)进行了多次人工干预，因为这些(b)(4)上未安装(b)(4)。这些干预可能对无菌工艺构成固有风险。

The ISO 5 area is critical because sterile product is exposed and therefore vulnerable to contamination. Your aseptic filling process should be designed, and operations executed, to prevent contamination hazards to your sterile product. The flawed design of the filling line and execution of the aseptic operations promote influx of contamination into the critical filling areas.

学习心得：

• 生产过程中，在A级区域使用无菌的消毒剂或杀孢子剂喷洒时，需要确保不会对敞口的瓶子、胶塞以及灌装未加塞的产品造成污染，这个细节比较重要。怎么评估？应通过气流模型研究，模型实际喷洒操作的位置、高度、喷嘴调节的开度。
• 定期对操作人员的无菌行为规范性进行回顾也是比较重要的，怎么做？比如在半年内（培养基模拟灌装的间隔时间）对每个灌装区的操作人员抽检三个批次（前中后三个批次）的行为（回看录像），输出培养基模拟灌装定期再验证时需要重点考察的人员名单，同时评估是否需要再培训或者资质再确认。