参考PDA- TR-22 无菌工艺验证指南的定义（2025版）
Aseptic Process Simulation(APS)无菌工艺模拟(APS)：A simulation of the entire aseptic manufacturing process in order to demonstrate the capability of the
process to assure product sterility. Includes all aseptic operations associated with routine manufacturing,e.g., equipment assembly, formulation, filling, lyophilization, and sealing processes, as necessary.模拟整个无菌生产工艺,以证明该工艺确保产品无菌的能力。包括与常规生产相关的所有无菌操作,如必要,设备组装、配制、灌装、冻干和密封过程。
基于上面的定义，我们需要能很清晰确认我们的无菌操作界面在隔离器内？C级背景区域在我们无菌操作界面外。
2、PDA- TR-22 3.33 Worst-Case Scenarios 最坏的情况
Worst-case conditions vary depending on the operations or risk being considered. For example,executing the APS using the maximum number of personnel is often considered the worst-case, aspersonnel are the greatest source of microbial contamination in an aseptic process. However, in some situations, the worst- case may include executing the process with fewer people if this results in excessive movement by the process operators, or if it complicates the process steps. Therefore, only the number of people used for the routine process should be considered for the APS for their longest duration of activities.最差条件因所考虑的操作或风险而异。例如,使用最大人员数量执行无菌工艺模拟(APS)通常被视为最差条件,因为人员是无菌工艺中微生物污染的主要来源。但在某些情况下,若人员减少导致操作员移动过多或工艺步骤复杂化,则最差条件可能包括以更少人员执行工艺。因此,无菌操作规程仅应考虑常规工艺中人员操作的最长时间段。
参考这里的要求，进行最大人数模拟应该是基于这里无菌操作涉及的人员，而不是整个区域内人员的情况，例如设置为B+A 的oRABs区域灌装的，我们仅会模拟进入B级区域的最大人数，而不会模拟C级人员的情况。同理在采用C+A隔离器灌装，这里人员是涉及到无菌操作的人员，即通过隔离手套操作的人员，因此做通过隔离手套同时操作的模式就好，不需要做C级区最大人数的挑战。
参考PDA- TR-22 无菌工艺验证指南的定义（2025版）
Aseptic Process Simulation(APS)无菌工艺模拟(APS)：A simulation of the entire aseptic manufacturing process in order to demonstrate the capability of the
process to assure product sterility. Includes all aseptic operations associated with routine manufacturing,e.g., equipment assembly, formulation, filling, lyophilization, and sealing processes, as necessary.模拟整个无菌生产工艺,以证明该工艺确保产品无菌的能力。包括与常规生产相关的所有无菌操作,如必要,设备组装、配制、灌装、冻干和密封过程。
基于上面的定义，我们需要能很清晰确认我们的无菌操作界面在隔离器内？C级背景区域在我们无菌操作界面外。
2、PDA- TR-22 3.33 Worst-Case Scenarios 最坏的情况
Worst-case conditions vary depending on the operations or risk being considered. For example,executing the APS using the maximum number of personnel is often considered the worst-case, aspersonnel are the greatest source of microbial contamination in an aseptic process. However, in some situations, the worst- case may include executing the process with fewer people if this results in excessive movement by the process operators, or if it complicates the process steps. Therefore, only the number of people used for the routine process should be considered for the APS for their longest duration of activities.最差条件因所考虑的操作或风险而异。例如,使用最大人员数量执行无菌工艺模拟(APS)通常被视为最差条件,因为人员是无菌工艺中微生物污染的主要来源。但在某些情况下,若人员减少导致操作员移动过多或工艺步骤复杂化,则最差条件可能包括以更少人员执行工艺。因此,无菌操作规程仅应考虑常规工艺中人员操作的最长时间段。
参考这里的要求，进行最大人数模拟应该是基于这里无菌操作涉及的人员，而不是整个区域内人员的情况，例如设置为B+A 的oRABs区域灌装的，我们仅会模拟进入B级区域的最大人数，而不会模拟C级人员的情况。同理在采用C+A隔离器灌装，这里人员是涉及到无菌操作的人员，即通过隔离手套操作的人员，因此做通过隔离手套同时操作的模式就好，不需要做C级区最大人数的挑战。
PDA TR 22 2025修订版中有说明
4.3.3 Isolator Technology 隔离器技术
Isolators eliminate direct access of personnel into the critical environment by defined mechanical and barrier systems and are intended to eliminate human-borne contamination within the aseptic environment where sterile products, containers, closures, and equipment are exposed. Whereas glove ports are still the most common design to reduce contamination risk during interventions, gloveless isolators eliminate risks associated with human interventions. Isolators are
decontaminated and material entry is accomplished using validated transfer systems.
隔离器通过预设的机械屏障系统,杜绝人员直接进入关键环境,旨在消除无菌环境中因人为因素导致的污染风险 -- 该环境涉及无菌产品、容器、密封件及设备的暴露操作。尽管手套端口仍是降低干预操作污染风险的主流设计,无手套隔离器则彻底消除了人为干预相关的风险。隔离器经消毒处理后,物料进出均通过经验证的转移系统完成。
Although the same principles of APS design apply for isolators, when evaluating worst-case conditions to simulate, the relative risk may vary, and this can lead to a different design. For example, because the aseptic process space is completely separated from the surrounding room and operators during filling, the maximum number of people allowed in the room where the isolator is located or the impact of activities occurring in those areas from operational shift changes are not relevant worst-case conditions. However, if multiple operators interact with the isolator simultaneously (using glove ports), it could represent a worst-case scenario related to pressure or air flow, for example.
尽管APS设计的相同原则适用于隔离器,但在评估要模拟的最坏情况条件时,相对风险可能会有所不同,这可能会导致不同的设计。例如,由于灌装过程中无菌工艺空间与周围房间和操作员完全隔离,因此隔离器所在房间允许的最大人数或这些区域发生的活动对操作换班的影响不是相关的最坏情况条件。然而,如果多个操作员同时与隔离器交互(使用手套端口),则可能代表与压力或气流相关的最坏情况。
APS（培养基模拟）层面 APS 的目标：挑战产品暴露的 A 级无菌空间的污染风险。
- 密闭隔离器：舱体与 C 级背景物理屏障，人员在 C 级产生的粒子 / 微生物不会直接进入隔离器 A 级区；房间里站多少人、走动，不纳入 APS 最差挑战。
- 开放式隔离器（open isolator，背景 C 级）：需要做气流研究证明不会发生背景空气倒灌进隔离器；但依然不强制在 APS 中挑战房间满员，风险写在 CCS 里。
- 纳入 APS的可以是：同时使用手套口干预的人数（多人同时伸手进手套操作，会带来手套、密封、压差、操作失误风险）
C 级洁净房间本身的确认层面（独立于 APS）
- C 级洁净房间本身的确认层面（独立于 APS） EU Annex1 7.2：洁净区应仅保留最少必要人员，最大人数需评估、文件化并验证，保证不损害无菌保证水平Directorat...。
- C 级房间要单独评估最大允许人数：新风量、人均面积、动态粒子 / 浮游菌，在洁净室 OQ/PQ 完成，不是 APS 试验里去挑战。
- 目的：保证 C 级房间本身动态符合 C 级限度；如果 C 级因为人太多、活动剧烈导致背景严重超标，极端情况下（隔离器破损、传递舱失效）会成为潜在污染源。
- 管理要求：SOP 限制房间最大准入人数，门禁计数；这属于洁净室日常管控，不是 APS 试验条件。
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