Filtration Technologies Advance to Meet Bioprocessing Needs

May 01, 2015
Volume 28, Issue 5


The harvesting of biologic actives from cell media and other downstream separation processes, such as viral clearance, rely on filtration technologies, in large part due to the sensitivity of biomolecules to heat and many chemical treatments. This sensitivity precludes the use of alternative methods. Filter manufacturers have been challenged with increasing titers and cell densities, greater expectations for viral clearance, and the desire of biopharmaceutical manufacturers to employ single-use technologies at an increasingly larger scale. They have responded with higher-capacity, higher-performance filters based on new materials, membrane structures, and filter designs.

Market size
The global pharmaceutical membrane filtration market was estimated by Markets and Markets to be valued at $3.69 billion in 2013, and the market research firm expects it will grow to $7.96 billion by 2018 (1). This estimate includes microfiltration, ultrafiltration, nanofiltration, reverse osmosis, and ion-exchange filtration technologies used for cell separation, protein purification, sterilization, virus removal, and water management. In 2013, protein purification accounted for the largest share of the filtration market, but demand for membrane filters for sterilization is growing the fastest. Overall drivers of the market for membrane filters include the growth of the global pharmaceutical/biopharmaceutical industry, particularly in the Asia-Pacific region and in other emerging markets. Increasing demand for single-use technologies is a second important driver of growth, according to Markets and Markets.

The move to single-use
The adoption of single-use technologies for downstream biomanufacturing processes can present filtration challenges. The use of disposable technology has grown, however, to cover more process operations and larger scales of production. “Filtration technology has evolved to adapt to these challenges as suppliers leverage new materials and innovations that enable higher capacities,” asserts Richard Pearce, director of downstream processing for EMD Millipore. He adds that the integration of filtration technologies into larger scale single-use manufacturing processes must also be addressed; as the trend for larger scale, single-use manufacturing systems grows, filtration technologies will need to be able to operate in this environment. Pearce believes that products offering more efficient filtration will lead to a reduction in the size of filters, thus simplifying their integration with single-use technologies.

Handling higher cell densities
One of the key trends in biopharmaceutical manufacturing over the past decade has been the dramatic increase in titers and subsequently, cell densities enabling drug manufacturers to shift from large 10,000-L stainless steel reactors to smaller disposable bioreactors, according to Rene Faber, vice-president of filtration technologies at Sartorius Stedim Biotech. He also notes that biopharmaceutical products are becoming more difficult to filter. These higher cell densities and titers have introduced challenges for initial clarification in monoclonal antibody production. “Existing filtration technologies don’t have the capacity to handle these large cell masses. In addition, manufacturers are adding additives into the bioreactor in order to help with clarification steps, and filtration technologies must have the capacity to handle them,” says Pearce.

At the same time, the demand for higher standards of filter performance, economy, safety, and impact on final product quality continue to challenge filter vendors, according to Oliver Triebsch, senior director of marketing with Pall Life Sciences. He notes that this need for better economy (filter capacity per cost) is also driven by the higher-concentration, more challenging-to-filter fluids coming from bioreactors, or alternatively, a need to process clean fluids more rapidly.

Filter manufacturers have responded to these challenges by developing high-capacity filters with the ability to process higher masses of protein or cell mass with better retention performance. For example, EMD Millipore has introduced new products for clarification that retain cell mass, precipitants, and flocculants, providing an excellent level of protection to the downstream steps, according to Pearce.

Innovative pleat geometries and advanced membrane designs have also been developed to address flow rate or throughput demands, according to Triebsch. “Such enhancements enable quicker processing at stable flow rates in combination with high volumetric throughputs until blockage, and provide consistent processing with reduced filter footprints and more manageable filter costs,” he says.

High-performance depth filter media in disposable filter capsule devices have also been introduced that increase process efficiencies and address the needs for simplicity, safety, speed, and intuitive operation, according to Triebsch. “These filters remove whole cells and debris in monoclonal antibody or recombinant protein processes and improve existing filtrations while eliminating the need for centrifugation,” he observes.

Tailor-made depth filter grades for the vaccine industry also deliver high virus yields with significantly reduced turbidity, enabling efficient, robust, and economic cell and cell debris removal from the bulk reactor output containing the virus or virus-like particles directly after cell culture.

Sartorius, for example, focused on the need for large-scale single-use filters so that customers could have an integrated, modular, single-use cell-harvesting system for modern processes with high cell densities, according to Faber. To do so, the company adapted dynamic body-feed (DBF) filtration technology from the plasma and food and beverage industries, which enables the filtration of feedstreams with high-particulate loads. “DBF is similar to depth filtration, but a high-purity diatomaceous earth (DE) is used with cell material to form a cake that acts as a very efficient filter layer, providing high productivity and reproducibility for a variety of feedstocks, even with high biomass,” Faber says.

Innovative new technologies for primary and secondary clarification will still be needed as cell densities coming out of bioreactors continue to increase, according to Pearce. Better retention with those high cell masses will also be important. EMD Millipore, Sartorius, Pall, and other filter manufacturers are investigating new materials, new variations on existing materials, and new filter designs.

Focus on tangential flow filtration
Tangential-flow filtration (TFF) has faced challenges as well, and in particular the need to recirculate the concentrating sample through a TFF cassette using a pumping system has been problematic. Recirculation results in a constantly varying solute concentration in the recirculating feed, extending process times—which can impact product stability—and causing potential exposure and damage to shear-sensitive biological products during the recirculation process, according to Triebsch.

To address this issue, Pall Life Sciences has developed single-pass TFF systems based on proprietary cassette designs and flow paths that enable the concentration of target bioproducts without the need to recirculate the retentate. “With these systems, the consistency of the feed, retentate, and permeate is maintained during the entire filtration process, minimizing the specific filtration process time and eliminating the potential issues associated with recirculation of the retentate and feed,” Triebsch explains. In addition, he notes that the filters are suitable for monoclonal antibodies, antibody fragments, immunoglobulins, and enzymes; are reliably scalable; can be effectively coupled with chromatography (column and membrane) steps and other unit operations; and can operate continuously.

Other harvesting challenges
Other challenges related to filtration still need to be addressed. Pearce notes that there is a need for filtration technology for the primary clarification step that will work with a variety of feedstocks. “We currently have good technologies for mammalian feedstock and mammalian feedstock with added flocculants and precipitants, but there is a wide range of flocculants and precipitants that must be addressed.”

Filtration of high-concentration final protein formulations also poses challenges. The high viscosities of these solutions require pressures that make it difficult to use existing ultrafiltration (UF) technologies, and as a result, the recovery of those systems is more involved and a greater burden is placed on the filtration steps, according to Pearce. To address this issue, EMD Millipore has developed a range of filters that can process concentrations over 200g/L.

The growing numbers of antibody-drug conjugates (ADCs) in development also require advanced filtration systems, according to Faber. “These biopharmaceuticals are particularly challenging because they are highly potent and require special handling to protect operators and reduce the amount of wash water needed, because water used for processing highly potent compounds must be burned for disposal, which is very costly,” he explains. For example, ADC manufacturers are looking for fully closed, single-use crossflow cassettes and fully automated systems that are compatible with organic solvents needed for ADC production, Faber notes.

Meeting demanding virus filtration needs
In the area of virus filtration, currently available high-capacity virus filters are now challenged with higher log-reduction values for the retention of viruses and small organisms while maintaining performance under variable process conditions, such as depressurization during process interruptions, according to Pearce. To address this issue, membrane morphologies have been carefully adapted to combine high viral clearance of small viruses like parvovirus with high-throughput capacity and been demonstrated to provide constant, stable flow rates in both dilute and more complex and concentrated biological fluids, according to Triebsch. For these next-generation virus removal and sterile filter membranes, EMD Millipore uses a patented selective layer technique, while Pall has implemented an innovative laid-over pleat filter construction and narrower cores. Sartorius uses an advanced asymmetric hollow-fiber membrane structure that ensures high capacities with no impact on virus retention through pressure variations, high loads, or process interruptions. The filter comes ready-to-use, which eliminates costly sanitization and is gamma compatible for easy implementation in single-use mAb processes, according to Faber.

New bioproducts, continuous manufacturing, and more
As newer bioproducts are designed and developed, there will always be a need to generate relevant application support information and new products. “The preference is to employ existing, well-established and industry-accepted products, but as newer molecules such as antibody constructs and conjugates, viral vaccines, nanoplexes, and cell therapies, etc., are developed, there may be a need to supplement existing filtration products with additional membranes or housing components with different properties, including porosity or chemical and biological compatibility,” states Triebsch.

Customers are also beginning to look at the overall cost of filtration processes with the desire to reduce them. “The filter is only a small part of the filtration process costs. Minimizing WFI and energy consumption is becoming important for many biopharmaceutical manufacturers, as is the better utilization of existing manufacturing infrastructure. Most are also looking to improve the yields of their filtration processes, because in general, biologic substances are very valuable, and even a small increase in recovery can significantly improve the overall process economy,” comments Faber. He notes that filter manufacturers can help address these issues by modifying the surface chemistry of filters to reduce the adsorption of biomolecules on their membranes.

Legacy filtration processes come increasingly under scrutiny of regulatory agencies looking for more information on the design and development of filtration processes. “We are finding that if appropriate quality-by-design approaches have not been applied properly, in some cases, filtration processes lack sufficient reproducibility and must be further optimized to meet regulatory requirements,” Faber observes.

The ability of filtration technology to be employed for continuous manufacturing is another issue that filter producers are tackling today, according to Pearce. “We expect that as the adoption of integrated continuous processes proceeds, the application of continuous filtration processes will become more established, and in fact, enable continuous operations,” asserts Triebsch. At the same time, he believes that continuous, integrated downstream processing will facilitate new applications and modes of use for filtration processes.

For the longer term, filter manufacturers are developing filtration technologies that can provide both separation and purification through combination of the size exclusion and physical removal capabilities of filtration with the charge and affinity capabilities of purification, according to Pearce. “The creation and use of new materials will be required, and the challenge will be to develop these technologies in a cost-effective manner and in forms that can be used for single-use and large-scale manufacturing,” he states. “There are new materials that enable very high-surface-area filtration with high permeability, and it will be interesting to see if they can be produced cost effectively for downstream manufacturing,” Pearce adds.

Article Details
BioPharm International
Vol. 28, No. 5
Pages: 26–28
Citation: When referring to this article, please cite it as C. Challener, "Filtration Technologies Advance to Meet Bioprocessing Needs," BioPharm International 28 (5) 2015.


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