An ideal liquid filter would have following attributes:
-The filter should have a high flow rate at low differential pressures
-The filter should have a high total throughput performance
-The filter must retain contaminants, especially microbial, as defined and desired
-The filter membrane polymer should be low adsorptive, if used in specific applications, which do not have the need of adsorptive retention
-The filter requires to have a high mechanical robustness to withstand possible differential pressure surges
-The filter requires to withstand up to 134 degC steam sterilization temperatures or be able to be gamma irradiated
Such filter represents the "perfect world". Most commonly one has to settle for a compromise between the listed attributes. There is no such filter optimal for every application. Liquid filters are commonly developed and designed to work best within specific applications.

Solvent (API) Filtration
Filters within this type of application require being highly compatible to aggressive solutions, like organic solvents or process parameters. Due to the destructive nature of the solutions utilized, the best filters to be found for such applications are Polyamide or Polytetrafluoroethylene membrane polymers. Before the filters can be used within such application, appropriate performance qualification trials should be completed to assure the filter is compatible with the fluid and process parameters. Especially subtle incompatibilities can cause major problems if not determine early enough. The liquid filters used in this application are polishing or bioburden reducing filters. The bioburden in aggressive solutions may mainly be spores as the fluids are commonly bactericidal. However, any potential contaminant requires to be removed to avoid microbial contamination in the downstream process.

Ophthalmics Filtration
Ophthalmic solutions require two main attributes, besides the obvious microbial retentivity; a) high total throughputs for cellulosic based complex solutions with high viscosities and b) low unspecific adsorption for solutions containing preservatives like Benzalconiumchloride or Chlorhexadine. The total throughput determination can take place via 47 mm disc trials (Indicator Trials) followed by verification trials with small scale pleated devices. The solutions are complex and may require pre-filter/final filter combinations. During the filterability trial work it is of importance to sample the filtrate in specific volume or time intervals and check the filtrate in regard to the preservative concentration, if applicable. Preservative adsorption to the membrane filter polymer is not uncommon and requires to be determined to avoid an out-of-specification event of the preservative level within the final container. Low adsorptive polymeric membranes should be used, for example Polyvinyldienefluoride, Cellulose Acetate or modified Polyethersulfone. It might be that the solution requires to be recirculated over the membrane to saturate the adsorptive sites, before the solution is redirected to the fill line. Often ophthalmic solutions are filled utilizing blow-fill-seal equipment, which could mean a prolonged filling period. If this is the case, the filter validation (retention study) requires including such prolonged filling periods.

Cell Culture Media
Media are available in large variety from different raw material sources and of different compositions. Moreover the raw material quality experiences seasonal, dietary, growth and regional variations, which makes it in instances difficult to define the exact quality and composition of the raw material. This factor can be challenging when filtration systems have to be chosen and sized. Therefore, the main performance criterion for filtration systems for media is total throughput or filter capacity, the total amount of fluid which can be filtered through a specified filtration area. Filters used in media filtration require to be optimized to achieve the highest total throughput and will be tested accordingly. To achieve reliable data, it is always of advantage when the test batch is at the lower end of the quality specification to gain a worse case scenario. Temperature, differential pressure and pretreatment of the filter play an important role in performance enhancement of the filter system (1). For example, it has been experienced that lower temperature of the media filtered and even the filter system, might enhance the total throughput by 30 %. The flow rate will be affected by the higher viscosity, but again the essential performance part is not flow, but total throughput. Too high flow rates in the filtration of biological solutions, showed the negative side effect of gel formation (fouling) on the membrane and therefore premature blockage. To start with lower differential pressure has been seen advantageous, as again gel formation and/or cake compaction will be avoided. The lower the differential pressure at start of the filtration, the better the performance. A pre-flush of the filter system with preferably cold buffer, will also enhance the total throughput. Hitting the filter with just the media has been found to foul the filter faster and therefore reduce the filter's capacity. In instances it is necessary to utilize pre-filtration combinations to avoid fouling or blocking of the sterilizing grade or 0.1 micron final filter element. These combinations need to be determined in filterability trials to gain the most optimal combination to filter the particular media and to size the system appropriately.
Another important, but often overlooked factor of media filtration is the influence of unspecific adsorption of the filter material. To separate lipids in the media raw material adsorptive filter media are desired. However, in cell culture media, especially containing growth promoters unspecific adsorption has to be avoided. Certain membrane polymers do have a higher unspecific adsorption. Sometimes the membrane polymer can be of similar type, but the surface treatment of the polymer is different or the design of the filter device is different. In any case, high unspecific adsorption can have an influence on growth promoters like IGF (Insulin-like Growth Factor).

Buffer Filtration
Since buffers are commonly of high purity the filter performance criteria focuses on flow rate and not total throughput. A premature blocking of the filter is often not experienced. Flow though is the determining factor of process time within the buffer preparation process. The faster the flow rate of the filter the higher the equipment utilization. The better the flow rate of the filter the lower the required effective filtration area, respectively the cost per liter will be reduced. For example, a low flow rate (2,500 L/hour), 0.2 micron-rated filter would require 48 minutes to filter a 2,000 liter volume versus only 20 minutes for a high flow filter (6,000 L/hour). This would reduce equipment use time by half or the effective filtration area could be reduced, which would cut filter costs.
Another important factor to consider is the buffer's pH range or the variety of buffers used. One can find is certain pharmaceutical processes that the pH ranges from 1 - 14, the full spectrum, which in some polymers are capable to withstand and others not. Again filter vendors are aware about this fact and developed high flow filters most often with a polyethersulfone base polymer as this material is compatible over the entire pH range.

Air & Gases
An ideal gas filter requires listed attributes:
-The filter must retain microorganisms and other contaminants, even under unfavorable conditions such as high humidity
-The filter must have high thermal and mechanical resistance
-The filter ought to withstand multiple steam sterilization cycles
-The filter should allow high gas flow rates at low differential pressures
-The membrane should be hydrophobic to resist blockage by elevated humidity, condensate or water remaining from a water intrusion test
-The filter must not release fibers
-The filter must be integrity testable with a test correlated to removal efficiency with various contaminants
An optimized air filter can be described as a perfected recipe, as all components utilized, the design of the filter require fulfilling the listed attributes. If only one of the attributes is focused on, it might be that the filter is imbalanced and does not meet other criteria of importance.

Fermentor Inlet Air
Air volume requirements vary during the different stages of fermentation and therefore the filter system used in large volume fermentation are of different sizes. For example filter systems size used for seed fermentors are usually single round 10" or 20" filter cartridges, whereby filter systems for large scale fermentation can have a size of 12 round 30", depending on the product and fermentor volume. Such filter systems are used on a long-term basis and could be used for over a year, i.e. these kind of filters require a high mechanical and thermal stability. Air filters withstand sterilizing cycles of up to 200 cycles at temperatures of up to 134 °C. The filter manufacturers optimized membrane filter cartridges to create high flow rates at very low differential pressures. Membrane materials were chosen to achieve high pore volumes, hydrophobicities and sterile filtration capability, commonly PTFE. Construction of the filter cartridges was optimized to avoid water logging and high velocities which created resulting pressure losses.
Fermentation can last up to 10 days, in instances of perfusion mode reactors up to 40 days, therefore high security is required. It would be disastrous in terms of the product intake and running costs, if such large scale fermentor became infected after several days of fermentation.

Fermentor Off-Gas
Off-gas filtration becomes a major concern and requirement, especially in the biotech industry. In the past most of the fermentation sites did not use any exhaust filter system, because the head pressure in the fermentor eliminated the risk of contamination from the off-gas side. Due to new restrictions and an environmental awareness, more and more facilities employ exhaust filter systems. The aim here is not to protect the fermentor content, but rather the environment of microbial contamination. For this reason different separation methods were evaluated, for example cyclones in combination with depth filter types or heat. Both methods do not create the assurance level needed, beside one is very costly, therefore the use of membrane filter system becomes common practice.
The filtration of exhaust gases creates some major problems due to the moisture content which the gas carries. The gas is usually warm and saturated with moisture due to the contact with the fermentation medium. When the exhaust gas cools down, large amount of condensate will be the result, which could water block the sterilizing grade filter and increase the pressure drop over the filter. An increase in pressure drop means an immediate rise of the head pressure of the fermentor, which needs to be avoided. Particles and microbial contamination carried over from the fermentor into the exhaust stream could block the filter device. The retentive ability of such filter needs to be high, otherwise organisms will penetrate through the filter element. In some instances the microbial load of such filter can be up to 1011 organisms in 7 days of fermentation. Often enough, when the microbial fermentation runs at the highest gas and agitation rate, foaming of the fermentor broth happens and can blind the filter.
Heating by steam and electrical tracing of the filter housings or pipe work will avoid condensation due to the fact that the system temperature is held above the dew point of the air. If condensation occurs, the filter needs to be able to achieve required flow rates due its hydrophobicity. Condensate will be repelled and drained from the system. To assure that the filter will not loose its performance due to foam reaching the membrane either antifoam agents are used or mechanical foam breakers like demisters and baffles or cyclones. Antifoam agents can have the disadvantage of fouling downstream processing filter devices rapidly, besides the antifoam agent needs to be sterile filtered. Mechanical foam breakers and cyclones avoid the mentioned disadvantages, but usually work only effectively at specific air flow rates which vary from phase to phase of the fermentation process. Fine aerosol carried over from demisters or cyclones can be separated by tight depth filter cartridges containing Polypropylene fleeces. These filters are very sufficiently protecting the costly sterilizing grade filter, due to the high dirt load capacity and a certain hydrophobicity, which avoids blocking of the depth filter fleeces. The void volume of these filter is very high, therefore the pressure losses are minimal. Particles and microbial contamination will be greatly reduced and the lifetime of the sterilizing grade filter prolonged.

Vent Filters on Tanks
Every pharmaceutical application uses tanks, containers and/or bags for a wide variety of purposes, for example storage tanks for intermediate or final products, water storage tanks, transport vessels or mixing tanks. Some applications only require a depth filter type, due to the product or medium stored in the tanks, which is unsuitable for any microorganism growth. Nevertheless most of the tank venting applications have in common that the air supplied into these tanks needs to be sterile and free of contaminations, usually achieved via a sterilizing grade, hydrophobic membrane filter.
When liquid is drawn from the tank or added to the tank, the air needs to be vented into or from the tank. Open to the atmosphere, the air needs to filtered through a sterilizing grade vent filter to avoid any contaminations. Often enough the product fed into the tank is sterile filtered and the tank steam sterilized, therefore the vent filter needs to perform with highest level to ensure sterility. The filter needs to be and remain hydrophobic to avoid any condensate blockage and microbial growth on or within the filter matrix, especially when the vent filter is used over a long period of time without steam sterilization. This often the case on water storage tanks, which hold water of lower quality than Water for Injection (WFI), which is stored at around 80 °C. The water temperature of WFI avoids or restricts microbial growth, but has the side effect of a high condensate rate, due to the high humidity of the air overlaying the hot water. A condensation of water on the filter cartridge can be avoided by using heat jacketed filter housings, preferably an electrical heater. Using such heat jacketed housing the filter cartridge must be visually checked on a routine basis, some manufacturers quote around every 3 months, to see whether parts of the filter are damaged by oxidization.
Non vacuum resistant tanks, which are steam sterilized, need to be equipped with an appropriately sized vent filter system to overcome the condensation vacuum, created by the collapsing steam when the tank cools down (1). If the filter system is not correctly sized or the vent filter blocks due to a low hydrophobicity, the imposed vacuum could cause an implosion of the tank. Therefore sizing of such vent filter systems is done by experienced and trained professionals. In instances, the volume of some tanks is too large to use a static vent filter system at that point compressed air is pushed into the tank via a sterilizing grade filter to break the vacuum in the tank. Implosion of the tank can also be avoided by using burst discs or pressure relief valves, which open up when the vacuum in the tank reaches the maximum allowable limit. Unfiltered air rushes into the tank and breaks the increasing vacuum, which means burst discs and pressure relief valves are just precautions in case of an insufficient working vent filter.
Vent filters on tanks and vessels are often enough steamed from the reverse flow direction. In this instance the differential pressure over the filter device during steaming needs to be operated carefully. Most of the filter manufacturers allow a maximum differential of 0.2 - 0.5 bar at around 134 °C steam temperature. Steaming in reverse direction is usually more stressful to the filter construction. It is therefore advisable to integrity test the filter system after steam sterilization.

Autoclave and Lyophilizer Vent Filter
In the past the vent filters used for autoclaves and lyophilizers were depth filter type cartridges, sometimes even coalescing type filters. Due to stringent quality standards and demands of the regulatory agencies, these filter were replaced by sterilizing grade membrane filters. When breaking the vacuum created in the equipment, the air vented into the chambers can come in direct contact with the product. Therefore, it is of great importance that these filters stand up to the quality requirements set, most importantly sterility of the gas vented into the chamber.
Another important aspect is the hydrophobicity of the filter membrane and the construction of the cartridge, as pointed out in the section on sterilizing grade filters. If the hydrophobicity of the membrane material used, is insufficient, the pore structure could block by condensate, especially after steam sterilization. At this point the vacuum in the chamber cannot be broken and the filter needs to be bypassed, which means the chamber is compromised with environmental air. It goes without saying that hydrophobicity is of major importance, yet in the field some filter users still have major problems with filters of lower hydrophobicity. Some users were even advised to use hydrophilic sterilizing grade filters to overcome the use of wetting media like solvent/water mixtures, just using water to integrity test the hydrophilic filters. To create airflow through this type of filter the Bubble Point needs to be exceeded, even when heat jacketed housings are in use. This does not only create insecurities but process failures. The construction of the filter cartridge needs to be optimized so that condensate can run into the condensate chamber and drain. The size of the filter system used on these units is usually bigger, due to the amount of condensation and the low differential pressures, down to 10 mbar, especially close to the end of the venting process.
These filters must withstand a high amount of steaming cycles. Some large volume hospital sterilizers are used up to five times a day and more, i.e. the filter will be steam sterilized five times. Certainly these filters are not changed every so often. The amount steaming cycles can be as high as 250 cycles. Often enough the steaming happens to be in reverse direction of the filter cartridge, which is a higher stress factor to the material and construction of the filter cartridge. The maximum differential pressure over the filter must be checked carefully, otherwise the filter could be damaged. Filter manufacturers quote maximum allowable differential pressure at elevated temperature of 134 °C from 0.2 - 0.5 bar. As one recognizes there is a higher risk factor of damage of these filter cartridges due to mentioned stress factors and therefore these filters should be integrity tested on a routine basis.
In the past the filters were either not tested and discarded after a certain period of time or tested off-line, before steam sterilization. These days, filter manufacturers offer integrity test methods, which are able to integrity test the filter in-place, even after steam sterilization. These tests methods either accommodate the common solvent/water mixture to integrity test the filter via Diffusion or Bubble Point test or just water for the Water Intrusion Test. Moreover, manufacturers of autoclaves and lyophilizers start incorporating fully automatic integrity tests methods in their equipment or advise their clients to install additional test equipment subsequently.

Filtration of Service Gases
Services gases are usually air and nitrogen used for pneumatic actuated valves and switches, head pressures of tank, transfer gases, drying purposes and filling machines. These gases need to be sterile, because they are commonly supplied into cleanroom or sterile areas and come in contact with the product or the container, like vials, flasks, bottles and tanks. Unfortunately, often enough these filters are overlooked, because there are so many in a standard pharmaceutical facility and sometimes not easily accessible or not obvious. This usually means that these filters are not integrity tested on a routine basis or not exchanged for a long period of time. Due to the more stringent requirements of the regulatory bodies, the awareness level for those filter units has increased and maintenance and quality assurance departments enforce checks on a regular basis.
With some exceptions, service gas filters are installed either not easily accessible or in pipe work, which is not steam sterilized. One major exception are blow-fill-seal filling machines. These filling machines mold the required containers, sterile fill them and seal the containers. The need of an excessive amount of sterile air for extrusion, cooling and overlaying purposes is obvious. Often these filling machines are equipped with up to four different air filtration units, for their different functions. Important here is that the air comes into direct contact with the plastic container and is introduced into the filling area. Therefore the emphasis of routine steam sterilization and integrity testing of the filters is evident.
Integrity testing of such filters is done off-line, otherwise the solvent/water mixture, used to wet the hydrophobic filter and perform the Diffusion or Bubble Point test contaminate the process. Tested off-line the filter is then flushed and dried, afterwards installed and steam sterilized. This certainly created insecurity, because there was no assurance that the filter was integral after steam sterilization. Nowadays water based tests, like the Water Intrusion or Water Flow Integrity Test are used to integrity test the filters in-place after steam sterilization As with the autoclave and lyophilizer vent filters, the filter elements can be tested fully automatically on a routine basis, preferably after every sterilization cycle.