Hollow fibre systems

Optimal fermentation parameters have been well established and air-lift, stirred tank, and hollow fibre systems have all been used. At commercial scale, fermentation volumes in excess of 1000 litres can be used, which can yield 100 g or more of final product. While hybridoma growth is straightforward, production levels of antibody can be quite low compared with ascites-based production systems. Typically, fermentation yields antibody concentrations of 0.1-0.5 mg/ml. Removal of cells from the antibody-containing media is achieved by centrifugation or filtration. An ultrafiltration step is then normally undertaken in order to concentrate the filtrate by up to 20-fold. 

Hollow fibre systems are availabe from Amicon Corp., or BioRad Laboratories based on the semipermeable membranes used in dialysis and concentration cells. Alternatively the Opticel system is based on 1 mm2 pores in a ceramic cartridge. 

Scale-up of cell cultures makes use of suspension cultures (erythropoietic cells or microcarriers) or, less often use of capillary beds (hollow fibre systems or glass bead columns), but these suffer from the same disadvantages seen with smaller scale cultures ( 3.4.4). In particular, nutrients are depleted as the medium flows through long columns or beds and high rates of flow coupled with recirculation are often employed. Nevertheless, Organon have used a hollow fibre dialysis system for production of monoclonal antibodies (Schonherr et al., 1985). Invitron s hollow fibre system has been used to produce cell conditioned media and the Cell-Pharm System (Jencons Ltd. Appendix 3) will produce up to 20 g cell secreted product per month. 

The principle of ceramic matrix modules is the same as for hollow-fibre systems, with the exception that cells are not separated from the medium circulation by a membrane. Cells are held in the highly porous matrix and are supplied with... 

Finally, very recently Linkov and Sanderson et al. [55] modified and improved the method reported by Koresh and Softer and produced flat sheets as well as hollow-fibre systems. 

Mesoporous glass (Vycor type) can be produced by a combined heat-treatment and leaching procedure [9]. Modification of this process can lead to microporous hollow-fibre systems with interesting properties as discussed by Shelekhin, Ma et al [56]. For further discussion see Sections 9.4.2 to 9.4.4. 

Shelekhin et al. [92, 56] reported some interesting results for Vycor type of hollow-fibre membranes (for membrane characteristics see Section 9.4.2.2). The theory of permeation of hollow fibre systems will be treated in Section 9.5. 

The need for large volumes of material often leads to a scale-up of systems. With UF, for example, hollow fibre systems and stirred cells have been compared for the concentration and fractionation of HS. Kwak and Nelson (1977) showed that retention increased with pressure, decreased with ionic strength and was not concentration dependent. HoUow fibres proved ineffective for UF fractionation compared to flat sheet membranes due to clogging and indiscriminate retention effects (Kiichler et al (1994)). 

MF flux adapted to a more realistic value as reported in Chapter 3. Flux of MF in the e.xperiments is high due to the use of flat sheet membranes, where permeate side pressure drop is negligible compared to hollow fibre systems. 

Plate and frame membrane filters rely on seals on each plate and the clamps on the assembly for containment. Hollow fibre systems are pressure limited and are often fitted with a pressure switch in order to prevent the recirculation pump reaching the bursting pressure of the fibres. 

The hollow fibre systems are based on very small-bore tubes cemented at both ends in a wide plastic tube, which also serves as a receiver for the filtrate. A large membrane area can be packed into a small volume, and the liquid hold-up is also reduced. The main disadvantages of the hollow fibres are in their susceptibility to blocking due to the small internal diameters, and difficulties with cleaning. 

Moreover, with hollow fibre systems the formation shape and size of the hollow fibre lumen is dependent upon the injection rate and the composition of the internal coagulant, as well as the air-gap in the dry jet wet spinning system. An essential function of the injection fluid is to produce a circular lumen of sufficient diameter to allow the unimpeded flow of the faster permeant gas. 

Wicaksana, F, Fane, A G and Chen, V (2005), The relationship between critical flux and fibre movement induced by bubbling in a submerged hollow fibre system . Water Science and Technology, 271 186-195. 

New membranes have been developed with significantly enhanced mass-transfer characteristics. These membranes include rotating membrane systems that use a torsional oscillation to produce shear rates as high as 150,000 s. Coiled hollow fibres that exploit Dean vortices to increase solute transport and reduce fouling are receiving attention (Zydney, 2000). 

Keller, O.C., Poitry, S. and BufHe, J. (1994) A hollow fibre supported liquid membrane system for metal speciation and preconcentration calculation of the response time. J. Electroanal. Chem., 378, 165-175. 

Parthasarathy, N., Pelletier, M. and Buffle, J. (1997) Hollow fibre based supported liquid membrane a novel analytical system for trace metal analysis. Anal. Chim. Acta, 350, 183-195. 

Membrane-reservoir systems based on solution-diffusion mechanism have been utilized in different forms for the controlled delivery of therapeutic agents. These systems including membrane devices, microcapsules, liposomes, and hollow fibres have been applied to a number of areas ranging from birth control, transdermal delivery, to cancer therapy. Various polymeric materials including silicone rubber, ethylene vinylacetate copolymers, polyurethanes, and hydrogels have been employed in the fabrication of such membrane-reservoir systems (13). 

For membrane testing under process-conditions, select a commercially available macro-porous support that meets permeance and stability requirements. Make a well-considered choice between the different geometries available (flat, tubular, multichannel or hollow fibre) and test the support system under process-conditions. 

MARS The SPAD method was further developed into a combination of dialysis, filtration and adsorption (= molecular adsorbent recycling system). (103). The patient s blood is fed through a hollow-fibre filter and dialyzed against an albumin dialysate. The ABS (s. tab. 20.5) pass through the pores in the filter and become bonded. Plasma proteins, hormones and vitamins are not lost. The albumin dialysate is recirculated in a closed circuit where it is fed through a second dialyzer and two adsorber columns which bind the ABS. The albumin dialysate is returned to the hollow-fibre filter. It is dialyzed against a bicarbonate solution in order to remove the excess water and water-soluble substances (ammonia,... 

BLSS The bioartificial hver support system is made up of a blood pump, a heat exchanger to control the blood temperature, as well as an oxygenator and a bioreactor. The hollow-fibre bioreactor generally contains 70—100 g of porcine hver cells. Initial experience with BLSS is encouraging. (92)... 

Gill, W.N. and Bansal, B., Hollow fibre reverse osmosis systems Analysis and design. AIChE J., 19, 823, 1973. 

These membrane systems, mainly provided in the form of low cost hollow fibres, offer a high interfacial area, significantly greater than most traditional absorbers, between two phases to achieve high overall rates of mass transfer. Furthermore, whereas the design of the conventional devices is restricted by limitations in the relative flows of the fluid streams, membrane contactors give an active area which is independent of the liquid fluid dynamics. 

Advances in the HPIC technique have resulted in various other choices of eluant depending upon the particular system, and modern suppressor columns may use a packed hollow fibre membrane design. The principles remain the same and in combination with an additional ion pre-concentration column, detection limits of a fraction of a microgram per litre (ppb) are achievable for a host of inorganic and organic ions. 

Low-volume (under 11) but very high density (1-2 x 10 mH) heterogeneous systems (e.g. hollow-fibre bioreactors). 

The most common cell culture systems developed for pilot- and commercial-scale production of monoclonal antibodies (MAbs) are hollow-fibre and ceramic matrix modules, stirred bioreactors and airlift fermenters. These systems allow cultivation of cells in batch, fed-batch, continuous or perfusion mode. The selection of a culture system and culture mode for the large-scale production of a particular MAb should take into account the growth and antibody-production characteristics of the particular hybridoma line. This module therefore presents an overview of the important characteristics of these systems. Detailed descriptions with accompanying results and a large collection of cited literature are given elsewhere (Seaver, 1987 Mizrahi, 1989 sections 5.1 and 5.9). 

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