Design Considerations and Best Practices for Tank Vent Filtration

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Design Considerations and Best Practices for Tank Vent FiltrationUnderstanding the diverse applications of vent filters is critical to their proper implementation and use.

By Michael Felo, EMD Millipore Nov 09, 2011

  



   Many biopharmaceutical applications require vent filters—hydrophobic sterilizing-grade filters used as air vents on processing tanks. The purpose of the tank vent filter is twofold:  maintain near ambient pressure in the tank while ensuring sterility in the tank. The tank vent filter removes viruses and microorganisms from the gas as it flows into or out of the tank.
To ensure proper operation and sterility, a bioreactor, for example, may have a number of vent filters including those for the tank vent, the sparge gas inlet, and the overlay gas inlet.  

Understanding the diverse applications of vent filters is critical to their proper implementation and use.
A number of factors must be considered in advance of vent filter implementation including filter sizing, housing and piping design, condensate control, regulatory requirements, and operational considerations such as clean- and steam-in-place (CIP, SIP) and integrity testing. Employing best practices for vent filter use can avoid common problems during installation, CIP, SIP, integrity testing, and operation.

This article will describe an application-based approach to vent filter sizing, in situ integrity testing of the filter design, best practices for housing design and vent filter operation, and a risk management approach to implementation and replacement of vent filters.
Vent Filter SizingAir flows in and out of a process tank commonly for two reasons: the first is to replace a volume of liquid as it is pumped in or out of the tank. Sizing the tank vent filter for pump-out or fill rate is relatively simple as the air flow rate will be equal to the pump-out or fill rate. With flow rate and pressure determined, a flow/pressure change (&#196) curve can be used to determine sizing.

The second reason air will flow into a process tank is to compensate for the volume change associated with steam condensation. At the end of a tank SIP procedure, steam in the tank will cool and undergo a phase change to liquid water. There is more than a 1,000x difference in volume between an amount of water in gas phase vs. liquid phase. During cooling, sterilized ambient air must be allowed into the tank to prevent vacuum. Sizing the vent filter for steam collapse requires knowing the vacuum rating of the tank and the convective cooling rate. These can be calculated based on the tank dimensions including height, diameter, and wall thickness. At EMD Millipore, we have developed a computer program to facilitate these calculations.

Improper tank vent sizing can result in low pump-out rates, loss of sterility due to a ruptured disk or filter failure, or worst case, tank implosion. Fortunately, proper sizing is not difficult as long as the flow requirements and driving force are understood.

Tank venting can be static or dynamic with each requiring filters that are sized slightly differently. For static venting, the air outside of the tank is assumed to be at ambient pressure, so the driving force for airflow is determine by the pressure difference between the inside of the tank and the atmosphere. For dynamic venting, compressed air is fed to the tank in order to minimize any difference in pressure that occurs between the tank and atmosphere.

Static tank venting is commonly used for buffer tanks and intermediate storage tanks. To determine the proper size for a static tank vent filter, we utilize a four-step process:

• Determine the maximum flow rate for venting that the vent filter will need to provide. This will be either the process flow rate or steam collapse rate after an SIP cycle.
• Select the maximum pressure drop that you want the filter to experience.  The pressure drop is typically less than 5 psi and should be dictated by the vacuum rating for the tank or rupture disk vacuum rating. Clearly, it is important to avoid pulling a strong vacuum on the tank that might cause collapse.
• Calculate the number of filters or filter area required to meet flow rate and pressure drop requirements.
• Ensure an adequate safety factor (~1.5x) and select the appropriate filter configuration for the tank or application.
  

Table 1 shows the vent sizing process for a static vent. This example represents a hold tank used for ambient temperature water storage with a maximum pump-out rate of 400 liters per minute.  No SIP is necessary and the tank has no vacuum rating.  
   
    Table 1. Vent sizing process for a static vent.

Common uses for dynamic tank venting include bioreactors and other applications where steam is replaced with compressed air after an SIP cycle. In this case, the process for sizing a filter varies slightly from the static model and is as follows:

• Select the desired pressure drop. Pressure drop is typically less than or equal to 2 psi, especially when calculating for bioreactors where minimizing vacuum is key to maintaining a sterile environment in the tank.
• Calculate the air flow rate necessary to replace the steam during steam collapse post-SIP.
• Calculate the number of filters or filter area needed to meet flow rate and pressure drop requirements.
• Ensure an adequate safety factor (~1.5x) and select the appropriate filter configuration for the tank or application.
  

Dynamic vent sizing can be significantly more complex than static venting since the steam collapse rate needs to be calculated for the specific tank and process conditions being used. In this case, it is recommended that software, such as that developed by EMD Millipore, be used to calculate the proper dynamic vent filter sizing.


In Situ Integrity Testing of FiltersVent filters are typically tested using the Hydrocorr water flow integrity test (Hydrocorr Validation Guide, MM document VG050).1 The test measures the resistance of the filter to water intrusion (Figure 1). A filter is placed in a stainless steel housing which is flooded with water. Under a pressure of 40 psi, there is compaction of the filter. Over time, the compaction stabilizes and the flow decreases.  Once stabilization is complete, an instantaneous flow measurement can be taken; if the measurement is below the specification of the vent filter, it is considered to be integral.  


Figure 1. Hydrocorr water flow integrity testing process.

In situ water-based testing can be conducted when the filter is attached to the tank using a manual or fully automated process. With the manual process, the filter is flooded, the Hydrocorr integrity test is conducted, and once a passing value is achieved, the vent filter housing is drained. The same steps are used in the fully automated process, which can be a more efficient way of testing when in a commercial operations setting.


Housing Design and Vent Filter OperationBest practices for the implementation of vent filters include selection of the proper housing. Three housing options are available (Figure 2):

• C-line. Offers the best condensate trapping capacity on the upstream side of the filter.  If the stream is in an especially moist or humid environment, the C-line format allows excellent removal of condensate.
• T-line. While this format is popular, it is not optimal for vent filtration, as the housing has to be tilted for proper condensate drainage.
• In-line. This format allows the downstream condensate to drain directly into the vessel.
  

Figure 2. Vent filter housing options.

In all cases, a vertical mounting of the housing is always required to enable the most effective drainage of condensate.  

The life cycle of the vent filter includes installation in the housing on the tank, CIP, SIP, and operation. Adopting best practices at each step can help ensure proper functioning. During installation, filter o-rings should be pre-wetted for easier installation in filter housings. Code 7 tabs at the bottom of the cartridge should be locked in to their housings as venting occurs in the reverse direction and, if there is pressure pulsing, the cartridge may be ejected from the filter housing.  

During CIP, the sprayball direction should be adjusted so that CIP liquids do not reach the filter as caustic solutions can impact the strength of the membrane. A heat jacket, blanket, or trace should be used to minimize condensate buildup in the filter housing during the CIP cycle. CIP creates a moist, humid environment so it is important to avoid instantaneous release of high pressure, moist gas through the vent filter, which can cause damage.  

SIP is the most mechanically strenuous step that a vent filter will experience. A number of best practices can be employed to prevent damage to the filter:

• Avoid pressure pulsing across the vent filter.
• Minimize a high-pressure change across the filter at high temperature as the filter can become weaker at elevated temperatures.
• Steam the vent filter in reverse direction from the tank to ensure condensate removal from the core of the filter.
• Delay the vent filter sterilization step until after the tank heating phase is complete.
• Air/condensate should be sent via the drain and not the vent filter during the heating phase.
  

During the operation phase, it is best to avoid fouling of the filter from entrained liquid in the tank especially when using the filter on a bioreactor. A heat jacket/blanket/trace should be used during the process if the potential exists for moisture build-up.
Risk Management Regulatory authorities have addressed the implementation of vent filters. All advocate a risk-based approach be used to establish filter re-use and integrity testing policy.  

A typical risk assessment and process validation plan should consider the criticality of the process and application of the vent filter, the number of re-use cycles, process implications, and the impact on filter lifetime.   

Regulatory documents establish two types of applications for vent filters:  critical and moderately critical applications. Critical applications are those in which filtered gas is in direct contact with the sterile final product.  In this situation, the sterilization cycle must be validated and performed before each use of the vent filter. The filter must be integrity tested upon installation and following each use.

In moderately critical applications, the filtered gas is not in direct contact with the final product. In these applications, sterilization and integrity testing frequency should be established based on the following risk assessment parameters:

• Historical in-process filter integrity test data
• Microbiological/bioburden limits established for the filter
• Filter process conditions
  

It is common practice to reuse vent filters over multiple cycles. A risk-based assessment should help guide reuse and change-out criteria. The assessment should consider the following:

• Maximum number of sterilization cycles (a manufacturer or internally set limit)
• Preventative maintenance schedules for related equipment (the tank on which the vent is mounted)
• Potential for cross contamination from different product strains
• History of integrity test failures
• Humidity during operation
• Maximum pressure drop for non-clean air stream
• Service life of the filter at the temperature for heat traced housing
• Specified utilization number of uses expected for the filter
  

ConclusionVent filters are used in a number of applications, each of which can bring different requirements for proper implementation and use. Different sizing methods exist and selecting the right parameters can help ensure safe and economical use. Housing selection and orientation is important for proper operation and the application of best practices for vent filter use can avoid most common problems during CIP, SIP, and integrity testing.

An applications-based risk assessment should be used in order to properly establish vent filter integrity testing and change-out plans.  

References
1.    Jaenchen, R., Schubert, J., Jafari, S., and West, A. “Studies on the theoretical basis of the water intrusion test (WIT). European Journal of Parenteral Sciences, 1997, Vol. 2, No. 2, 39–45.
2.    Technical report no.40 “Sterilizing filtration of gases” PDA Journal of Pharmaceutical Science and Technology, 2005, Vol. 58, No.S-1.
3.    Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-Operation Scheme. Recommendation on the Validation of Aseptic Processes. Section 9.6.1, January 2011.
4.    EC guide to GMP Annex 1 “Manufacturing of sterile medicinal product”, 2003.

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设计注意事项和最佳实践油箱通风FiltrationUnderstanding排气过滤器的各种应用是其正确实施和使用的关键。
迈克尔Felo，EMD Millipore公司2011年11月9日


  



   许多生物制药应用程序需要使用空气通风口上的处理罐通风过滤器，疏水性除菌级过滤器。罐通风过滤器的目的是双重的：接近环境压力保持在罐，同时确保在罐无菌。罐通风过滤器去除病毒和微生物从气体，因为它流入或流出罐。
为了确保正确的操作和无菌性，生物反应器，例如，可能有许多的排气过滤器，包括那些为箱排放，在喷射气体入口，和覆盖气体入口。

了解排气过滤器的各种应用是其正确实施和使用的关键。
有许多因素必须提前通风过滤器实施，包括过滤器大小，住房和管道设计，冷凝水控制，监管要求和运营方面的考虑，如洁净和蒸汽就地（CIP，SIP）和完整性测试加以考虑。采用最佳实践的通风过滤器使用可安装，CIP，SIP，完整性测试，在操作过程中避免常见的问题。

本文将介绍基于应用程序的方法，排气过滤器的大小，在滤波器设计原位完整性测试，对房屋设计的最佳实践和排气过滤器的操作，以及风险管理的实施方法和更换排气过滤器。
通风过滤器SizingAir进出一个处理槽的通常的原因有两个流：第一是取代一定体积的液体，因为它被泵中或从槽中取出。上浆罐通风过滤器的泵出或填充速率相对简单的空气流率将等于泵出或填充速率。与流速和压力决定的，一个流量/压力变化（A）曲线可以被用于确定尺寸。

第二个原因空气将流入一个处理槽是以补偿与蒸汽冷凝相关的体积变化。在一个罐的SIP过程结束，蒸气在罐的冷却和经历相变到液态水。有一个以上的体积的水的量之间在气相一个1000倍的差异与液相。在冷却过程中，消毒环境空气必须被允许进入油箱，防止真空。上浆通风过滤器的蒸汽崩溃需要知道该储箱的真空等级和对流冷却速率。这些可以基于罐尺寸，包括高度，直径和壁厚来计算。在EMD Millipore公司，我们已经开发出一种计算机程序，以方便这些计算。

不当箱排放施胶可导致低泵出率，不育性的损失，由于破裂盘或过滤器故障，或者最坏的情况下，罐的内爆。幸运的是，适当的大小并不难，只要流量要求和驱动力被理解。

箱排气可以是静态或动态的，每个都需要过滤器，其尺寸略有不同。对于静态排气，罐外的空气被认为是在环境压力下，所以对于气流的驱动力是确定由箱的内部和大气之间的压力差。对于动态放空，压缩空气被输送到罐中，以尽量减少在压力罐和大气之间发生的任何差异。

静态箱排气通常用于缓冲罐和中间储罐。要确定一个静态罐通风过滤器的适当尺寸，我们利用一个四步过程：


确定的最大流速为排气的通气滤膜将需要提供。这个位将是一个SIP循环后的过程流率或蒸汽崩溃率。
选择您要过滤器体验的最大压降。压降通常小于5psi的，并应通过真空等级为罐或断裂盘真空等级决定。显然，以避免对可能导致崩溃罐抽真空强是很重要的。
计算的，以满足流量和压力降的要求所需的过滤器或过滤面积的数量。
确保有足够的安全系数（～1.5倍），并选择坦克或应用适当的过滤器配置。

表1示出了排气口上浆工艺为静态通风口。本实施例表示用于室温水储存与400升每分钟的最大泵出速率的保持罐。没有SIP是必要的，该箱具有没有真空等级。
    
    表1.通风上浆工艺的静态发泄。

动态油箱排气常见的用途包括生物反应器和其他应用蒸汽代替压缩空气的SIP周期之后。在这种情况下，处理上浆的过滤器从静态模型略有不同并且是如下：
选择所需的压降。压降通常小于或等于2磅，计算用于生物反应器，其中最小化真空的关键是维持无菌环境中的罐时尤其如此。
计算所需的空气流率蒸汽崩溃后的SIP过程，以代替蒸汽。
计算的过滤器或需要满足的流量和压降的要求过滤面积的数量。
确保有足够的安全系数（～1.5倍），并选择坦克或应用适当的过滤器配置。
动态通气上浆可显著比静态排气更复杂，因为蒸汽崩溃率需要计算的特定罐和工艺条件被使用。在这种情况下，建议的软件，诸如由EMD Millipore公司开发的，可用于计算正确的动态通风过滤器的大小。


原位的FiltersVent滤波器完整性测试通常使用Hydrocorr水流完整性测试（Hydrocorr验证指南，MM文件VG050）0.1该试验测定的过滤器，以水侵入的电阻（图1）进行测试。过滤器被放置在一个不锈钢外壳被水淹没。下的40psi的一个压力，存在过滤器的压实。随着时间的推移，压实稳定和流量减小。一旦稳定完成后，瞬时流量测量可以采取;如果测量是通风过滤器的规格以下，它被认为是一体的。


图1. Hydrocorr水流完整性测试过程。

原位水性测试可以当过滤器安装到使用手动或完全自动化的过程的罐中进行。与手动过程中，过滤器被水淹没，所述Hydrocorr完整性测试中进行的，并且一旦传递值实现的，所述通风过滤器壳体被排出。相同的步骤被用在完全自动化的过程，它可以是测试的一种更有效的方式，当在一个工业操作设定。


对排气过滤器的实现住宅设计和空气过滤器OperationBest做法包括选择合适的住房。三房可供选择（图2）：
C线。提供在过滤器的上游侧的最佳冷凝捕集容量。如果流是在一个特别湿润或潮湿的环境，C线格式允许优良去除冷凝物。
T线。虽然这种格式是流行，它是不是最佳的通气过滤，作为壳体具有要倾斜适当冷凝水。
排队。这个格式允许在下游冷凝水直接排放到容器中。


图2.通风过滤器的住房选择。

在所有的情况下，外壳的一个垂直安装总是需要使冷凝物的最有效的排水。

通风过滤器的生命周期包括安装在上箱，CIP，SIP和操作壳体。采用在每一步的最佳实践可以帮助确保正常运行。在安装过程中，过滤器O型圈应预先湿润易于安装的过滤器外壳。代码7片在盒的底部应锁定到其外壳的通风发生在相反方向上，并且如果有压力脉冲，盒可以从过滤器壳体弹出。

期间的CIP，所述sprayball方向应调整以使CIP液体不到达滤波器作为苛性碱溶液可影响膜的强度。一种热夹套，毛毯，或跟踪应该被用来与CIP循环期间最小化在过滤器壳体冷凝堆积。 CIP创建湿润，潮湿的环境中，因此通过通气过滤器，这会导致损坏，以避免高压，潮湿气体瞬间释放是重要的。

SIP是最机械费劲步骤，一个通风过滤器将经历。一些最好的做法可以用于防止损坏过滤器：
避免在通风过滤器压力脉冲。
最小化通过过滤器在高温下作为滤波器高压变化可以在升高的温度变弱。
从水箱蒸汽以相反方向上的通风过滤器，以确保冷凝物移除从过滤器的核心。
延时通风过滤器除菌步骤之后才槽加热阶段完成。
空气/冷凝物应通过漏极与未在加热阶段被发送通风过滤器。
在操作过程中相，最好是使用上的生物反应器中过滤器特别是当以避免在罐从夹带的液体的过滤器的结垢。一种热夹套/毯/跟踪应该如果潜在存在湿气积聚的过程中被使用。
风险管理监管部门已经解决了排气过滤器的实现。所有倡导以风险为基础的方法被用来建立过滤再利用和完整性测试的政策。

一个典型的风险评估和工艺验证计划应考虑方法和应用的通气滤膜，再利用的周期，过程影响的数量，并在过滤器寿命的影响的关键性。

规范性文件设立两个类型的应用程序的排气过滤器：重要的和适度的关键应用。关键应用是其中经过滤的气体与所述无菌最终产品直接接触。在这种情况下，灭菌周期必须验证并每次使用通风过滤器之前进行。该过滤器必须完整安装后测试，在每次使用后。

在中等严重的应用中，过滤的气体不与最终产品直接接触。在这些应用中，杀菌和完整性测试频率应根据以下的风险评估参数建立：
历史过程中的过滤器完整性测试数据
建立了微生物过滤器/生物负载极限
过滤工艺条件
通常的作法是在多个周期重用排气过滤器。以风险为基础的评估应该帮助指导重用，改变出标准。评估应考虑以下几点：
灭菌周期的最大数量（制造商或内部设置限制）
预防性维护时间表相关设备（在其上排气阀被安装在罐）
势从不同产品菌株的交叉污染
完整性测试失败史
运行期间湿度
用于非清洁空气流最大压力降
该过滤器的热追踪房屋的温度使用寿命
预计过滤器的用途指定使用数量
ConclusionVent滤波器被用在许多应用中，每一个都可以带来的执行及使用不同的要求。不同大小的方法存在，并且选择合适的参数，可以帮助确保安全和经济地使用。房屋的选择和方向是正确的操作和最佳实践的应用通风过滤器使用可CIP，SIP和完整性测试过程中避免最常见的问题很重要。

一个应用程序为基础的风险评估应以适当建立通风过滤器完整性测试，改变淘汰计划中。

参考
1. Jaenchen，R.，舒伯特，J.，贾法里，南，西，水侵入测试（WIT）的理论基础A.“研究。欧洲杂志的肠外科学，1997年，卷。 2，第2号，39-45。
2.技术报告40号“消毒气体过滤”PDA杂志药物科学与技术，2005年，卷。 58，编号S-1。
3.药品检查公约，药品检查合作计划。建议在无菌工艺的验证。第9.6.1节，2011年1月。
4. EC指导GMP附录1“无菌药品的生产”，2003年。

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