Sterile liquid filtration

• Supor Prime: High-capacity filtration of challenging feeds in high concentration proteins, liposomes, lipid nanoparticles, and viral vectors. Typical applications include post UF/DF, bulk drug substance, final formulation and fill.
• Supor EX ECV: Excellent pH compatibility and protein transmission of hard-to-filter fluids. Typical applications include sterile filtration of cell harvest material, process intermediates, growth media, buffers, and final bulk biological process fluids.
• Supor EKV: Optimum flow, throughput, protein binding, and chemical (pH) compatibility for maximum transmission of high-value active ingredients and preparative applications. Typical applications include growth media, bioreactor feeds, buffers, and process intermediates.
• Fluorodyne II DFL: Low extractables and absorption in low-fouling pharmaceutical process fluids such as active ingredients, biologicals, biotech proteins, ophthalmics and other dilute preservative solutions. Typical applications include, low-fouling process intermediates, filtration of bulk drug substance, and final sterile filtration of drug product.
• Fluorodyne EX EDF: Hybrid filtration media for high fouling fluids. Typical applications include clarified cell harvest, and nanosuspensions such as liposomes and emulsions.
• Posidyne: Removal of contaminants such as cell debris and endotoxin smaller than the filter rating.

All Supor™ PES membrane filters including EKV, EAV, Supor™ EX (ECV), SuporLife™, SuporFlow™ should be in a water wet state prior to sterilization (by autoclave or steam-in-place) to reduce false integrity test failures when there is a requirement to perform post-use post-sterilization integrity testing (PUPSIT), with water as wetting fluid.

It is important to note that performance of the filter is not affected whether the filter is sterilized in a wet or dry state.

When the filter devices are autoclaved/in situ steamed “dry”, they may not reliably wet with water for subsequent post-sterilization integrity (forward flow, bubble point) testing. The integrity of the filter devices can then only be proven using a low surface tension wetting fluid, such as isopropanol/water mixtures and/or product wet integrity test value and/or using product wet integrity test values. With regards to filter wetting, please refer to application note Wetting and Flushing of Pall Microbially-Rated Filter Cartridges and Capsules. We recommend a flush regime for about 5 min. When the filter is integrity tested with water as wetting fluid before sterilization, filter is sufficiently wetted for autoclave and/or in situ steaming.

For more information, please see:

• USD 3297 - Wetting and Flushing of Microbially-Rated Filter Cartridges and Capsules
• USTR 805 - Steam-sterilization of Filter Assemblies which Utilize Replaceable Filter Cartridges

There is no general rule to this and depends on the filter application.

The user should qualify the filter change-out frequency for their specific application, but this should never exceed our claims for cumulative sterilization cycles and/or the maximum differential pressure. These specifications were established in controlled laboratory conditions with filters that were not exposed to any process (including manufacturing or production) conditions.

The filter lifetime and change-out should be based on a risk assessment by the user for their specific application including relevant validation/qualification data.

For example, the impact of a post-use integrity test failure of the filter should be considered.

For gas filtration in compressed gas, tank vent, or utilities setting, industry best practice is to replace the filter under a pre-defined preventative maintenance schedule (that is, at a minimum of 12 -month cycle).

For critical applications, single use is recommended to eliminate the risks of cross contamination between batches.

For more information, please see Re-use of sterilizing grade filters —– considerations and risk assessments

There are various reasons why a filter may require to be dried, which include, but are not limited to:

1. Drying after integrity testing prior to filtration of a water-insoluble liquid
2. Drying of a hydrophobic filter such as Emflon™ PFR, prior to Water Intrusion Testing
3. Removal of water from a filter after integrity testing to allow the passage of moist heat (steam) for sterilization

In principle, there are three possible scenarios for a drying process:

1. Off-line oven drying
2. In-line using pressurized gas
3. Applying a vacuum

The selection of the drying method is determined by the level of dryness required for the application. For example, for a filter that will be used for the sterilization of a water-insoluble product, a high level of dryness is required (oven drying). If the purpose of the drying is allowing the passage of steam, a low to moderate level of drying is required (in-line using pressurized gas).

In order to determine if a capsule or cartridge filter has been completely dried, the filter can be weighed before wetting and after drying. A weight within approximately 1% of the pre-wet weight will indicate sufficient drying depending on the application.

It is recommended that the drying procedure simulates the individual process and environmental conditions. Therefore, it is suggested that this study be done on-site by the end user.

Oven Drying

1.1 Pre-treatment

To reduce the amount of fluid in the filter pack and thus speed up drying, the filter can be "blown down" with pressured gas prior to drying. A considerable amount of liquid will be expelled if the filter is subjected to the Forward Flow test pressure. Even more fluid will be expelled if a gas pressure above the bubble point is applied.

Note: for safety reasons it is important to remain within the maximum operating conditions assigned to the filter capsule or housing. Temporary excursions above this maximum pressure may be allowed – please contact a Cytiva representative for further guidance.

1.2 Equipment

We recommend the use of a fan-assisted oven to support the removal of moisture. A vacuum drying oven is a highly effective means of drying a filter in a short period.

1.3 Static drying parameters

The following table below shows suggested oven drying temperatures and times for membranes (these conditions can be reduced if using a vacuum drying oven).

*Max Drying temperature is 96°C for 6 to 12 Hours
**Max Drying temperature is 96°C for 12 Hours
***Max Drying temperature is 96°C for 16 Hours

NOTES:

• Alcohol-wet filters should be flushed with water prior to drying
• All temperatures are ± 2°C
• Capsules need a prolonged drying time because the transport of moisture from the filter pack is hindered by the capsule shell.

Dry in-line using pressurized gas

Note: Compressed air or an inert gas should be used. For safety reasons, reactive gases such as oxygen should never be used for filter drying.

Note: for safety reasons it is important to remain within the maximum operating conditions assigned to the filter capsule or housing. Temporary excursions above this maximum pressure may be allowed – please contact a Cytiva representative for further guidance.

2.1 Blowdown

For this drying procedure, it is necessary to apply a gas pressure above the bubble point of the filter with the respective wetting fluid.

2.2 Physical parameters influencing the drying process

The effectiveness of the drying cycle will be influenced by the following parameters:

• Nature of the wetting fluid
• Gas phase (dryness, temperature)
• Gas flow rate

The following table below shows suggested gas flow rates and times for some filter types to dry the filter of water to within 1% of the pre-wet weight.

Longer times and higher flow rates will be required for larger area filters.

2.3 Drying using a pre-set pressure for a specified time is also a common method used for filter drying. Generally, a starting pressure 25% above the minimum bubble point is recommended. The pressure is expected to drop immediately as more pores of the membrane become evacuated of liquid (the resistance to the gas pressure decreases).

Drying times will be specific to the filter type and the drying apparatus. The following document offers guidance for drying times and pressures, and gives an overview of how a drying procedure should be evaluated:

Drying by applying a vacuum

This method is often used for the drying of vent filters in automated systems, such as freeze dryers. Applying a vacuum can considerably shorten the drying times so that a drying time below 1 h becomes feasible.
For more information, please see In situ drying of hydrophobic air filters prior to moist heat sterilization.

Cytiva uses a double-layer construction for sterilizing grade filter for combining the highest removal safety with optimum economics. Cytiva produces a range of sterilizing grade filter for use in liquids and gases, covering a wide range of target applications. The various filter designs address the respective application requirements and ensure optimum suitability for the target application.

Cytiva has historically used a double-layer construction for sterilizing grade filters, where the two layers consist of 0.2 µm rated membranes of the same type. This construction is well suited for final formulation and filling applications and critical gas filtration applications. Examples of filters with this construction include:

Other filters feature a construction of two membrane layers, where the upstream membrane layer has a different pore rating from the downstream layer, depending on the respective target application. This construction is well suited for the filtration of difficult-to-filter fluids or challenging contamination control tasks. Examples of filters with this construction include:

FDA and EMA authorities do not prohibit filter reuse, however, they strongly discourage reuse, especially for sterilizing-grade filters, as the increased risk of reuse must be mitigated by often extensive, process-specific validation studies.

Reuse of any disposable equipment is subject to risks and hazards that must be controlled to ensure the equipment remains safe and effective and continues to meet its manufacturer’s specifications and requirements for use.

Where justified, sterilizing filters may be reused in some cases, but their reuse must be validated to not compromise filter sterilizing performance or filtrate quality.

In addition to basic sterilizing validation studies, as recommended in PDA Technical Report 26 and FDA’s aseptic processing guidance, validation of multiply reused sterilizing filters should include thorough testing of process filters exposed to the maximum specified number of cleanings, re-sterilization, drying and reuse cycles. Integrity testing alone cannot be relied on to predict sterilizing performance of reused filters without adequate bacterial challenge validation employing used filter cartridges. Finally, users should carefully consider the level of risk and validation costs involved in satisfactory reuse of sterilizing filters versus the seemingly apparent economics of reuse when designing and qualifying sterilization filtration processes.

For additional information on sterile filter validation, refer to Reuse of sterilizing grade filters – considerations and risk assessments.