Cost efficient approach for quality premium biomedical grade polymers

To produce high purity polymers for biomedical use, a purification step is usually required. After the synthesis step(s) of polymers, heterogeneous polymeric populations in terms of size and/or chemical properties could be obtained as well as the generation of by-product(s). Consequently, the need to remove different types of impurities or contaminants is required, such as removing low molecular weight monofunctional organic polymers derivatives, solvent or additive traces, to purify high molecular weight polymer products. To ensure cost efficient approach and avoid techniques such as ion exchange chromatographic approach or additional protection/deprotection steps, the Tangential Flow Filtration (TFF) technique has proved to be an efficient method for lab and industrial production.

Tangential Flow Filtration Technique

Membrane filtration is a widely used separation technique in the field of life science, and it is categorized based on membrane porosity into microfiltration and ultrafiltration (Figure 1). Microfiltration involves membranes with pore sizes ranging from 0.1 to 10 micrometers and is typically used for tasks such as clarification, sterilization, removal of microparticles. In contrast, ultrafiltration uses membranes with much smaller pores, between 0.001 and 0.1 micrometers, and is employed for concentrating and desalting dissolved biomolecules like proteins, peptides, carbohydrates, as well as for buffer exchange and broad molecular fractionation. Unlike microfiltration, ultrafiltration membranes are usually defined by their molecular weight cut off (MWCO) rather than pore size.

Figure 1. Schematic representation of filtration technique versus biomolecule size

There are two main operational modes for membrane filtration: Direct Flow Filtration (DFF) and Tangential Flow Filtration (TFF).

Figure 2. (A) The feed is introduced into the membrane, where molecules larger than the pore size accumulate on the surface, forming a gel layer. This buildup leads to membrane fouling, which obstructs the flow of liquid. As more volume is filtered, fouling intensifies, causing a rapid decline in the flux rate. (B) In tangential flow filtration (TFF), the media solution moves through the feed channel, flowing both across the membrane surface and through it. This crossflow action helps prevent the accumulation of molecules on the membrane, which can lead to fouling. Unlike direct flow filtration, TFF minimizes the rapid decline in flux rate, enabling a larger volume to be processed per unit area of membrane surface.

DFF, also known as dead-end filtration, directs the fluid perpendicularly toward the membrane, aiming to push all of it through. However, this can lead to clogging as larger particles accumulate on the membrane surface, forming a barrier that hinders further filtration. On the other hand, TFF, or crossflow filtration, moves the fluid parallel to the membrane surface. In this mode, part of the fluid passes through the membrane (the permeate), while the rest (the retentate) is recirculated. This continuous flow helps prevent the buildup of particles on the membrane, maintaining efficiency and allowing smaller molecules to pass through more easily. In solution, TFF reduces the formation of a gel-like layer on the membrane surface, known as gel polarization, by sweeping away aggregating molecules. This makes TFF generally faster and more efficient than DFF for separating molecules by size.
The primary applications for TFF are concentration, diafiltration (desalting and buffer exchange), and fractionation of large from small biomolecules. TFF⁽¹⁾ can be used to concentrate and desalt sample solutions ranging in volume from a few milliliters up to thousands of liters. It can be used to fractionate large from small biomolecules. Selection of the appropriate operating conditions requires a deep understanding of the process requirements and parameters.

Concentration

The concentration process uses a tangential flow filtration (TFF) system, where the sample is circulated, pressure is applied, and filtrate is collected until the desired concentration is reached.

Diafiltration

Diafiltration is a separation technique used to remove small molecules like salts, solvents, or additives from a solution without changing the concentration of larger molecules. It works by washing these small molecules through a membrane while retaining the larger ones in the retentate.
Pre-concentrating the sample before diafiltration can significantly reduce the volume of buffer needed, although it may slow down the process due to increased viscosity, which lowers the filtration rate.
There are two main methods: continuous diafiltration, where buffer or water is added at the same rate as filtrate is removed, keeping the volume constant and efficiently washing out small molecules; and discontinuous diafiltration, where the solution is diluted and then reconcentrated repeatedly. Continuous diafiltration is generally more efficient, requiring less buffer to achieve the same level of small molecule removal.

Scale-up studies for Tangential Flow Filtration technique

In tangential flow filtration (TFF), there are mainly two key parameters that determine performance: transmembrane pressure (TMP) and crossflow velocity (CF). TMP is the pressure that pushes fluid through the membrane, allowing smaller molecules to pass through as filtrate. CF is the speed at which the solution flows across the membrane surface, helping to prevent membrane fouling by sweeping away larger molecules and aggregates. Selection of the appropriate TFF equipment and operating conditions requires a good understanding of the process requirements and parameters

Figure 3. Flow path into a schematic representation of TFF device

The fluid circulates from the sample reservoir through the feed port, across the membrane, and back via the retentate port. As it flows, a pressure gradient forms between the feed and retentate ports, creating TMP. This pressure can be increased by raising the crossflow rate or restricting the retentate tubing. Effective TFF operation depends on carefully balancing TMP and CF to avoid clogging and maximize throughput.

At SEQENS, our industrial expertise in polymers is backed by 25 years of production of GMP polymers for long-acting injectable forms.

Our expertise in process development allows us to scale-up polymer processes and the use of TFF is efficiently transposed from lab to industrial scale.

We have invested in new state of the art R&D, Kilo lab and GMP pilots facilities between 2022 and 2024 both in Europe and USA.

Our expertise in Advanced Polymers and Lipids is centralized within our 3 developments centers, Seqens’Lab near Paris; Aramon’Lab in South of France and Boston’Lab, in Devens, MA, USA.

We cover manufacturing at different scales, purification & drying and characterization:

• Highly experienced dedicated R&D and Manufacturing teams are experts at synthesizing a broad range of polymetric materials lab scale, GMP pilots scale and industrial scales

• Purification and drying techniques: TFF, Chromatography, Spray-drying, Freeze-drying,

• Polymer and lipids characterization techniques for IPC & QC release: GPC/SEC, HPLC, NMR, FT-IR, NIR, DSC, TGA, CAD, MALS, DLS, Melt index, tap density

Discover our offer of custom polymers and catalog products and contact us to discuss your tailored solutions !

(1) Agrawal P. et al. A Review of Tangential Flow Filtration: Process Development and Applications in the Pharmaceutical Industry, Org. Proc. R&D, 2023, 571-610.