the second one is a smart surface modifica- tion. Alternated Pleating Technology. The effective filtration area (EFA) pe
F i lt r at i o n
Filtration Technology Revisited Adjusting Filter Standards It is becoming increasingly important for the biopharmaceutical industry to reduce production costs. In this regard, the latest developments in filtration technology focus on three main factors: filtration efficiency, process safety and cost-effectiveness. This article describes two innovative technologies implemented in the new Sartopore Platinum filter cartridges featuring performance specifications that significantly help optimize processes and filter handling.
Polyethersulfone (PES) membranes are characterized by high total throughput and flow rate performance, reliable microbial retention and broad chemical resistance in a pH range of 1-14. Additionally, two innovative technologies have been established in these new filters in order to further increase throughput and flow rate performance, improve thermal resistance and wettability, and to reduce protein binding. The first of these technologies is a newly developed geometry of the filters and the second one is a smart surface modification.
Alternated Pleating Technology The effective filtration area (EFA) per cartridge must be maximized to obtain the best possible performance without influencing the hydrodynamics during filtration. If the individual pleats are packed too densely, the liquid, which is undergoing filtration, cannot access all parts of the membrane. Consequently, this will lower the over-all filtration performance. As the liquid approaches the inner diameter of a cartridge there is gradually less space (fig. 1). To address this issue an alternating sequence of long and short pleats was introduced, which increases the membrane area, especially in the outer diameter region, whereas the membrane area nearest to the inner diameter remains unchanged. In combination with the specific angle of the pleats, this so called Twinpleat geometry increases the membrane area by 66% – 1 m2 per 10” cartridge.
Membrane Surface Modification The second key technology of the new filter is a special modification procedure of the PES membrane. Basically, PES is a hydrophobic polymer. In order to render the PES membrane surface hydrophilic to allow filtration of aqueous solutions, a special modification treatment during membrane manufacture is required. In this case an exceptionally hydrophilic polymer with remarkably high thermal resistance is covalently bonded to the membrane, covering its entire surface.
Accessibility of the Membrane The Twinpleat technology not only increases the effective membrane surface, which directly affects the total throughput. It also ensures optimized hydrodynamics during filtration and total accessibility of the membrane. This can be visualized by filtering a colored test solution through comparable cartridges
34 • GIT Special · Separation 1/2013
Filtration
with and without this special geometry. The colored test solution stains the Sartopore Platinum membrane entirely brown, including all parts of each pleat. The same test procedure for a competitor cartridge leads to white patches between the pleats (fig. 2). These white patches cover up to 30% of the membrane area indicating that a large part of the membrane was inaccessible to the liquid and, consequently, unused in the filtration process. The improvements provided by the new geometry reduce the amount of filter cartridges needed to reliably filter the same quantity of solution, which also positively affects the total filtration costs.
Scalability Direct linear scale-up from small elements to large process-scale filters requires comparable performance data per membrane area. Here, even the smallest pleated elements (size 4 capsule, 0.021 m2) show a total throughput per square meter of filter area that is almost identical to a 30’’ cartridge with 3 m2 (fig. 3). Therefore, linear scale-up during the different stages of product development is guaranteed.
Flushing Volume for Reliable Wetting Reliable wetting is required for integrity testing of sterilizing-grade filters. In most cases, Water for Injection (WFI) is used for wetting. WFI itself costs at least € 3-5 per liter. According to the wetting instructions of many filter manufacturers (5 min of wetting at 300 mbar), roughly 100 l of WFI are required to wet out a single 10’’ cartridge reliably. The increased hydrophilicity of the developed, modified PES membrane shows enhanced wetting behavior requiring fewer than 5 l of WFI for a 10” cartridge.
Importance of Thermal Resistance Thermal resistance also plays a crucial role because filter cartridges need to withstand thermal stress especially during the heating and cooling phase of steaming and autoclaving. The high thermal resistance of the surface modified PES membrane enables it to withstand situations like dry steaming, either in a forward or a reverse direction, without its flow characteristics, wetting behavior or integrity values being affected. As soon as a filter becomes difficult to wet, this tends to increase WFI usage and, even more important, the risk that the cartridge will fail an integrity test. This means that this test has to be repeated, which involves more intense rewetting. The risk of test failure also significantly increases the subsequent risk of losing an entire product batch. Keeping in mind that the cost of a single batch can easily reach a few hundred thousand euros, any risk of failing a test or even of losing a batch must be avoided in any case. The thermal resistance of the modified surface combined with optimized wettabiltiy allows the filters to be reliably integrity tested even after exposing them to extreme conditions.
Low Nonspecific Protein Binding It is common practice to filter solutions containing biomolecules, such as proteins, polysaccharides, lipids, and nucleic acids. For effective filtration a filter material with low nonspecific protein binding is beneficial. The amount of protein binding to membranes is specific for different molecules. In this study monoclonal antibodies (mAbs) were used as test molecules to quantify nonspecific protein binding. Such target proteins have a high value (€ 500–1,000 per
Standard Pleating
Twin Pleat
Fig. 1: Twinpleat technology. The arrangement of the pleats at a specific angle, combined with an alternating sequence of long and short pleats, increases the membrane area by 66 %.
F i lt r at i o n
Sartopore Platinum
Competitor A
Fig. 2: Accessibility of the membrane: By filtering a brown test solution, it was demonstrated that Sartopore Platinum uses the entire membrane area available for filtration. A competitive pleating technology results in white patches between the pleats, covering up to 30%; i.e., the area is not completely used in filtration.
Fig. 3: Standardized total throughput (kg/m2 EFA, yellow bars) for different filter sizes (red curve: increasing membrane area). All pleated elements show similar total throughput per m2.
gram), thus, a loss of yield because of nonspecific binding can be very expensive. Figure 4 shows the protein binding of different filter cartridges. It can easily be seen that the nonspecific binding is the lowest for the left filter (with surface modification). In this case the binding of mAbs to the membrane material is lowest, which means that less protein is lost because of nonspecific binding. Of course, the specific quantity of loss in yield depends on the particular protein, cartridge type and membrane area. But this example shows the importance of factors like nonspecific adsorption that impact total process costs.
Single-Use Applications The trend toward single-use bag systems also poses the requirement of testing filter cap-
36 • GIT Special · Separation 1/2013
Fig. 4: Comparison of unspecific protein binding (example of a monoclonal antibody) of different filter cartridges. Although Sartopore Platinum has the largest membrane area per cartridge, it shows the lowest protein adsorption, which leads to significantly higher product yields.
sules that are mounted on a bag. First, to perform a pre-use test, the filters have to be wetted while mounted directly on the bag system. This requires an additional bag just for collecting the water used to wet the membranes. For these filters users can employ the smallest bag size, which saves space and costs. Combined with the reliable integrity testing the risk of obtaining false-negative results is eliminated, which otherwise would require rewetting and retesting.
Conclusion Two new technologies used in sterilizinggrade filter cartridges of the Sartopore Platinum filters are presented. The enlargement of their effective filtration area by the Twinpleat technology, combined with their new surface-
modified membrane properties, results in remarkable filtration performance, coupled with high process safety and significantly lower cost of ownership.
Contact Dr. Jens Meyer Product Manager Filtration Technologies Sartorius Stedim Biotech Tel.: 0551/308-3534
[email protected] www.sartorius-stedim.com
