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这个发现项是2021年，FDA对于礼来美国印第安纳无菌生产工厂的483中其中一个子项。（这份483的回复最终是获得了FDA的认可，其最终结果是VAI 即Voluntary Action Indicated。今天看了下他的回复94页，非常赞）
此前我有对此有过一段遐（瞎）想：从一个483发现项看压差报警延时设置来源（
从一个483发现项看压差报警延时设置来源）
从一个483发现项看压差报警延时设置来源）Summary 下先
压差报警延迟的制定应根据验证确认数据、设备能力、操作利用率和历史数据的审核，
1.压差报警延迟目的
压差报警建立适当延迟的主要目的是提供对非典型压力变化的及时检测，同时留出足够的时间来适应差压测量和控制系统动态变化以及设施常规操作引起的压力波动。报警延迟设定是为了给人员或物料通过气闸室的日常移动留出适当的时间，并适应气闸室门控制定时器的不同持续时间。
2.措施
2.1验证：每个气闸间自净恢复确认+环境监测EMPQ
该验证确认验证了当xxx气闸之间的门保持打开状态持续xxx时，气闸保持其颗粒分类的能力
每个单独的气闸上进行该验证确认, 每个气闸进行“恢复”测试，该测试证明了HVAC系统高换气率的有效性。进行环境监测性能确认研究，以进一步评估气闸在静止和运行条件下的可接受操作和使用情况，符合适用的房间分类和测试指南。
2.2日常数据回顾
审查验证确认和运行数据，包括气闸压差报警延迟的恢复研究，为现有压差报警延迟的可接受性提供理由和支持。
2.3 设备性能
正常运行期间的差压预计不会发生显著变化。无论是基于设备的控制还是管理控制.
延迟是根据以下因素确定的:
房间压力是一个动态参数。房间压力受许多因素影响
差压测量仪器的可变性。(ISPE基线指南的建议是在建立警报/报警延迟时使用时间加权滚动平均值来解决这种可变性。)
主动差压控制响应时间。
Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas.贵公司未能建立一个适当的系统来监控无菌加工区的环境条件。
The following discrepancies were noted during the qualification of the aseptic B103 vial filling line:在无菌B103小瓶灌装线的验证确认过程中发现了以下差异:
The xxx alarm time delay (between Grade B to Grade D transition) and the xxx alarm time delay (between Grade B to Grade C gown room/airlock) for pressure differentials are not based on scientific rational. The firm had only two DP alarms in the last year in the B103 aseptic vial filling area.压差的xxx报警时间延时(B级到D级过渡之间)和xxx报警时间延时(B级到C级更衣室/气闸之间)没有科学依据。该公司去年在B103无菌小瓶灌装区只有两个DP报警。
以下英文摘抄自其483回复
Our holistic strategy provides assurance ofenvironmental control and product protection. However, we will implementimprovements in the program as discussed in the detailed responses below,including the following:我们的整体战略为环境控制和产品保护提供了保证。但是，我们将按照以下详细回复中的讨论对计划进行改进，包括以下内容:
1. Although B103 data support theexisting differential pressure alarm delays, the xxx differential pressure alarmdelay for airlocks will be reduced to xxx based on qualification data,equipment capability, operational utilization, and review of historical performance.The xxx differential pressure alarm delay will be reduced to xxx based on roompressure, DP measurement instrument variability, and active DP control responsetime. The rationale will be documented in the B103 Critical Operation Data(COD) documents. These changes will be implemented in B103 by xxx (shutdowncompletion). A similar· assessment will be conducted for the other asepticmanufacturing facilities, and modification to the differential pressure alarmdelays will be made based on a documented rationale during the next plannedfacility shutdowns (xxx for Bl05A and xxx for B105).尽管B103数据支持现有的压差报警延迟，但根据验证确认数据、设备能力、操作利用率和历史性能审查，气闸室的xxx压差报警延迟将减少至xxx。根据室内压力、差压测量仪表可变性和主动差压控制响应时间，xxx差压报警延迟将减少至xxx。理由将记录在B103关键操作数据（COD）文件中。xxx（关闭完成）将在B103中实施这些变更。将对其他无菌生产设施进行类似的评估，并在下一次计划的设施关闭期间（Bl05A的xxx和B105的xxx）根据记录的理由修改压差报警延迟。
Detailed Response to Observation l.B.1:Existing Differential Pressure Alarm Delay is Supported by Qualification andOperational Data对观察结果l.B.1的详细回应:现有压差报警延迟已验证确认和得到运行数据的支持
The primary goal of establishing anapprop1iate delay for DP alarms is to provide a prompt detection of atypicalpressure changes while allowing enough time to accommodate variabilityassociated with DP measurement and control system dynamics as well as pressurefluctuations due to routine operations in the facility.差报警建立适当延迟的主要目的是提供对非典型压力变化的及时检测，同时留出足够的时间来适应差压测量和控制系统动态变化以及设施常规操作引起的压力波动。
Lilly IPM has xxx distinct critical DP alarmdelays depending on the configuration and functionality of the xxx rooms/areasbeing monitored xxx礼来IPM有xxx个明显的临界DP报警延迟，具体取决于xxx个被监控房间/区域的配置和功能xxx
Xxx DP Alarm Delay xxx制剂车间报警延迟
The xxx critical DP alarm delay isassociated with airlocks. The alarm delay is specified to allow for anappropriate amount of time for routine movement of personnel or materialsthrough the airlocks as well as to accommodate varying durations of airlockdoor control timers. A formal qualification test case is executed for allairlocks to confirm the performance of the HV AC system serving the airlock.Specific ally, this qualification test verifies an airlock's ability tomaintain its particulate classification when the door between xxx airlocks isheld open for a period of xxxxxx临界差压报警延迟与气闸有关。报警延迟设定是为了给人员或物料通过气闸室的日常移动留出适当的时间，并适应气闸室门控制定时器的不同持续时间。对所有气闸室执行正式的验证确认，以确认服务于气闸室的高压空调系统的性能。具体来说，该验证确认验证了当xxx气闸之间的门保持打开状态持续xxx时，气闸保持其颗粒分类的能力
This qualification test is conducted oneach individual airlock to generate data supporting the xxx DP alarm delay.This test involves xxx . This test confirms the airborne particulate counts inthe higher classification airlock/area does not exceed its airborne particulatelimits while the airlock door is open.在每个单独的气闸上进行该验证确认，以生成支持xxx差压报警延迟的数据。本次测试涉及xxx。该试验确认在气闸室门打开时，高等级气闸室/区域中的空气传播颗粒数不超过其空气传播颗粒限值。
In conjunction with this qualificationtest, each airlock is also tested for 'recovery' to verify its ability toquickly clear· the airlock of airborne contaminants. The recovery tests verifythat particulate conditions for each area, in the at-rest state, are achievedin the unmanned state after a short 'clean up period' of no greater than xxx .This test is conducted by xxx Acceptance criteria for this test is a xxx inairborne particulate counts within xxx . This test demonstrates theeffectiveness of high air change rates from the HVAC system. For airlocks, therecovery rates are often significantly less than xxx.在进行验证确认的同时，还对每个气闸进行“恢复”测试，以验证其快速清除气闸中空气污染物的能力。恢复试验验证在不超过xxx的短暂“清理期”后，处于静止状态的每个区域的微粒状况在无人状态下达到。该测试由xxx进行。该测试的验收标准是空气中的微粒数量在xxx以内。该测试证明了HVAC系统高换气率的有效性。对于气闸室而言，回收率通常远低于xxx。
Following HVAC system qualification testingassociated with airlock performance, environmental monitoring performancequalification studies are conducted to further assess the acceptable operationand use of airlocks under both at-rest and operational conditions perapplicable room classifications and testing guidelines.
在与气闸性能相关的HVAC系统验证确认测试之后，进行环境监测性能确认研究，以进一步评估气闸在静止和运行条件下的可接受操作和使用情况，符合适用的房间分类和测试指南。
Review of qualification and operationaldata for B 103, including recovery studies for the xxx delay for airlocks,provides rationale for and supports acceptability of the existing differentialpressure alarm delay.审查B 103的验证确认和运行数据，包括气闸xxx延迟的恢复研究，为现有压差报警延迟的可接受性提供理由和支持。
Xxx DP Alarm Delay
This delay is associated with the followingtwo facility configurations:这种延迟与以下两种设施配置有关:
DP is monitored between two rooms of different classification thatare separated by equipment that facilitates the transfer of materials betweenthem (e.g xxx etc.)在两个不同等级的房间之间进行压差监控，这两个房间由便于在它们之间传输物料的设备（例如xxx等）隔开。)
DP is monitored between a classified room and an adjacent(unclassified) technical space connected with a maintenance access or emergencyegress door (not utilized during normal operations).在密闭房间和与维护通道或紧急出口门相连的相邻（非密闭）技术空间之间监控差压（正常运行期间不使用）。
For the two configurations that have thexxx alarm delay, a significant change in DP during normal operations is notexpected. A DP alarm for these would indicate a failure of operational controlswhether equipment-based or administrative. This delay has been specified basedon the following factors:对于具有xxx报警延迟的两种配置，正常运行期间的差压预计不会发生显著变化。无论是基于设备的控制还是管理控制，这些设备的DP警报都会指示操作控制故障。这一延迟是根据以下因素确定的:
Room pressure is a dynamic parameter. Room pressure is influenced bymany factors including xxx房间压力是一个动态参数。房间压力受许多因素影响，包括xxx
DP measurement instrumentation variability. DP measurements at lowpressures are inherently more variable. Recommendation from ISPE baseline guideis to use a time-weighted rolling average when establishing alert/alarm delaysto address this variability. For example, utilizing a xxx or xxx will help identify trends while limiting the appearance of"nuisance" alarms (ISPE Baseline Guide - Sterile ProductManufacturing Facilities, Volume 3).差压测量仪器的可变性。低压下的差压测量本质上更加多变。ISPE基线指南的建议是在建立警报/报警延迟时使用时间加权滚动平均值来解决这种可变性。例如，利用xxx或xxx将有助于识别趋势，同时限制“有害”警报的出现（ISPE基线指南-无菌产品生产设施，第3卷）。
Active DP control response time. For rooms equipped with activepressure control, the time duration needed for room pressure control devices toreact/adjust to room pressure changes must be accounted for. Several rooms incorporatexxx " pressure control valves to affect a quicker response time toaccommodate certain operations that have a frequent and more significant impacton room pressurization.主动差压控制响应时间。对于配备主动压力控制的房间，必须考虑房间压力控制设备对房间压力变化做出反应/调整所需的持续时间。几个房间装有xxx”压力控制阀，以实现更快的响应时间，从而适应某些对房间加压有频繁和更显著影响的操作。
Review of B103 hist01ical DP data as wellas response times associated with various active pressure control devicesprovides rationale for and suppo11s acceptability of the existing differentialpressure alarm delay.对B103历史差压数据以及与各种主动压力控制装置相关的响应时间的审查为现有差压报警延迟提供了依据并支持其可接受性。
Although B103 data support the existingdifferential pressure alarm delays, Lilly IPM will execute the followingactions to afford tighter differential pressure control which allows forwell-timed detection of atypical pressure changes. The data review and approvedrationale is documented in the "B103 Critical Alarm Delay Rationale"(Appendix D).尽管B103数据支持现有的压差报警延迟，但礼来IPM将执行以下措施以提供更严格的压差控制，从而及时检测非典型压力变化。数据审查和批准的理由记录在“B103关键警报延迟理由”中（附录D）。
Action
1. For B103, the xxx differentialpressure alarm delay for airlocks will be reduced to xxx based on qualificationdata, equipment capability, operational utilization, and review of historicalperformance. The xxx differential pressure alarm delay will be reduced to xxxbased on room pressure, DP measurement instrument variability, and active DPcontrol response time. The rationale will be documented in the B103 CriticalOperation Data (COD) document.对于B103，根据验证确认数据、设备能力、操作利用率和历史性能审查，气闸室的xxx差压报警延迟将减少至xxx。根据室内压力、差压测量仪表可变性和主动差压控制响应时间，xxx差压报警延迟将减少至xxx。理由将记录在B103关键操作数据（COD）文件中。
These changes will be implemented in B103according to change control TR40224509 by xxx (shutdown completion). A similar assessmentwill be conducted for the other aseptic manufacturing facilities, andmodification to the differential pressure alarm delays will be made based on adocumented rationale during the next planned facility shutdown xxx for B105Aand for B105).xxx（关闭完成）将根据变更控制TR40224509在B103中实施这些变更。将对其他无菌生产设施进行类似的评估，在B105A和B105的下一次计划设施关闭xxx期间，将根据记录的理由对压差报警延迟进行修改。
一些往期EMS的发现项
以及一些关于EMS的思考
