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洁净室的自净时间与恢复时间的区别

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发表时间:2024-07-01 14:43
“自净时间”(附录1)和“恢复时间”(ISO 14644-3,信息部分B.4)这两个术语经常用于描述相同的程序,但它们彼此完全不同。这些测试方法对于空气中的微生物是无效的,微生物在很大程度上取决于房间里的人数以及他们的衣服和活动。

Clean up period according to Annex 1

EU GMP指南附录1中的自净期

The particle count limits for the "at rest" condition should be reached for a room free of personnel after a short clean up period of 20 minutes (guidance value) once activities are completed ("in operation" state) (Annex 1 (2022), Item 4.29 iii.; Annex 1 (2008), Item 14 after 15–20 minutes).

一旦活动完成(结束“运行”状态),在一个没有人员的房间,经过20分钟的短暂自净时间(指导值)后,应达到“静态”的粒子计数限度(附录1(2022),第4.29 iii.;附录1(2008),第14项15-20分钟后)。
The particle limits for the "at rest" state should be achieved within 20 minutes after the completion of operations and any cleaning. Implementation of this recommendation means that:
“静态”的微粒限度应在操作和任何清洁完成后20分钟内达到。执行这项建议意味着:
  • The particle measurement would be performed during actual operations. Additional personnel in the room performing the measurement have to be considered.
  • 微粒测量将在实际操作中进行,必须考虑房间中执行测量的其他人员。

  • After completing operation, the personnel leave the room.
  • 操作结束后,人员应离开房间。
  • The measurements are continued. The particle limit for the "at rest" state should be reached within 20 minutes.
  • 继续进行测量,“静态”的粒子限度应在20分钟内达到。

The implied conclusion would be that for optimal air flow conditions, the room content should be "flushed out" after 20 minutes. In this case the recommended air exchange rate would have theoretically be 3 (20 minutes).

隐含的结论是,在最佳气流条件下,室内内容物应在20分钟后“冲出去”。在这种情况下,理论上建议的空气交换率为3(20分钟)。

This makes it necessary to define the critical areas of a cleanroom which are tested. Preferably a programmable particle counter should be used so that a timeframe of more than 20 minutes can be tested with repeated printout or storage of values every minute, for example. The evaluation of the results would show if the result conforms within that timeframe. A resulting clean up period requiring much less than 20 minutes to reach the limit value at rest is a sign that:

这就有必要确定要测试的洁净室的关键区域。最好使用程序性粒子计数器,以便可以通过例如每分钟重复打印输出或存储值来测试超过20分钟的时间范围。对结果的评估将显示结果在该时间范围内是否符合要求。因此,在不到20分钟的时间内达到静态的限值表明:
  • the volumetric air flow rate (or exchange rate) that is (too) high and/or,
  • 体积空气流量(或交换率)过高和/或,
  • a more than adequate rate of airborne contaminant removal is provided.
  • 提供了超过适当的空气污染物去除率。

It is up to the pharmaceutical manufacturer to assess the actual clean up period and the necessary power consumption to achieve the high air change rates versus the impact to product safety (risk analysis!).

这取决于制药商评估实际的自净期和实现高换气率所需的电力消耗,以及对产品安全的影响(风险分析!)。

Testing the recovery time according to ISO 14644-3

根据ISO 14644-3测试恢复时间

In the DIN ISO 14644:2020 standard, Annex B.4, the methods for testing the recovery time for units with turbulent airflow are described. Measurement of the recovery time for ISO class 8 (C) and 9 (D), as well as for low-turbulence plug-flow airflows, is not recommended. Measurements should be conducted in any agreed state (preferably in the at rest state), and thus it is a potential test item during operational qualification testing.

在DIN ISO 14644:2020标准附录B.4中,描述了具有湍流气流的装置的恢复时间测试方法。不建议测量ISO 8级(C)和9级(D)以及低湍流塞流气流的恢复时间。测量应该在任何商定的状态下进行(最好是在静止状态下),因此它是运行确认期间的潜在测试项目。
This testing is used to determine the ventilation effectiveness at the measurement location and thus the capabilities of the AHU to achieve the target cleanroom class within a limited time period after loading the room with airborne particles.
该测试用于确定测量位置的通风有效性,从而确定房间中的空气充满颗粒后,AHU在有限时间内达到目标洁净室级别的能力。
The time required to reduce the introduced particle concentration down to 1% of the starting value is determined. When the particles are introduced (e.g. with an aerosol generator), it should be ensured that the initial particle concentration is at least 100 times the target cleanroom class limit value.
恢复时间确定了将引入的粒子浓度降低到初始值的1%所需的时间。当粒子被引入时(例如使用气溶胶发生器),应确保初始粒子浓度至少是目标洁净室级别限值的100倍。

In the pharmaceuticals industry defining a grade D not to have limits in the "in operation" state should only be done with adequate justification. And thus, the recovery time for GMP grade D with the specified limit values (in logical consequence: ISO class 9) should be determined and proven.

在制药行业,只有在有充分理由的情况下,才能定义D级在“动态”下没有限值。因此,GMP D级的恢复时间与规定的限值(逻辑结果:ISO 9级)应该确定和证明。

Practical testing recommendations

实用测试建议

The "combination" of both methods, i.e. measuring the recovery time (according to ISO) within 20 minutes (from Annex 1), which is often observed in practice, leads to false conclusions about the effectiveness of air purification and particle removal: For example, the air purity of particles in the "in operation" state can easily be < 15% of the limit value and the recovery time 100:1 according to ISO can be 30 minutes.

两种方法的“结合”,即测量20分钟内(根据ISO)的恢复时间(见附录1),在实践中经常观察到,导致对空气净化和粒子去除有效性的错误结论:例如,粒子在“动态”下的空气纯度很容易<限值的15%,根据ISO 100:1的恢复时间可能为30分钟。
One alternative test procedure could take the following form to make a conclusion about the flushing behavior of the AHU possible:
一种替代测试程序可以采取以下形式,以得出关于AHU的换气活动的结论:
  • The room is artificially subjected to a load of 0.5µm sized particles (using an aerosol generator) to the point at which the maximum monitoring limit for "in operation" is met (alternatively with about 30% of the limit). This creates a simulated operating state.
  • 室内人工创造0.5µm大小颗粒的负荷(使用气溶胶发生器),达到“动态”的最大监测限值(或者约为限值的30%)。这将创建一个模拟的运行状态。

  • Afterwards, the aerosol generator is turned off and the time is measured how long it takes for the particle concentration to reach the limit value for the "at rest" status. This particle count level should be reached within a time span of 15–20 minutes.
  • 之后,关闭气溶胶发生器,测量粒子浓度达到“静态”的极限值所需的时间。该粒子计数水平应在15-20分钟内达到。

Example: 例子

  • A grade C cleanroom for production is subjected to a particle loading with 0.5µm particles up to a level of 1,050,000 particles/m3 (30% of the "in operation" limit for grade C according to Annex 1 is 3,520,000 particles/m3).

  • 用于生产的C级洁净室创建的颗粒负荷为0.5 μ m,最高可达1,050,000颗粒/m3(根据附录1,C级“动态”限值的30%为3,520,000颗粒/m3)。

  • The aerosol generator is turned off and measurements are conducted with the particle counter until the number of 0.5µm particles falls below 352,000 ("at rest" limit for grade C). The measured time corresponds to the clean up period.

  • 关闭气溶胶发生器,使用粒子计数器进行测量,直到0.5µm颗粒的数量低于352,000 (C级“静态”限值)。测量的时间对应于自净期。

This test simulates the operating condition (setting the maximum particle concentration in the "in operation" state) for the cleanroom. The capability to uphold the recommended "cleanup" of 20 minutes fits the recommendations given in Annex 1 (2022). The ability to meet the requirement to maintain particle concentrations below this artificially created maximum can be proven under normal operating conditions during the validation phase for the production equipment (APS – Aseptic Process Simulation, formally known as media fills, conformance lots). Additional testing is possible as part of periodic or continual particle monitoring.

该测试模拟洁净室的运行条件(在“动态”下设置最大颗粒浓度)。维持建议的20分钟“自净”能力符合附录1(2022)中给出的建议。在生产设备的验证阶段(APS -无菌工艺模拟,通常也被成为培养基模拟灌装)的正常操作条件下,能够满足将粒子浓度维持在人工创造的最大值以下的要求。作为定期或连续粒子监测的一部分,可以进行额外的测试。
In practice, the clean up period and recovery time are often mistaken – people may refer to the clean up period but perform a recovery time measurement or vice versa. From a legal and normative point of view, these measurements should be seen as recommendations, but from the point of view of the authorities, they must be applied.
在实践中,自净期和恢复时间经常是错误的——人们可能指的是自净期,但执行的是恢复时间测量,反之亦然。从法律和规范的角度来看,这些措施应被视为建议,但从当局的角度来看,它们必须得到应用。
Truth is: Annex 1 (2022) recommends determining the cleanup period, i.e. the time required to return from "in operation" to "at rest". For grade B that is a factor of 100:1, for grades C and D a factor of 10:1. Annex 1 refers at other locations to the cleanroom requirements given in ISO 14644-3 – in this standard the recovery time measurement is described measuring a 100:1 or 10:1 dilution. According to Annex 1 (2022), the recovery time must also be determined for the qualification.
事实是:附录1(2022)建议确定自净期,即从“动态”恢复到“静态”所需的时间。对于B级,这个比例是100:1,对于C和D级,这个比例是10:1。附录1参照ISO 14644-3中给出的洁净室要求,在该标准中描述了测量100:1或10:1稀释的恢复时间。根据附录1(2022),恢复时间也必须在确认中进行确定。


【自净时间和恢复时间的区别?】

With the new Annex 1 and the ISO 14644 series, detailed guidelines apply to the planning and GMP-compliant operation of cleanrooms and theirHVAC systems. Nevertheless, or precisely because of this, in practice there is often the question of the "recovery time" and the required "clean-up phase". Are these different requirements, or are they the same? Do they only apply to sterile or also to non-sterile medicinal products? Do they have to be measured in operation or at rest?

新版的EU GMP指南附录1ISO 14644系列作为详细的指导文件,适用于洁净区及其HVAC系统的规划和GMP合规性操作。然而,或者正因为如此,在实践中经常存在“恢复时间”和所需的“自净期”的问题。这些要求是不同的,还是相同的呢?它们只适用于无菌药品还是也适用于非无菌药品?必须进行动态检测还是在静止检测?

Clean-up phase 自净期

The determination of the clean-up phase is a requirement of Annex 1. It is defined as the time that elapses until the ventilation system has cleaned the particle concentration in the operating state "in operation" to the limit value of the particle concentration for the operating state "at rest". Consequently, the clean-up time is measured starting in the operating state "in operation" and ending in the operating state "at rest". The requirement is that the clean-up phase is less than 20 minutes.

确定自净期是EU GMP指南附录1的一项要求。定义为通风系统在“动态”运行状态下的微粒浓度净化到“静态”运行状态下的微粒限度所经过的时间。因此,确定自净时间时,从“动态”运行状态开始,到“静态”运行状态结束。要求是自净时间低于20分钟。Annex 1 applies to the production of sterile medicinal products, but can also be used for the production of other forms. This is also extremely sensible, as especially in the dusty production of e.g. solid dosage forms, the avoidance of cross-contamination during a product change is essential. Besides cleaning the manufacturing equipment, the premises and the air in the rooms must also be cleaned before a new product is produced. So it must be known how long the ventilation system needs to reach the clean (at rest) state again. The clean-up phase is determined for premises of cleanliness classes B, C and D (not for zone A) as well as in the non-sterile production areas, as far as reasonable (risk analysis or contamination control strategy).EU GMP指南附录1适用于无菌药品的生产,但也可适用于其他类型药品的生产。这也是非常明智的,特别是在产尘的药品生产中,例如固体剂型,在产品转换期间避免交叉污染是必不可少的。除了清洁生产设备外,在生产新产品之前,还必须清洁厂房和房间里的空气。因此,必须知道通风系统需要多长时间才能再次达到清洁(静态)状态。在合理的情况下(风险分析或污染控制策略),对洁净等级为BCD的区域(不包括A级区)以及非无菌生产区域确定自净期。So, in addition to cleaning validation, compliance with the clean-up phase after product changeover is part of the answer to a GMP inspector's question: "How do you prevent cross-contamination?". And it isalso helpful to know the answer in the production of non-sterile, solid dosage forms.因此,除了清洁验证之外,产品转换后的自净期是否符合GMP检查员的问题“如何防止交叉污染?”也是答案的一部分。在非无菌固体剂型的生产中,知道答案也很有帮助。

Recovery time 恢复时间

The recovery time is a requirement of ISO 14644. The recovery time test is performed to determine whether the cleanroom is capable of returning to its specified cleanliness class within a limited period of time after brief exposure to a source of airborne particles. This test is not recommended for low-turbulence displacement flow (as for the clean-up phase, see above). The recovery time is thus measured in the state at rest, after an amount of particles has been added. The recovery time also provides information on the locking times in airlocks. It is therefore not only recommended for production rooms, but for all rooms with turbulent dilution flow. There is no normative requirement for a recovery time; each company is obliged to define a recovery time. Also, no time interval for measuring the recovery time is specified, but it is carried out during the initial qualification (classification) and is repeated in the event of a change in the room or the air change rate.

恢复时间是ISO 14644的要求。进行恢复时间测试是为了确定洁净室在短暂暴露于某种悬浮粒子后,是否能够在有限的时间内恢复到规定的洁净度等级。这种测试不建议用于低湍流度的置换流(如自净阶段,见上文)。因此,在加入一定量的粒子后,在“静态”状态下测量恢复时间。恢复时间还提供了气闸锁定时间的信息。因此,它不仅推荐用于生产洁净区,而且适用于所有具有湍流稀释流的房间。目前没有对恢复时间有正式的要求,每家公司都有义务规定一个恢复时间。此外,没有规定测量恢复时间的时间间隔,但应在初始确认(分类)期间进行,并在房间或空气换气率发生变化时重复进行。Since both measurements are completely different, measurements of both the recovery time and the clean-up phasehave to be carried out.由于这两种测量方法完全不同,因此必须对恢复时间和自净时间进行确定。

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