Abstract
To provide biotechnological filtration possibilities with which the danger of contamination is low and at the same time an optimum flow profile can be achieved, the use of a filter module 100 is proposed, the latter having, in a filter housing 110, a filter, with a bundle of hollow fibres 114, and a centrifugal pump rotor 132, for a biotechnological production method, and a filter module 100 for the filtration of a biotechnological liquid L, having a filter housing 110, a filter arranged in the filter housing 110 with a bundle of hollow fibres 114, a centrifugal pump rotor 132 arranged in the filter housing 110 such that it is fluidically connected to the interior of the hollow fibres 114, wherein the centrifugal pump rotor 132 is able to be magnetically driven such that it can force a liquid L through the hollow fibres 114, a first port 102 for the supply of a biotechnological liquid L to be filtered, which first port 102 is fluidically connected to the interior of the hollow fibres 114 of the filter, a second port 104 for the removal of a biotechnological liquid L to be filtered, which second port 104 is fluidically connected to the interior of the hollow fibres 114 of the filter, and a third port 107 for the removal of precipitated waste liquid, which third port 107 is fluidically connected to the exterior of the hollow fibres 114, and a filtration device 1100, 1200, 1300 having a filter module 100, which is able to be coupled to a drive unit, and a drive unit for magnetically driving the centrifugal pump rotor 132 of the filter module 100, which drive unit can generate dynamic magnetic fields for magnetically driving and magnetically supporting the centrifugal pump rotor 132 when the filter module 100 is coupled to the drive module.
Claims
1. A method for processing of biotechnological liquids, said method comprising passing a biotechnological liquid through a filter module, said filter module comprising a filter housing, and a filter, with a bundle of hollow fibres, and a centrifugal pump rotor in said filter housing.
2. The method of claim 1, wherein the method is a filtration method.
3. The method of claim 2, wherein the method is a tangential flow filtration (TFF) method.
4. The method of claim 3, wherein the method is a method for the filtration or concentration of biological macromolecules and biological microstructures.
5. The method of claim 4, wherein the method is a tangential flow filtration (TFF) method for the filtration or concentration of biological macromolecules and biological microstructures.
6. A filter module for the filtration of a biotechnological liquid, said filter module comprising: a. a filter housing, b. a filter arranged in the filter housing with a bundle of hollow fibres, c. a centrifugal pump rotor arranged in the filter housing such that the centrifugal pump rotor is fluidically connected to an interior of the hollow fibres, wherein the centrifugal pump rotor is able to be magnetically driven such that the centrifugal pump rotor is capable of forcing a liquid through the hollow fibres, d. a first port for the supply of the biotechnological liquid to be filtered, which said first port is fluidically connected to the interior of the hollow fibres, e. a second port for the removal of biotechnological liquid to be filtered, which said second port is fluidically connected to the interior of the hollow fibres of the filter, f. a third port for the removal of precipitated waste liquid, which said third port is fluidically connected to an exterior of the hollow fibres.
7. The filter module according to claim 6, wherein the centrifugal pump rotor is arranged fluidically downstream or upstream on a longitudinal axis of the filter.
8. The filter module according to claim 7, wherein the longitudinal axis of the centrifugal pump rotor associated with the operation of the centrifugal pump rotor lies on a longitudinal axis of the filter.
9. The filter module according to claim 6, wherein the filter is a dialyser for haemodialysis.
10. The filter module according to claim 6, wherein the centrifugal pump rotor is equipped with permanent magnets in such a way that the centrifugal pump rotor is operable and/or driven in a manner supported by magnetic levitation.
11. The filter module according to claim 6, wherein the filter housing has a first end cap, which defines an inlet flow path for a liquid to the centrifugal pump rotor such that a liquid is flowable into the filter housing perpendicular to the longitudinal axis of the filter and is deflectable such that the liquid flows onto the centrifugal pump rotor parallel to the longitudinal axis.
12. The filter module according to claim 11, wherein the inlet flow path is designed such that the liquid flows into an hollow centre of the centrifugal pump rotor.
13. The filter module according to claim 11, wherein centrifugal pump rotor and said first end cap define a liquid path such that said liquid is flowable centrifugally out of the centrifugal pump rotor perpendicular to the longitudinal axis of the filter and is deflected such that the liquid thereafter flows parallel to the longitudinal axis of the filter and enters the hollow fibres of the filter when the centrifugal pump rotor is rotated.
14. A filtration device comprising a. the filter module according to claim 6, which is able to be coupled to a drive unit, and b. said drive unit for magnetically driving the centrifugal pump rotor of the filter module, which drive unit is capable of generating dynamic magnetic fields for magnetically driving and magnetically supporting the centrifugal pump rotor when the filter module is coupled to the drive unit.
15. A method for filtration or concentration of biotechnological liquids, said method comprising passing a biotechnological liquid through said filter module according to claim 6 to achieve concentration or filtration of biological macromolecules and/or biological microstructures in said biotechnological liquid.
16. A method for filtration or concentration of biotechnological liquids, said method comprising passing a biotechnological liquid through said filtration device of claim 14 to achieve concentration or filtration of biological macromolecules and/or biological microstructures in said biotechnological liquid.
17. The method of claim 3, wherein the method is a method for the filtration or concentration of extracellular vesicles in the biotechnological liquid.
18. The method of claim 4, wherein the method is a tangential flow filtration (TFF) method for the filtration or concentration of extracellular vesicles in the biotechnological liquid.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] The device and the method are described below with reference to the drawing, in which:
[0046] FIG. 1 shows a schematic representation of a filter module according to the invention for use for filtration of a biotechnological liquid (in a first embodiment),
[0047] FIG. 2 shows a sectional view through the region of the first end cap of an illustrative embodiment of a filter module according to the invention,
[0048] FIG. 3 shows the same arrangement as in FIG. 2, but in a perspective view, wherein an optional inner supporting plate with openings can additionally be seen in the first end cap,
[0049] FIG. 4 shows an illustrative embodiment of a centrifugal pump rotor according to the invention,
[0050] FIG. 5 shows the flow diagram of an illustrative embodiment of a filtration device according to the invention, as employed in a use, according to the invention, of a filter module having, in a filter housing, a filter, with a bundle of hollow fibres, and a centrifugal pump rotor, for a biotechnological production method,
[0051] FIG. 6 shows the flow diagram of a particular embodiment of a filtration device according to the invention in which the filter of the filter module is constructed like a known dialyser for haemodialysis, wherein the filtration device has an additional pump downstream from the permeate port,
[0052] FIG. 7 shows the flow diagram from FIG. 6, additionally with an optional check valve, which is arranged downstream from the additional pump at the port for removal of permeate.
[0053] In the figures, identical or similar elements may be referred to by the same reference signs.
[0054] FIG. 1 shows a filter module 100 for the filtration of a biotechnological liquid L, having a housing 110 with a first end cap 120, a second end cap 140, and a middle part 112 between the end caps. A bundle of hollow fibres 114 is arranged therein such that it extends with its longitudinal axis from the first end cap 120 to the second end cap 140 through the middle part 112 of the housing. The first end cap 120 has a centrifugal pump rotor housing 130, in which a centrifugal pump rotor 132, preferably an impeller, is arranged. Moreover, arranged at the first end cap 120 is a first port 102, which serves to supply a biotechnological liquid to be filtered and which is fluidically connected to the interior of the hollow fibres 114 of the filter. Arranged at the second end cap 140 is a second port 104 for the removal of a biotechnological liquid L to be filtered, which port 104 is likewise fluidically connected to the interior of the hollow fibres 114 of the filter. When the device is being used for the filtration of a biotechnological liquid L, the centrifugal pump rotor 132 rotates, and it pumps the biotechnological liquid L, which flows in through the first port 102, into the cavity in the interior of the fibres 114 of the fibre bundle. Some of the liquid L passes through the fibre walls into the exterior of the fibres. The liquid that has passed through the fibres, a liquid usually regarded as waste, the permeate, can be removed through a third port 107 arranged on the filter housing 110. This third port 107 can be arranged on the first end cap 120 (as shown by 107a), on the second end cap 140 (not shown) or on the middle part 112 (shown for example by 107b). FIG. 1 shows two alternatives as to where the third port 107 can be arranged, but only one of the ports shown is required. It cannot be inferred from the depiction of two third ports 107a, 107b that this is necessary for the present application. Rather, this serves to illustrate different possibilities. The important aspect of this third port 107 is that it is fluidically connected to the exterior of the fibres of the fibre bundle 114 of the filter and that it is at the same time separated by the membrane from the interior of the hollow fibres of the fibre bundle. In the second end cap 140, the portion of the biotechnological liquid that has not passed through the fibre wall but has remained in the interior, the retentate, can leave the fibre bundle again and be removed from the filter module through the second port 104. In the course of a biotechnological filtration, a biotechnological liquid typically has to make several passes through a filter module 100 in order to achieve a desired concentration in the biotechnological liquid L. Therefore, in known biotechnological filtration arrangements, a circuit with a pump and a reservoir is often formed such that the liquid can be pumped several times through a filter module. A circuit of this kind is not shown in FIG. 1, but is shown in FIGS. 5, 6 and 7.
[0055] FIG. 2 shows a sectional view through the region of the first end cap 120 of an illustrative embodiment of a filter module 100 according to the invention. The aim here is to illustrate how the filter module 100 can be designed by way of example, in the region of the first end cap 120 and the centrifugal pump rotor housing 130, such that an inlet flow path for a liquid L is formed, according to which the liquid L can flow into the housing 110 perpendicular to the longitudinal axis of the filter 114 and can be deflected such that it can however thereafter flow onto the centrifugal pump rotor 132 parallel to the longitudinal axis of the bundle of hollow fibres 114 and thus of the filter module 100. Here, reference sign 115 designates the means for fixing the fibres 114 of the fibre bundle in the housing 110. In the case of a dialyser for haemodialysis, this can involve what is called potting. Moreover, the embodiment shown in FIG. 2 is designed such that the liquid L can flow into the centre of the centrifugal pump rotor 132. Moreover, the embodiment shown in FIG. 2 is designed such that centrifugal pump rotor 132, centrifugal pump rotor housing 130 and end cap 120 define a liquid path such that liquid L can flow centrifugally out from the centrifugal pump rotor 132 perpendicular to the longitudinal axis of the filter and is deflected such that, downstream from the centrifugal pump rotor 132 and before entry into the fibres 114, it flows parallel to the longitudinal axis of the filter 114 when the centrifugal pump rotor 132 is rotated. The overall mechanical configuration of the filter housing 110 in the region of the first end cap 120, the centrifugal pump rotor 132 and the centrifugal pump rotor housing 130 results in a flow path which, in one section, can be described as being coaxial and antiparallel: In the orientation of the figure, the interior or hollow centre of the centrifugal pump rotor can be subjected to flow perpendicularly from the top downwards, pumped liquid L is conveyed radially outwards from the centrifugal pump rotor 132 when the centrifugal pump rotor 132 rotates, and it is deflected such that, in the orientation of the figure, it can thereafter flow perpendicularly upwards to the hollow fibres 114 of the fibre bundle of the filter. On the axis of the centrifugal pump rotor 132, the liquid on the inlet side of the centrifugal pump rotor 132 flows centrally downwards, coaxially and annularly about the axis of the centrifugal pump rotor 132; the liquid on the outlet side of the centrifugal pump rotor 132 flows perpendicularly upwards. A vertical arrangement of the centrifugal pump rotor and of the hollow fibres 114 of the fibre bundle affords the advantage that gas accumulations present within the liquid L are transported away upwards by buoyancy and at the same time by the liquid flow generated by the centrifugal pump rotor 132 of the pump. The above-described coaxial arrangement of centrifugal pump rotor 132 and the fibre bundle permits a particularly symmetrical flow of a liquid L through the centrifugal pump rotor 132 into the interior of the hollow fibres 114 of the fibre bundle. As will be seen from FIG. 2, antiparallel, coaxial flows of liquid exist in some sections in such a situation. The liquid flows onto the centrifugal pump rotor on the longitudinal axis of the fibre bundle, which is coincident with the rotation axis of the centrifugal pump rotor, and, after leaving the centrifugal pump rotor, is deflected such that it flows in parallel but with opposite directionality to the fibre bundle. The fibre bundle is preferably approximately cylindrical at the macroscopic level. The centrifugal pump rotor is hydraulically stabilized by this symmetrical flow arrangement. This minimizes a potential fluttering of the centrifugal pump rotor. Fluttering of the centrifugal pump rotor could lead to the biotechnological liquid being damaged. Thus, possible damage to the biotechnological liquid is also avoided. Particularly in the case of centrifugal pump rotors supported by magnetic levitation, there is also the advantage that less eccentric bearing moments occur, or the eccentric bearing moments are less strong. Therefore, less strong magnetic fields suffice for driving and supporting the centrifugal pump rotor. The less strong magnetic fields in turn mean that less energy and/or less electric current is needed in the generator of the magnetic alternating fields of the drive unit. For improved flow conduction in the substantially annular outflow region 128 of the centrifugal pump rotor 132, an optional inner supporting plate 121 can be provided in the first end cap 120. An optional seal 170 can be provided between the fibre bundle of hollow fibres 114 and the wall of the first end cap 120 or the optional potting 115.
[0056] FIG. 3 shows the same arrangement as FIG. 2, but in a perspective view. Openings 123 can additionally be seen here in an optional inner supporting plate 121 in the first end cap 120, which openings 123 are arranged between the centrifugal pump rotor 132 and the filter bundle 114 such that liquid L flows from the centrifugal pump rotor 132 through the openings 123 and then to the fibres 114 of the filter when the centrifugal pump rotor 132 has been set in rotation. Arrows indicate the flow of a biotechnological liquid L when the centrifugal pump rotor is rotating. For example, the centrifugal pump rotor 132 is subjected to flow such that the liquid is supplied through a central opening 134 in a disc 133 into a central cavity of the centrifugal pump rotor 132 on the rotation axis thereof.
[0057] FIG. 4 shows an illustrative embodiment of a centrifugal pump rotor according to the invention. This takes the form of an impeller rotor with a hollow centre. The figure illustrates how the blades 135 of the centrifugal pump rotor can for example be bent, for example in a spiral shape. The blades are arranged between two discs, wherein the lower disc in the figure adjoins the permanent magnets 136 arranged in the centrifugal pump rotor, and the upper disc 133 has a central opening 134 through which liquid to be pumped can flow into the hollow centre of the centrifugal pump rotor 132.
[0058] FIG. 5 shows schematically the flow diagram of an embodiment of a filtration device 1100 according to the invention. Besides the filter module 100, there are, for example, a runoff 300 and a reservoir 200 for the liquid L. The filtration arrangement 1100 is set up as a circuit for the biotechnological liquid L that is to be filtered or purified. This figure shows a biotechnological filtration arrangement 1100 formed as a circuit having a pump with a centrifugal pump rotor 132 and having a reservoir for the biotechnological liquid L circulating in the circuit, wherein a liquid L to be filtered can be pumped several times through a filter module 100. The dotted line indicates that the centrifugal pump rotor and the filter with the bundle of hollow fibres 114 are arranged in a common filter housing 110. The figure does not show the drive unit to which the filter module 100 is able to be coupled and which can generate dynamic magnetic fields that can magnetically drive and/or magnetically support by levitation the centrifugal pump rotor 132, since the latter has permanent magnets.
[0059] FIG. 6 shows schematically the flow diagram of a particular embodiment of a filtration device 1200 according to the invention. Here, the filter of the filter module 100 is constructed like a known dialyser for haemodialysis. Compared to filters of the kind commonly used in biotechnological filtration devices, a dialyser particularly advantageously has a fibre arrangement that is more stable with respect to pressure differences: The fibres 114 have, in relation to the external diameter, a smaller fibre internal diameter. This provides the increased stability of the hollow-fibre membranes. In addition, the fibres 114 of a dialyser are typically shorter, which also results in increased stability. In order to compensate for the shorter fibres 114 and the thicker membrane walls, as regards the filtration yield, a dialyser has a larger number of fibres 114. Through the use of a dialyser as a filter in the filter module 100, and from the increased stability with respect to pressure differences inside/outside the fibres 114, an additional pump 400 can be arranged such that it is connected to the port 107 for the removal of precipitated waste liquid, which is fluidically connected to the exterior of the hollow fibres 114. The pumping direction is chosen such that the permeate is sucked from the exterior of the fibres 114. If the additional pump 400 were operated in known filtration devices, such an arrangement would lead to the membranes being damaged. Particularly advantageously, the arrangement of this additional pump 400 at the port 107 for permeate removal has the effect of allowing a defined concentration to be achieved with fewer passes of the biotechnological liquid L to be concentrated than would be the case without the additional pump 400. On the one hand, the time needed to reach a defined concentration is thus particularly advantageously reduced. On the other hand, a particular advantage is that the biotechnological liquid L is subjected to fewer passes through the filter, and thus experiences less damage. The more often a biotechnological liquid passes through a filter, the greater the potential damage. A further advantage of this arrangement is that the additional pump 400 does not cause any additional damage to the biotechnological liquid L that is to be concentrated: The additional pump 400 comes into contact only with the permeate, which is a waste product.
[0060] FIG. 7 shows the flow diagram of a filtration device 1300 from FIG. 6, additionally with an optional check valve 500, which is arranged downstream from the additional pump 400, at the port 107 for removal of permeate. The check valve 500 is located on the permeate line between the additional pump 400 and the runoff 300.
[0061] By virtue of this optional, additional check valve 500, the pressure ratios at the membrane of the filter can be adjusted, particularly advantageously in interaction with the additional pump 400. To this end, a check valve 500 is used which opens when subjected to a suitably chosen minimum pressure from the additional pump 400.
