Tangential Flow Filtration (TFF or crossflow filtration) refers to a filtration process where the feed stream passes parallel to the membrane face as one portion passes through the membrane (permeate) while the remainder (retentate) is recirculated back to the feed reservoir. In other words, the sample mixture circulates across the top of the membrane while applied pressure causes certain solutes and small molecules to pass through the membrane. The filtration membrane has a pore size with a certain cut off value.  In TFF, a pressure differential across the membrane causes fluid and filterable solutes (whose molecular weight is smaller than that of the membranes or behaves like so, such as globular proteins) to flow through the filter. This can be conducted as a continous flow process, since the solution is passed repeatedly over the membrane while the fluid that passes through the filter is continually drawn off into a separate circuit. The flow of solution accross the membrane during TFF helps prevent a gel of aggregated molecules form forming on the surface of the membrane. As a result, the flux rate for TFF drops off much more slowly as filtration proceeds than occurs during DFF. 

TFF is preferred when large amounts of polymer and molecule are to be recovered as TFF is less subject to clogging or fouling than NF methods (US 8,362,217).

 Types of TFF Filters

Examples of different filter modules include hollow fibre modules, spiral wound modules, tubular modules and plate modules. If desirable, TFF can be used to exchange the bufer in which the protein of interest is solubilized into another buffer that is more suitable for binding onto a chromatography resin.

System Confingurations:

Kevin (EP 2583744) disclsoes a TFF system that provides for a plurality of fluidly-interconnected filtration modules where each module is configured to route received feed material and deluent adjacent a filter to provide permeate and retentate. At least one of the modules has a permeate withdrawl flo line for withdrawing permeate from the syste. A plurality of the modules have a permeate flow line configured for returning permeate back to an inlet side of a same or a preceding module within the system. The system permits enhanced control of collections and purificaitons of premeate produces, retentate produces or both. Each filter can includes an ultrafiltration membrane and the system can be a tangential flow filtration system. 

Teshner (US 16/188,839, published as US 2019/0085064) discloses and UF/DF system )DF is performed withthe same membrane as UF) which includes where in order to recover the complete residual protein in the system, the post-wash of teh first larger UF ystem is done with at ealst 2 imtes teh dead volume in re-circulation mode to assure that all protein is washed out. Then the post-wash of the first UF system is concentrated to a protein concentraiton of at least 22% w/v iwth a seocnd UF/DF system equipped with the same type of membrane which is dimensioned a tenth or less of teh first one. The post-wash concetnrate is added to the bulk solution. 

 Operating Parameters (See also operating parameters for filtration)

There are two important variables involved in all tangential flow devices: the transmembrane pressure (TMP) and the crossflow velocity (CF). The TMP is the force that actually pushes molecules through the pores of the filter. The crossflow velocity is the flow rate of the solution across the membrane. It provides the force that sweeps away larger molecules that can clog the membrane thereby reducing the effectivenss of the process. In practice a fluid feedstream is pumped from the sample feed container source across the membrane surface (crossflow) in the filter and back into the sample feed container as the retentate. Backpressue appplied to the retentate tube by a clamp creates a transmembrane pressure which drives molecules smaller than the membrane pores through the filter and into the filtrate (or permeate) fraction. The crossflow sweeps larger molecules, which are retained on the surface of the membrane, back to the feed as retentate. The primary objective for the successful implementation of a TFF protocol is to optimize the TMP and CF so that the largest volumen of sample can be filtered without creating membrane clogging gell. A TMP is “substantially contast” if the TMP does not increase or decrease along the lenght of the membrane generally by more than about 10 psi of the average TMP and preferably by more than about 5 psi. As to the level of the TMP throught the filtration, the TMP is held constant or is lowered during the concentraiton step to retain selectivity at higher concentrations.(US 2005/091801).

Buffers: 

–Low concentration of acetate or histidine buffer (of from about 2 MM to about 48 mM) shown to stabilize antibody preparation during concentration by membrane filtration, lowering the viscosity of the antibody solution and suppressing aggregation (WO 2004/001007). 

–Adjustment of Concentration Prior to TFF: Hepbildikler (US13395893) discloses a TFF/UF method for concentrating an immunoglobulin solution by adjusting a first concentration of the buffer to a second concentration whereby the second concentration is calculated with one mathematical equation if the buffer is a cation/neutral pair such as histidine or with a second equation if the buffer is a neutral/anion pair such as acetate. The method is based on unequal partioning of compounds during diafiltration and concentration in excipient concentrations, pH and conducitvity values which are significantly different fro those of the diafiltration buffer used at the start of the prcoess. This influences stability of the final product. Although such changes which occur during TFF can be solved by restock/diluting with a buffer solution after concentration, the invention solves the problem by using a defined addition/reduction of solute concentration prior to the TFF in order to correct the concentration changes. For example, ine one embodiment in case of histidine buffer (solute) and adjustment at about pH 5.0 to 29.6 mM and 60 MM histidine, respectively, before TFF is required to achieve a predifined histine buffer concentration of 20 mM and 46 mM histidine respectively after TFF in the concentration of IgG1 and IgG4 to 215 mg/ml.