Modular bioprocessing unit and bioprocessing system employing multiple units

Abstract

A modular bioprocessing unit (100) is disclosed, the modular bioprocessing unit (100) comprising: a housing (110) having one or more internal fluidic pathways (101), the housing having at least one inlet and at least one outlet (5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70) each in fluid communication with a fluid pathway or one or more of the fluid pathways; one or more sensor elements (120, 150, 170, 190) operatively associated with the or each pathway, the sensor element(s) comprising elements of one or more of: a flow sensor, a flow rate sensor, a conductivity sensor, a pressure sensor, a pH sensor and a light absorbance sensor (such as a UV spectroscopic concentration sensor); one or more fluid flow inducing means (140) operatively associated with the or each fluid pathway; and a plurality of valves (180) for preventing or reducing flow in the or each pathway, the housing, inlet(s), outlet(s), flow inducing means(s) and valve(s) being arranged to operate together as a bioprocessing unit within or substantially within the housing.

Description

Technical Field

[0001] This invention relates to a modular biological processing unit, such as a cartridge for processing biological materials (e.g., aggregated cells, single cells, cell products (e.g., antibodies or other proteins), viruses, bacteria, molecules, or other similar materials wholly suspended in a fluid (e.g., liquid). In particular, but not exclusively, this invention relates to disposable or limited-reuse units that provide low-cost, integrated biological processing hardware. The invention also relates to biological processing systems formed by multiple biological processing units and methods of operation associated with such hardware. Background Technology

[0002] Biological processing is largely a mature technology with generally accepted and validated treatment methods. Each process generally has specific associated equipment. However, the cost of this equipment and the inflexibility of those accepted practices are barriers to entry into the industry. Furthermore, a common approach to validating a process is to start with a pilot-scale process before scaling up to increased throughput. The conventional way to scale up is to increase the size (and cost) of the equipment used, meaning that the process then needs to be revalidated, and the pilot-scale equipment is then redundant.

[0003] Throughout all stages of bioprocessing, skilled operators are typically required, adding to the cost and serving as a barrier to entry for developing economies. Bioprocessing equipment typically comprises discrete hardware components interconnected via fluid lines during use. While numerous efforts exist to simplify the individual components of this hardware, technological solutions integrating essentially complete bioprocessing hardware are rare in the pilot and scale-up phases, offering significant technological and commercial advantages.

[0004] Most biological processes are performed in batches because some of the hardware used can only process a certain volume before it needs to be changed. Each batch must be sterilized, resulting in additional costs.

[0005] Some attempts have been made at the microfluidic level to integrate biological processes, but the resulting devices are useless when processing useful amounts of material (e.g., several milliliters, tens of milliliters, or several liters) in biological processes. Summary of the Invention

[0006] The objective of embodiments of the present invention is to provide modular bioprocessing units with multiple hardware functions, assembled into a single, generally hermetically sealed housing, such that the unit can be used individually or in multiple systems for various bioprocessing functions when interconnected with other identical or similar units. Thus, aside from the unavoidable majority of a bioprocessing system (such as fluid reservoirs, chromatography columns, bioreactors, filters, or membranes), all or most of the hardware associated with bioprocessing can form a modular unit, wherein the term "modular unit" is intended to mean a unit suitable for operation with one or more similar units, for example, where each unit has complementary physical features to enable such cooperative operation. For ease of low-cost manufacturing and modularity, such units may have identical or similar external dimensions and be integrally formed by their common components, for example, connected in an adjoining relationship within an external frame or at complementary sides or edges of the units, and / or wherein the inlets and outlets of the units are arranged such that direct adjoining contact between the units provides fluid passage between them. Alternatively or additionally, in some cases, fluid interconnection may be achieved via intermediate tubing. The use of an external frame provides for electrical and / or pneumatic power, as well as electrical signal communication with the units forming the system.

[0007] When multiple units are used together, a continuously integrated biological treatment system may be formed, in which specific steps are performed in series and / or in parallel, as explained in more detail below. In particular, one unit may be used while another is being supplemented, cleaned, or otherwise prepared for further biological treatment while that unit is being processed.

[0008] Embodiments of the invention are set out in the independent claims appended herein, wherein preferred features are set out in the dependent claims. However, the invention extends to any novel features described, claimed, or shown herein, and such novel features are not intended to form an integral part of a more particular embodiment, even if the novel feature is mentioned only in relation to that particular embodiment.

[0009] The term "modular" as used herein is intended to encompass hardware that can be directly connected to or adjacent to other similar hardware in a stacked, row, column, array, or other manner, preferably such that the combined hardware operates together, for example, in series or parallel as a system, wherein, if desired, individual unconnected components of the hardware can operate independently as units. This invention differs from so-called modular components of a system, which comprise different hardware components performing specific, unique functions that can be combined in many ways. Such known modular components cannot be used independently as biological processing units but need to be combined with several other different components to construct such systems.

[0010] Further advantages and benefits of the invention will readily become apparent to those skilled in the art in light of the detailed description below. Attached Figure Description

[0011] The invention will now be described in more detail with reference to the accompanying drawings, in which: Figure 1 A schematic diagram of a biological treatment unit and a biological treatment system falling within the scope of the present invention is shown. Figure 2 Detailed and exploded diagrams of the biological treatment unit are shown; Figure 3 It shows Figure 2 Another exploded view of the unit shown in the figure; Figure 4a b, c, and d each show Figure 2 and Figure 3 The components of the unit shown in the figure; Figure 5 Another schematic diagram of the biological treatment unit is shown; Figure 6 This demonstrates its use in biological treatment applications. Figure 5 Biological processing units; Figure 7 , Figure 8 and Figure 9 Multiple units used in different biological treatment systems are shown; Figure 10 The layers show alternative constructions of the biological processing unit; and Figure 11 It shows Figure 10 Exploded view of an embodiment. Detailed Implementation

[0012] Figure 1A biological processing unit 100 is schematically shown, comprising a modular housing 110 in the form of a box, which includes various inlets and outlets described in more detail below. In summary, the unit has integral components comprising or consisting of: a selection valve 130 for selecting the input fluid (liquid or gas), typically a buffer fluid; a fluid flow induction component, in this case a pump 140; a flow meter 150; a sample fluid inlet 160, typically used to introduce sample fluid into the buffer fluid; various two-way valves 180, having a common construction and described in more detail below, but having the function of allowing fluid flow to enter or exit between the components listed herein; a pH sensor 170; a conductivity (Cond') sensor 190; and a UV flow cell spectrophotometer 120 for determining the light absorptivity characteristics of the fluid in the box or air trap (unlabeled). The construction of each of these components is generally known, but can be adapted to this application as described below. The components of unit 100 are interconnected within the housing via one or more fluid paths 101 to provide a substantially complete biological processing unit that can be used for a variety of applications. While the order of the components shown is preferred for practical reasons, the order can be changed without significant loss of practicality.

[0013] In order for multiple units to be placed together to form a biological treatment system, the box retainer 200 is in Figure 1 As shown, multiple units 100 can be held side-by-side, such that their inlets and outlets can be directly connected where possible, or connected via interconnected fluid paths (such as pipes fitted to quick-connect fittings). If the units are directly connected, the side inlets and outlets (e.g., 5, 10, 15...70, where "side" means...) Figure 1 Visible side and Figure 1 The opposite sides (not visible in the middle) can be placed together, allowing the units to be selectively put into use one after another, in series, or in parallel with the aid of valves and external controllers 220, to suit the required biological treatment function. A simple annular seal can be used around the inlet / outlet, connecting the units together, for example, as... Figure 1 As shown in the diagram, the cells are stacked. In this case, the stack of cells provides a three-dimensional arrangement of fluid paths 101, and with inlets and outlets arranged on both sides of the cells, valves can be used to control the inflow and outflow of cells from adjacent stacks. In cases where additional inlets and outlets are required, such as when a chromatography column is inserted into the fluid flow, such inlets and outlets can be formed at the edges of the cells (e.g., at...). Figure 1(Seen at the edge of the exposed stacked unit). It will be apparent that edge-to-edge adjacency will also be a viable arrangement, providing more pathways for fluid interconnection via interconnecting tubes. In this case, intermediate tubes can be used to form interconnections between multiple units of the system, optionally using sterile connectors, such as those commercially available by Medinstill Development LLC under the trade name INTACT Connectors.

[0014] Figure 2 and Figure 3 An example of a construction that can be used to make unit 100 is shown. Figure 2 An exploded view of the three main parts used is shown, and Figure 3 The same disassembled parts are shown, but viewed from different angles. The main parts are the front plate 112, the middle plate 114, and the rear plate 116, each formed of a plastic material (such as polypropylene or polycarbonate). Each plate forms a fluid-impermeable sealed contact with its adjacent plate by means of a hole 118 to form a fluid-impermeable assembly unit 100. The hole 118 allows fasteners (not shown) to compress the plates into the sealed contact.

[0015] The front panel 112 has a front surface 112f, which includes selectable inlets 5, 10, 15, 20, 25, 30, 35 and additional ports (inlets or outlets) formed by orifices 40, 45, 50, 55, 60, 65, 70. These ports are shown as simple through holes, but in practice they likely terminate at quick-connect fittings of known construction (suitable for fluid connection to external bioprocessing components or other units 100 in the system). Additionally, the front surface 112f of the panel 112 exposes the stems 182 of valves 180, which include slots 184 indicating the position of valves 180. The stem 132 of selector valve 130 is also exposed in the front surface 112f and includes markings indicating the wiring location of selector valve 130. The remaining features shown on the front surface 112f are markings indicating the internal sensors employed and the internal interconnections between the inlets, outlets, and valves.

[0016] 122r behind board 122 Figure 3 The diagram shows the inlet and port extending through the plate to the rear, as does the valve stem 182.

[0017] The intermediate plate 114 receives or discharges liquid flow via an inlet / outlet that extends through the front plate 112 to reach the front surface 114f of the intermediate plate. A channel 101 formed in the front surface 114f creates one or more fluid paths by interconnecting the various ports 40, 45, 50, 55, 60, 65, 70 and the components of unit 100. Although the unit flow is reversible, the preferred flow direction is indicated by the arrows shown within the channel 101. A rotatable valve stem 132 selects one of the selector valve inlets 5 to 35 to introduce fluid. A pump 140 (in this case, a flexible gear pump, where one of the gears is driven by an electric motor 144) is operable to induce flow. Such gear pumps are described in co-pending patent application PCT / EP2016 / 076149, filed October 28, 2016 (the disclosure of which is incorporated herein by reference). A flow meter 150 is positioned directly downstream of pump 140. The flow meter has a known construction, such as an optical flow meter, in which light is scattered as a particle passes through the first beam, and a detecting optics collects the scattered light on a photodetector, which then generates a pulse signal. As the same particle passes through the second beam, the detecting optics collect the scattered light on a second photodetector, which converts the incident light into a second electrical pulse. By measuring the time interval between these pulses, the fluid velocity is calculated as V = D / t, where D is the distance between the laser beams and t is the time interval. For a known cross-sectional area of ​​the flow path 101 and a known fluid density, the mass flow rate can be calculated.

[0018] Inlet 40 provides a pathway for injecting additional sample fluid into flow path 101. Two one-way valves 165 provide for sample injection directed only downstream of inlet 40. In use, the fluid flow then encounters a pressure sensor 136 of known construction, such as an elastic element tensioned by a pressure differential in the fluid path and connected to an optical element, which can be deflected by the elastic element and thereby used to quantify the pressure as a change in the characteristics of the optical element. After the pressure sensor, the fluid flow will encounter... Figure 2 One of the valves 180 shown in the figure, wherein its stem 182 is shown in cross section and thus shows an arcuate path through the stem ( Figure 4a (188) This path can be shifted by rotation of the valve stem to reposition the path to one of three flow positions. Thus, fluid can flow to the remaining components of housing 100 as shown, or exit via an adjacent path leading to orifice 45. The same description applies to two other valves directly downstream of the valve described above. Of course, pressurized flow can be directed to orifices 45, 50, and 55 and then guided by valve 180.

[0019] Further downstream are another pressure sensor 136, a pH sensor 170, a conductivity sensor 190, and a UV spectrophotometric flow cell for measuring the light absorptivity of the fluid, all of which have known constructions. Two additional valves 180 allow the fluid flow to be diverted during use, for example, in response to the outputs of the aforementioned sensors.

[0020] The backplate 116 has a front face 116f that carries electrical conductors 111 for transmitting power and signals to corresponding sensors, and the backplate 116 has an opening for holding the pump motor 144. The plate 116 also carries a connector block 113 for connecting the conductors to an external controller 220 via complementary connectors (not shown) located in the retainer 200. Figure 1 During assembly of plates 116, 114, and 112, the conductors contact the complementary conductive elements on the rear end 114r of the intermediate plate 114. Furthermore, the rod of the motor 144 engages with the driven gear of the pump 140 during assembly.

[0021] Figure 4a and Figure 4b An enlarged view of one of the valve stems 182 is shown, in which the groove 182 is shown more clearly, aligned with the arcuate conduit 188 in the stem, each side of which is a seal 186 for sealing against corresponding stem orifices in the front and middle plates.

[0022] Figure 4c An alternative pump configuration 140' is schematically shown, in which an actuator 142' reciprocates to drive a piston 144' within a chamber 146', and two one-way valves 145' restrict the inflow in the flow path F to one direction indicated by arrow F. This configuration provides a lower-cost solution to the gear pump 140 described above. For example, the actuator could be electrically or pneumatically driven.

[0023] Figure 4d An enlarged view of the selector valve stem 132 is shown, where the rear of the stem (in) Figure 3 The highest part (visible on face 112r) includes a selector valve passage 136 for diverting fluid flow from a desired inlet to an internal fluid flow path formed in face 114f and positioned at the center of rotation of the rod 132 (in this case). An annular seal 133 suppresses valve leakage.

[0024] It should be noted that one or more of sensors 120, 136, 170, and 190 may be replaced by inlets and outlets (with or without valve 180) arranged to divert any fluid flow to a remote sensor with equivalent functionality to the replaced sensor. In this case, such a remote sensor may be reused after the rest of unit 100 has been disposed of.

[0025] As will be readily apparent to those skilled in the art, the invention should not be construed as limited to the embodiments described above, but can be varied within the scope of the appended claims. For example, manually operable valves 130 and 180 are described and shown; however, it is contemplated that other valve configurations of the same low cost and thus suitable for disposable units may be used. One such valve configuration is a pneumatically operable diaphragm valve, such as the type of diaphragm valve described in co-pending patent application US2014 / 071405 (in which a pneumatic controller is used to open and close the valve, thereby replacing valve 180 in directing fluid flow). In this case, the pneumatic supply used to drive the valve may also be used to drive pump 140'. If pneumatic power and / or valve signals are employed, a connector block similar to connector block 113 will be used. While manual control of valve operation may be possible as described above, automatic control (e.g., via controller 220) is preferred. In this case, pneumatic or motorized valves may be used instead of the manually selectable valves 180 and 130 shown. Additionally, it should be noted that the specific embodiments described above can be constructed in various ways other than those shown. For example, the electrical power connection 111 can be omitted, and the sensor can be internally powered (e.g., by means of a battery), thus requiring only a signal connection. The sensor can be made RF-triggered and therefore requires no power other than that provided by the RF energy (which is used to induce a sensor response from the associated sensor). Thus, both the signal and power connections can be omitted except for the power / pneumatic supply to the pump 140. Since the units are formed entirely or primarily of plastic material and can be supplied in substantially sterile, hermetically sealed packages, they are suitable as single-use devices.

[0026] For cost-effectiveness, a single generic cartridge 100 can be manufactured, but with varying throughput capacities, such as different channel 101 cross-sectional areas and different pump capacities. In this way, system scaling is possible without requiring a revalidation process. Alternatively, the cartridge can be optimized for a predefined biological processing function, such as a cartridge specifically designed for chromatography, filtration, or virus inactivation, thereby eliminating the need for sensors or pumps not used for that particular application. However, the external construction of the cartridge can remain generic, allowing all cartridges to fit a common external holder, such as holder 200.

[0027] Figure 5 Unit 100 is shown as a functional schematic, with the unit components displayed in a linear series. In this variant, the UV absorbance meter is upstream of the conductivity sensor and the pH sensor, but this only shows the exact order of the components. Figures 1 to 3 The order shown is different.

[0028] Figure 6 The diagram illustrates the use of a chromatography column, filter, membrane, or other external components 300. Figure 5 The unit. The flow direction in use is indicated by the respective arrows, and in particular, the flow is diverted by valve 180 through external member 300. Selector valve 130 can be used initially to absorb fluid at inlet 5 (e.g., from cell culture vessels, etc. (not shown)), process that fluid, and deliver it to outlet 70 (while the sensor indicates that the desired fluid is available at outlet 70). Before and / or after this period, unwanted fluid can be delivered to outlet 65 as waste, etc. Clean fluid or secondary fluid can then be absorbed at inlet 10 and, if necessary, delivered to waste outlet 65.

[0029] Figure 7 A second application of unit 100 is illustrated, in which unit 100 is used in conjunction with a second unit 100' to form a biological processing system together with the filtration device 400 and the holding tank 500. Using this arrangement, conditioning steps, such as filtration or liquid conditioning between chromatography steps, can be performed. Sample processing can also be selectively performed by means of ultrafiltration, percolation, or cross-flow filtration and / or liquid conditioning.

[0030] Figure 8 Unit 100 is shown, together with a second unit 100' for virus inactivation, wherein a protein (referred to as protein A in this case) can be introduced from the chromatography apparatus or culture volume along with alkali from port 15 into port 160 and transferred to a holding tank 500 for virus inactivation. The pH of the tank can be adjusted by adding acid from port 10. After a period of time in the holding tank 500, the fluid can be processed in the second unit 100' by diverting the flow to a cross-flow filter 600' and exiting via valve 180c'. The virus inactivation step can be omitted by diverting the fluid along path 102 toward valve 180c and into the second unit 100' for filtration at filter 600'.

[0031] Figure 9Three units 100, 100', and 100'' are shown, which together are used for three stages of chromatographic bioprocessing of a sample S (e.g., a sample fluid containing the protein of interest to be concentrated), and include three chromatographic columns 300, 300', and 300''. Operation can be performed in series (i.e., one column after another is used for a higher concentration of elution product at output E), or sequentially (i.e., one unit can be operated until its chromatographic medium is saturated or fully bound, and a breakthrough is achieved at the second column until then the flow switches to the next unit, etc.), or continuously (i.e., in this sequential manner, but with an additional purify step, which is used to quiescent the column to prepare it for further operation if needed). In each case, the valves used can be switched accordingly, and waste products can be diverted to the waste path W instead of to output E.

[0032] Figure 10 and Figure 11 Another embodiment of the biological processing unit 700 is shown, which can operate in the same manner as the biological processing unit described above. Two main layers are shown: a fluid layer 714 and a pneumatic layer 710, separated by a support layer 711 and a flexible elastomer layer 712. The fluid layer 714 has fluid conduits 701 (only some of which are labeled) providing inlets and outlets (705-745, only two of which are labeled) as described above. The flow direction at the junction 730 in the path is controlled by open / closed diaphragm valves 780 (only one of which is labeled, e.g., one formed at each leg of the junction 730). By opening pairs of valves in the desired legs of the junction corresponding to the desired fluid flow path, fluid can be directed accordingly only along those opened legs. Flow can be separated by opening three or more diaphragm valves. Flow can be partially restricted by providing a small amount of gas pressure or vacuum in the pneumatic passage. Pulsed pressure or vacuum can also be used to partially restrict flow. Gas pressure / vacuum pulse width modulation can also be used to variably restrict flow. As directly mentioned above, the pneumatic layer 710 and the support layer 711 together guide gas pressure and / or vacuum via pneumatic channel 716 to deflect the associated portion of the membrane 712, thereby opening or closing the corresponding fluid path 701 for flow regulation by valve. Each pneumatic channel has a corresponding connector 715 for suitable pressurized gas supply and / or vacuum connection.

[0033] To induce fluid flow in fluid channel 701, a pump 720 is provided, which in this case consists of three compressible or expandable chambers. Preferably, each chamber has an inlet and an outlet, as well as check valves at its respective inlet and outlet, and so the arrangement for each chamber is similar to... Figure 4cPump 140 is shown in the diagram. However, the pump will operate with only one pair of check valves serving one or more chambers. The pump can be electrically powered via a solenoid or pneumatically powered using the same pressurized gas supply that operates the valves.

[0034] The examples above should not be considered limiting. Consider any of the following biological processing steps that can be performed using the units described above, either individually or as a system with multiple units: removal of cells by filtering liquid culture medium containing recombinant therapeutic proteins, etc.; performing chromatographic acquisition using additional equipment (such as chromatography columns or separation membranes) for obtaining cells, viruses, or recombinant therapeutic proteins from the liquid culture medium; virus inactivation; solution conditioning; performing one or more final purification steps via chromatography columns or membranes; ultrafiltration / percolation after chromatographic purification; sample / solution conditioning; and / or providing devices for column-switching chromatography. In the case where multiple units are used to form a system, controller 220 can be operated to control the operating sequence of the valves and pumps used, according to a predefined procedure (modified as necessary based on data representing sensor readings). It is also possible that each unit has its own controller, and the units can be connected via a communication bus, enabling communication between the units, for example, one unit designated as the master unit, and the remaining(s) units(s) acting as slave units.

[0035] The advantages of the described embodiments include: a small footprint due to the compact design; a functional closed-loop system at all stages of processing; an arrangement that can be easily reconfigured for different needs, including a single controller, which allows for simpler software for integrated, continuous, or semi-continuous processes; an easily scalable system where parallel units can be used to provide additional bioprocessing volumes, delivering product in batches greater than 50 ml, such as hundreds of ml or even several liters; and a system that is easy to transport. The embodiments are particularly suitable for the production of therapeutic protein pharmaceutical substances (such as recombinant proteins represented by cultured mammalian cells) and for single-use applications (where the low-cost nature of the embodiments makes disposal after a single use commercially possible). The low cost is aided by the shell portion of the described unit, which is formed essentially of plastic material and thermally bonded (also known as diffusion bonding). Sealing between the layers of the unit can be achieved using low-cost gaskets or continuously performed diffusion bonding. The peripheral edges of the unit may be bonded to provide an hermetically sealed unit that will remain sterile prior to use, where a peel-off seal can be used at the fluid inlet / outlet.

Claims

1. A modular biological processing unit (100), operable with similar units to provide a biological processing system, said modular biological processing unit (100) comprising: A housing (110) having one or more internal fluid paths (101), the housing having at least one inlet and at least one outlet (5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70), each of which is in fluid communication with the fluid path or one or more of the fluid paths; One or more sensor elements (120, 150, 170, 190) are operatively associated with the path or each path, the sensor elements comprising one or more of the following: flow rate sensor or flow direction sensor, conductivity sensor, pressure sensor, pH sensor, air trap, and light absorption rate sensor, such as a UV light absorption rate sensor. One or more fluid flow induction components (140) are operatively associated with the fluid path or each fluid path; as well as Multiple valves (180) are used to prevent or reduce flow in the path or in each path. The housing, inlet, outlet, flow-inducing components, and valves are arranged together within or substantially within the housing to operate as a biological treatment unit.

2. The modular biological processing unit according to claim 1, wherein, The unit includes a selection valve (130) for selecting an input from a plurality of sources into the path.

3. The modular biological processing unit according to claim 2, wherein, The flow-inducing member provides the direction of the desired flow in the unit, wherein the selection valve is upstream of the flow-inducing member, and the sensor and the plurality of valves are downstream of the selection valve.

4. A modular biological treatment unit, operable with similar units to form a biological treatment system, said unit comprising: A housing (110) having one or more internal fluid paths (101) and a plurality of inlets (5, 10, 15, 20, 25, 30, 35); Selector valve (130) is used to select the inlet; One or more fluid flow induction components (140) are operatively associated with the fluid path or each fluid path; Multiple additional ports (40, 45, 50, 55, 60, 65, 70) downstream of the expected flow in the shell path (101); One or more sensor elements (120, 150, 170, 190) operatively associated with the path or each path, the sensor elements comprising one or more of the following: flow sensors, conductivity sensors, pressure sensors, pH sensors, and light absorbance sensors, such as UV spectral concentration sensors; and Multiple valves (180) are used to prevent or reduce flow in the path or each path, and to selectively divert flow relative to the inlet / outlet and the sensor.

5. The modular biological processing unit according to any one of claims 1 to 4, wherein, The housing has an external box structure (110) arranged to be assembled within or adjacent to the box retainer (200).

6. Two or more modular biological treatment units, each according to any one of claims 1 to 5, wherein the two or more units have different biological treatment capacities, for example due to different cross-sectional areas of their respective internal fluid paths and / or their different respective pump capacities.

7. A biological treatment system, the biological treatment system comprising: Multiple biological processing units, each as described in any one of claims 1 to 6; as well as A box holder (200) is configured to receive the box or each box for use in supporting the boxes, for example, in a stack of the units.

8. The biological treatment system according to claim 7, wherein, The box holder and each box have complementary configurations for supplying power to the unit and for providing signal paths to and / or from each unit during use.

9. The biological treatment system according to claim 8, wherein, The complementary configuration of the retainer supplies electrical and / or pneumatic power as well as a signal path to each unit.

10. Use of the biological treatment system according to any one or more of the following steps, and if more than one, in any suitable order during execution: a) Removing cells by filtering liquid culture media containing recombinant therapeutic proteins, etc. b) Use additional equipment such as chromatography columns or separation membranes to perform chromatographic acquisition for obtaining cells, viruses or recombinant therapeutic proteins from liquid culture media; c) Virus inactivation; d) Solution adjustment; e) via one or more final purification steps through a chromatography column or membrane; f) Ultrafiltration / percolation after chromatographic purification; g) Sample / solution conditioning; and h) Column switching tomography.

11. The use of the biological treatment system according to claim 10 includes the step of increasing the capacity of the system by re-executing any of steps a to h using biological treatment units or multiple biological treatment units with increased capacity.

12. The biological treatment unit according to any one of claims 1 to 4, the biological treatment system according to any one of claims 6 to 9, or the method of using the biological treatment system according to claim 10 or 11, wherein, The biological processing unit or multiple biological processing units are: formed entirely or primarily of plastic material; supplied in a substantially sterile, airtight package; and intended for single use.

13. A biological processing unit (700) comprising two main layers, a fluid layer (714) and a pneumatic layer (710), the fluid layer (714) and the pneumatic layer (710) being separated by a support layer (711) and a flexible elastomer layer (712), wherein the fluid layer (714) has a fluid conduit (701) providing an inlet (705) and an outlet (745), and a junction (730), wherein the flow direction at the junction (730) in the path is controlled by an open / closed membrane valve (780).

14. The biological treatment unit (700) according to claim 13, wherein, The diaphragm valve (780) is formed at each leg of the engagement point (730).

15. The biological treatment unit (700) according to claim 14, wherein, The diaphragm valve (780) is configured to separate the flow by opening three or more diaphragm valves.

16. The biological processing unit (700) according to any one of claims 13 to 15, configured to restrict flow based on small, pulsed or variable gas pressure or vacuum in a pneumatic channel.

17. The biological treatment unit (700) according to any one of claims 13 to 16, wherein, The pneumatic layer (710) and the support layer (711) together guide gas pressure and / or vacuum via a pneumatic channel (716) to deflect the associated portion of the film (712), thereby opening or closing the corresponding fluid path (701) for regulating flow rate with a valve.

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