Modern Sterile Filtration - The Economics

Sterilizing grade membrane filters are widely used for the intermediate and final filtration of liquid drug products. Their function is either to reduce the bioburden level within intermediate production steps or to sterilize the final filled product. In 1918, Nobel Prize winner Richard Zsigmondy invented membrane filters that found commercial use in the pharmaceutical industry during the 1930s as flat filter devices (mainly 293 mm discs) and during the 1960s as pleated filter cartridges. When Pseudomonas diminuta (now Brevundimonas diminuta) penetrated 0.45 µm rated filters, the standard for sterilizing grade filters became 0.2 µm. In 1982, the Health Industry Manufacturers Association (HIMA) stipulated that these filters must retain 107 per cm2 B. diminuta; this is now (since 1988) required by the American Society for Testing and Materials (ASTM).1,2 Since this time, appropriate process validation has received greater priority than pore size ratings; under process conditions, such validation has provided a catalyst for improvement. This article evaluates performance developments of sterilizing grade filters during the last decade and the unfulfilled optimization potential of these systems compared with revalidation costs.

History of sterilizing grade filters

Materials. Flat 293 mm disc holders (Figure 1) or manifolds were used in process filtration before pleated filter cartridge devices (Figure 2) were developed. Such manifolds had disadvantages including a large footprint, possible leaks, cross-contamination and difficult assembly. The first pleated filter cartridge devices were designed and built to provide a larger filtration area within a smaller filter. These devices had a filtration area of approximately 4000 cm2 and a cylindrical pleat pack that was resin-bonded to the end caps.

Figure 1: A 293 mm flat filter holder.

Polyester materials were commonly used in the prefilter and support fleeces in the filters. Both the polyester and the resin (used to bond the membrane to the end cap) gave the filters low chemical and thermal resistance because of oxidative degradation during use. Furthermore, the fleece and resin components added to increasing extractable levels, which would be unacceptable under current standards. Cellulose acetate, cellulose nitrate, mixed cellulose esters, polyamide and polyvinylidenefluoride were the most commonly used filter membrane materials. These materials usually included surfactant or membrane surface treatments to achieve pleatability, wetability and membrane stability. Large water flush volumes were required before the filter could be used to wash out any residual surfactant or treatment.

Figure 2: A resin-bonded filter cartridge.

Optimization. The next development phase to optimize sterilizing grade filter products was replacing the resin bonding with heat welded thermoplastic materials used in the end caps, core, outer support and bonding materials (Figure 3). These filters demonstrated higher chemical, thermal and mechanical resistance, but still generated membrane weaknesses or potential membrane damage if an excess of welding material (commonly polypropylene melt) was forced into the tight pleats of the membrane. This could create hydrophobic spots that showed false negative integrity test results. Pleating of the membranes and the support layers developed further, and a higher pleat density was achieved resulting in significantly increased effective filtration areas from 0.4 m2 to up to 0.75 m2. To avoid inefficient use of the entire pleat pack, new fleece structures were developed to gain a wide enough gap between the pleatings.

Configurations. In addition to optimized prefilter fleeces, different membrane filter configurations were utilized as a single layer (for example, 0.2 µm only), a homogeneous double layer (for example, 0.2/0.2 µm) or a heterogeneous double layer filter (for example, 0.45/0.2 µm). Depending on the filter configuration, these filters displayed an effective filtration area of up to 7500 cm2. This represented a 15 fold increase compared with the 293 mm disc filter area and a 1.9 fold increase compared with the first pleated filter. The development of an effective filtration area resulted in a tremendous increase in total throughput for the industry; heterogeneous double layer membrane configurations increased the total throughput furthermore because of a fractionate retention of any contaminant. The contaminant load no longer restricted itself to the 0.2 µm final filter membrane.

Figure 3: A high pleat density filter cartridge.

Ultrasonic technology. To avoid heat welding weaknesses, ultrasonic welding was utilized and is still currently used. This allowed the mechanical and thermal stability to increase to an extraordinary level, considering the fragility of the membrane material. With polymer evolution, additional treatment steps and new membrane refinements eliminated the use of wetting agents and surface treatments that previously caused increased extractable levels and high flush volumes.

Surface treatments were included within the membrane production process, leading to chemical integration in the membrane matrix instead of having an individual membrane modification step. This also meant that the hydrophilicity of the membrane was retained even under stringent conditions such as steam sterilization or sodium hydroxide contact. The leachable level of such membranes was greatly reduced because of bonding between the surface treatments and the membrane. End caps. Eventually, polyester end caps became obsolete in multiple use applications such as air filtration because of the oxidization and degradation of the polymer. The most common end cap and support material is now polypropylene, which complies with regulations; some new poly-propylenes are also gamma irradiation stable. Safety was also enhanced by improving the designs of filter cartridge adapters, which are now tightly installed into the recess of filter housings. Instead of a double step adapter (where one O-ring is smaller than the other [also known as 2216 and 2218]), adapters with double O-ring seals of similar size (also known as 2226) and with bayonet locks are commonly used.3,4 This type of adapter is more secure because of the firm seat of the filter cartridge housing, particularly during variable pressures, back pressures and steam sterilization conditions. The increase in effective filtration areas and the new membrane configurations allowed higher flow rates and total throughputs, which still incorporated the same geometric dimensions as the first filter cartridges (Figure 4).

The status quo

Today, the design and construction of sterilizing grade membrane filters are optimized to fulfil the ever changing and increasingly stringent requirements of regulatory authorities and the biopharmaceutical industry. Optimization is continually evolving and has led to the following features of modern sterilizing grade filter elements:

• steam sterilization resistance up to 134 ºC and gamma irradiation resistance

• minimal amount of extractable substances

• mechanical resistance of 5000 pulsations at 5 bar differential pressure

• low adsorptivity grades

• optimal total throughputs to significantly reduce costs per litre

• optimized flow rates to reduce the processing times or effective filtration area

• integrity testing of common non-destructive tests, such as diffusive flow, pressure decay, water intrusion or bubble point

• full validation documentation and individual process validation under process conditions with the actual drug product.

Major filter manufacturers not only improved their production processes, but also asked the biopharmaceutical industry to help find reliable solutions. Research and development (R&D) investment in filter elements enhanced aseptic process security and also improved production economics. Today, filter production is undertaken to the highest pharmaceutical quality standards. By receiving input from the industry and regulatory authorities, filter manufacturers are able to produce a wide range of optimized filter products.

Table I: Total cost calculation of a historic and modern optimized filter system.

Savings. The total throughput of commercially available filters today is double compared with filters supplied 10 years ago (Figures 5 and 6). Improvements to reduce the effective filter area have resulted in a decrease in the running costs per litre and associated capital costs. Expensive multi-round stainless steel filter housings can now be replaced by single-round housings; a particular application that required a 3320 in. housing a decade ago, today only requires a single-round 30 in. housing. This, potentially, means a capital cost reduction of up to 70%. A similar cost calculation for filter elements can be demonstrated; assuming that a 10 in. filter element costs $150 and the filtration system is used for 200 days, then the consumable expenditure of multi-round versus single-round would be $900 and $450, respectively. This would give annual savings for consumables of up to $90000 (Table I).

Additional savings can be made but are often overlooked; for example, the integrity testing of multi-round housings (large volumes) is difficult and can result in longer downtimes, particularly in high water flush volumes. Assuming the net volume (housing including filter elements) of a 3320 in. multi-round housing is 6 L and that of a 1330 in. housing is 2 L, an additional 4 L are required just to fill the multi-round housing. Also, the assembly of 3320 in. filter elements requires a minimum of double the flush volume compared with a 1330 in. element. This would be 30 L more if it is assumed that there is only a 10 L flush volume per 10 in. filter cartridge. Therefore, the total amount of higher flush volume of water for injection (WFI) would be 34 L more at every filtration run, which would result in additional WFI usage of 6800 L.

Figure 4: A flow rate comparison of different sterilizing grade filter developments. Membrane material is 0.2 µm cellulose acetate and Figure 5: Total throughput comparison of 0.2 µm sterilizing grade filter cartidges with polysulfon (PS) membrane materials.

Savings differ greatly from application to application. In some, the throughput does not have much importance; however, processing time (flow rate through the filter element) is important. Some applications require a high batch volume filtration; therefore, an improved filter cartridge with enhanced flow rates allows high batch volumes to be processed faster without changing the equipment dimensions.

Use in industry

Although membrane filter performance has greatly improved, some aseptic processes that utilize the filters have not advanced significantly. Filters resembling those used more than a decade ago are still used today - possibly because of regulatory implications or a reluctance to change.

Obsolete filter products still seem to find a use, despite revalidation becoming easier5,6 and the savings that could be made by upgrading. All major filter manufacturers offer validation services and some provide a range of additional support services. Previously, such services and guidance were not available. Now, however, process validation and revalidation are necessary requirements that are well documented.

Support services are additionally available when conditions change during stability tests. Filter manufacturers have also established thorough testing procedures, such as monitoring adsorption levels of individual membrane polymers.

Figure 6: Total throughput comparison of 0.2 µm sterilizing grade filter cartidges composed of polyvinylidenefluoride (PVDF) membrane materials and Figure 7: Throughput trials with different prefilters (47 mm discs).

Outlook

Because of economic pressures and the need for increased efficiency, the biopharmaceutical industry is looking to use the most up-to-date equipment whenever possible. This has meant improved quality systems being installed within the filter manufac-turing process. Although the performance of individual equipment can be improved, this does not imply that such improvements can only be achieved by exchanging types of filters. Improvements made to sterilizing grade membrane filters has meant that prefilters have also been thoroughly reviewed by manufacturers (Figure 7).3,7 Performance and economic improvements can be enhanced by finding the optimal solution or combination of pre- and final filter. To find this optimum, filter manufacturers have established software-driven, highly effective filterability test systems and methodologies.

Initial trials are normally performed with 47 mm filter disc composites to establish the optimal retention rate/pore size combination. Once this optimal combination has been found, filter trials are performed with small-scale pleated filter devices. Filterability trials are useful in identifying the correct filtration combination and size; moreover, the filtrate of these trials can be used to test for any yield or activity losses resulting from unspecific adsorption. Yield losses, because of unspecific adsorption and undetermined dead volumes, must be avoided, particularly with low volume/high value products; for example, monoclonal antibodies or blood fractions. Any yield loss reduces the available production capability and product profitability. Evaluating filter size and material is a priority during the development and scale-up phases, and both should be evaluated within an existing filtration process.

In addition to improvements in filter equipment, filter systems have developed to become disposable, such as capsule filters. These are available in larger sizes with up to 1.8 m2 of effective filtration area. The benefit of such systems is the reduction in cleaning and downtime, resulting in reduced costs. Operator protection is enhanced because the user is not exposed to the filter and separated contaminant during filter exchange. Installing disposable filter systems is easier and avoids the risk of possible O-ring damage, which can occur in classical filter systems.

Summary

Sterilizing grade filters have experienced remarkable improvements during the last decade (such as thermal and mechanical stability), resulting in reliable, cost-effective filter units. Previous concerns regarding leachables from resins and surface treatments have almost been eliminated because of raw material and production process improvements. Additionally, the performance of sterilizing grade membrane filters (throughput and flow rates) has doubled, equating to lower costs per litre, and reduced downtimes and production times. Filter manufacturers are also providing a range of support services, and validation and revalidation support.

References

1. ASTM Committee, "Standard Test Methods for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration," Annual Book of ASTM Standards (American Society for Testing and Materials, Philadelphia, Pennsylvania, USA, 1988) pp 790-795.

2. "Microbiological Evaluation of Filters for Sterilizing Liquids," HIMA Document 3, Volume 4 (Health Industry Manufacturers Association, Washington DC, USA, 1982).

3. M.W. Jornitz and T.H. Meltzer, Sterile Filtration - A Practical Approach (Marcel Dekker, New York, New York, USA, 2001).

4. P. Soelkner and J. Rupp, "Cartridge Filters" in T.H. Meltzer and M.W. Jornitz, Eds., Filtration in the Biopharmaceutical Industry (Marcel Dekker, New York, New York, USA, 1998).

5. www.fda.gov/cder/guidance/4163fnl.htm

6. PDA Technical Report No. 26, "Sterilizing Filtration of Liquids," PDA J. Pharm. Sci. Tech. 52(Supplement Number 1), 1-34 (1998).

7. R.V. Levy, "Sterile Filtration of Liquids and Gases," in S.S. Block, Ed., Disinfection, Sterilization and Preservation (Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, USA, 2001).