New, improved production methods and technology are helping to significantly improve product purity, ensuring optimal safety and improving yields of plasma-derived proteins in plasma fractionation. Pall leads the way with an unrivalled range of innovative products, technologies and integrated processes to protect and enhance both the quality and safety of your plasma products, including:
Intravenous immunoglobulin (IVIG) Processing
IVIGs are increasingly used to treat immunodeficient patients as well as autoimmune, inflammatory or neurological disorders, and continue to be one of the dominant drivers of growth in plasma fractionation today.
Bringing its latest state-of-the-art products and technologies together, Pall introduces a new strategy for the purification of IVIGs, enabling significant improvements in both quality and yield.
At the heart of this strategy is a new chromatographic purification method combining consistently high-yield manufacturing with dedicated removal of contaminants – all without impairing IgG recovery1.
1 Wu Y.W., Champagne J., Toueille M., Gantier R., Burnouf T., “Dedicated removal of immunoglobulin (Ig)A, IgM, and Factor (F)XI/activated FXI from human plasma IgG”, Transfusion, 2014 Jan; 54(1):169-78. doi: 10.1111/trf.12243. Epub 2013 May 23 (link to external site)
- High IgG yield: recovery >85% total, final purity >99.5%
- High removal of potentially side-effect-causing contaminants: <0.5% IgA and IgM, Factor XI undetectable
- No UF/DF between HyperCel™ S capture step and HyperCel Star AX sorbent intermediate step
- If required, Mustang S membrane absorber can be used to remove Factor XI to processes starting with Fraction II+III
Modern plasma fractionation processes include ethanol precipitation, with precipitates usually separated using a combination of plate-and-frame filtration and depth filter sheet technology. Target proteins can be captured in either precipitate of filtrate (supernatant) or both. The technology is used in combination with depth filter sheets which provide easy, fast and quantitative separation of precipitate in single-pass filtration, as well as high yield precipitate harvest.
Filtration offers higher protein yield in simplified and faster separation processes.
Clarification and Pre-Filtration
Cost reduction in subsequent steps in the 'downstream' process can be achieved by optimizing clarifying filtration. Our wide range of Seitz® depth filters allows a cost-effective, convenient format to achieve the right balance between filter life and downstream protection in the bulk of applications. Specially-developed Seitz depth filters for color removal, lipid removal, PKA removal and prion removal represent very efficient purification technologies.
Filtration of Resuspended Precipitate
The clarification of resuspended precipitate by filtration is an important step for the efficiency of further downstream steps. Depth filtration with Stax systems offers significant advantages in terms of yield increase, cost reduction and GMP compliance.
- Up to 75% reduction in hold up volume
- Up to 80% reduction in draining time
- Significant reduction in post-wash volume due to favourable filter area/housing volume ratio
- Yield increase compared to conventional depth filter systems
- Single use, no CIP required
- No costs for cleaning validation
- No risk of cross contamination
- Movable system and flexible to use at different process steps
Protein Capture and Purification by Chromatography
Chromatography has become an important technology for process improvement. Today, ion-exchange and affinity chromatography are widely used in the plasma purification process. High performance media, combined with efficient column and system operation leads to improved protein recoveries and higher product purity as well as removal of viral inactivation agents, such as solvent/detergents. Pall offers a rapidly-expanding sorbent range for high-capacity ion-exchange and mixed-mode chromatgraphy, solvent/detergent (S/D) removal sorbents, specific affinity capabilities and the additional advantages of high flow-rate membrane chromatography.
Removal of Solvent and Detergent Viral Inactivating Agent
Solvent/detergent inactivation (SDI) is a robust, well established method for viral clearance of protein solutions, widely applied in plasma fractionation and receiving increasing attention in the Biotech industry as well. A key challenge of SDI however, is the removal of the S/D agents from the treated protein solution.
Pall’s SDR HyperD Solvent-Detergent Removal Chromatography sorbent combines a high protein exclusion limit to maximize proteins recovered in the flowthrough and a purpose-designed adsorbent chemistry that provides efficient, high capacity removal of the S/D agents.
Ultrafiltration and Diafiltration
Tangential Flow Filtration (TFF) has long been established as a leading technology for concentration and diafiltration of plasma proteins. Continuous improvement of the cassette performance and new Innovations ensures further improvements in modern plasma fractionation processing. High performance PES and regenerated cellulose membrane cassettes combined with significant material and design improvements deliver:
- Optimum mass transfer
- Lower extractables
- Easy scalability
Single-use TFF Cadence single-use tangential flow filtration modules are supplied gamma-irradiated and ready-to-use. Providing ease-of-use, quick turnaround and increased flexibility, safety and containment in cGMP operations, they are easily implemented in Allegro single-use TFF systems, scalable from R&D to full production.
Preferably used for small and mid size plasma batches like hyperimmunes as well as less abundant proteins (like coagulation factors, antithrombin, α1-antitrypsin protease inhibitors).
High-Quality Bioprocessing Solutions
Pall provides scalable, benchtop or custom designed TFF systems to suit your specific plasma fractionation process needs, covering the full technology range from conventional stainless steel systems to single-use TFF systems.
Cadence™ Single Pass Tangential Flow Filtration Technology (SPTFF) Systems are capable of achieving high concentration in direct flow operation which substantially simplifies and streamlines downstream processing.
- Successful use of Cadence single pass TFF systems for concentration of albumin and IgG solutions demonstrated in case studies (see reference)
- The single pass TFF technology is ideally suited for processing of higher concentrated intravenous and subcutaneous IgG formulation
- Concentrate chromatographic column eluates in-line
- Direct coupling with other DSP process steps
- Improved recovery capabilities (> 98 %)
- Processing of shear-sensitive products
- Increased capacity at reduced costs
- Elimination of costly storage tanks
- Reduced system hold-up volume
Single-use, In-Process Volume Reduction
Cadence Single-Pass TFF In-line concentrator modules incorporate a patented fluid path design that enables in-process volume reduction without the need for a holder. The modules can easily be connected to a pressure source (pump or pressure vessel), or can be implemented in a system to reduce process volumes by a factor of 2–4 in direct flow operation.
For all plasma-derived medicinal products, it is an objective to incorporate effective steps for inactivation/removal of a wide range of viruses of diverse physico-chemical characteristics.
In order to achieve this, it is desirable to incorporate at least two distinct effective steps. Virus filtration has demonstrated robust and reliable viral reduction and is a state of the art virus safety step in plasma fractionation processing.
Pegasus™ SV4 Virus Removal Filters combine high viral clearance and process cost control. They demonstrate highly-efficient clearance of both small "non-enveloped" viruses and large viruses and offers high retention robustness to pressure interruption (also described as pressure release or start/stop).
The filter membrane ensures a constant and stable flow-rate when used with either dilute or complex/concentrated biological fluids, which significantly improves virus filtration economy in plasma fractionation processing. All cartridge filters and single-use capsules can be autoclaved. In addition cartridge filters are fully compatible with SIP (steam-in-place). An easy and reliable in-situ integrity test can be applied pre-use and post-use. The filter is complemented by fully-automated virus filtration systems including the Allegro MVP system designed with a fully disposable fluid path. All these systems enable consistent and precise operation with improved process efficiency.
The Allegro MVP single-use system was designed to perform the pH adjustment steps needed in media preparation and virus inactivation, with fully automated addition of acid and base stock solutions. Allegro mixers can be used with the MVP system, to ensure rapid dispersal of the added fluids during these process steps.
A large selection of pre-designed manifolds is available, with a specially designed manifold selection tool to help identify the most suitable manifold for your application. A choice of sensors, connectors, tubing type, filters and pre-filters when selecting a flowpath ensures the manifold is completely suited to your process application. Mustang® membrane adsorbers add the capability to remove viruses by chromatography in highly-efficient way. Where SDI inactivation is used, SDR HyperD® Solvent-Detergent Removal chromatography sorbent is also used to achieve satisfactory removal of the S/D agents, without reducing protein yields.
Sterilizing Filtration and Bioburden Control
All the way through the process - for buffer, vents and right up to final filling, Pall® filters for both gases and liquids assure the highest level of protection in IVIG processing.
New Pall-patented technologies are incorporated into several new sterilizing-grade filters, contributing to higher flow rates and superior throughput performance to meet the increasing demand in high concentration IVIG application.
Supor® ECV filters and Fluorodyne EX Grade EDF filter cartridges are validated high-flow, high-capacity sterilizing-grade filters. They are constructed with patented laid-over pleat technology combined with a built-in asymmetric prefilter layer.
- Enables superior high flow rates and throughputs also in complex and high concentrated IVIGs
- Significantly reduces COGS
A proven technology alternative in plasma fractionation offering several significant advantages over standard reusable stainless steel systems, single-use technologies can improve the handling of intermediates (freeze/thaw, liquid transport, storage), and can also:
- Reduce the risk of cross-contamination
- Remove the need for cleaning and associated cleaning validation
- Minimise capital investment
- Reduce lead times and the number of connections, to enhance sterility assurance
- Hold up volume and post wash volume
- Reduce COGS in water consumption and autoclaving
- Reduced consumption from utilities and energy
Let’s find the right solution, together.
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