AUTOMATED MODULAR FILTRATION SYSTEM

Abstract

An automated modular filtration system, particularly for low volume tangential flow filtration processes, comprises a plurality of filtration modules formed as separate assemblies and at least one control unit for jointly controlling filtration processes of individual filtration units. Each filtration module contains at least one individual filtration unit for executing a filtration process independent of the other filtration units, first input ports for receiving a first type of fluids, second input ports for receiving a second type of fluids, and exit ports for outputting unused system fluids. First type fluids are process fluids are specific to the filtration processes executed in individual filtration units. Second type fluids are system fluids not specific to filtration processes executed in the individual filtration units. The second input and exit ports establish inter-module connections so system fluids can be forwarded from one filtration module to an adjacent filtration module of the filtration system.

Claims

1. An automated modular filtration system, the filtration system comprising a plurality of filtration modules formed as separate assemblies, each filtration module containing at least one individual filtration unit, each filtration unit being designed for executing a filtration process independent of the other filtration units of the filtration system, each filtration module also including first input ports for receiving a first type of fluids, the fluids of the first type being process fluids which are specific to the respective filtration processes executed in the individual filtration units, each filtration module also including second input ports for receiving a second type of fluids, the fluids of the second type being system fluids which are not specific to the respective filtration processes executed in the individual filtration units, and each filtration module also including exit ports for outputting unused system fluids, the second input and exit ports being designed for establishing inter-module connections so that the system fluids can be forwarded from one filtration module (10) to an adjacent filtration module of the filtration system, the modular filtration system further comprising at least one control unit designed for jointly controlling the filtration processes executed in the individual filtration units.

2. The modular filtration system according to claim 1, characterised by a distributed control architecture where each individual functional filtration unit incorporates a dedicated local unit controller, distinct from the control unit.

3. The modular filtration system according to claim 1, characterised in that lines leading from the second input ports to the exit ports within the filtration modules branch off to the individual filtration units.

4. The modular filtration system according to claim 1, characterised in that the second input ports of a first filtration module of the filtration system are connected to system fluid reservoirs.

5. The modular filtration system according to claim 4, characterised in that the system fluid reservoirs include at least one of: a cleaning fluid reservoir, a buffer solution reservoir for calibration, a fluid reservoir for water, a storage solution reservoir with the storage solution being used to maintain physical and chemical integrity of the system during periods of non-use.

6. The modular filtration system according to claim 1, characterised in that at least one process fluid reservoir is connected to input lines of several filtration units.

7. The modular filtration system according to claim 6, characterised in that the process fluid reservoir is a reservoir containing a protein solution or a buffer solution.

8. The modular filtration system according to claim 1, characterised in that permeate and/or waste stream channels of several filtration units lead to a common tank, or the permeate and/or waste stream channels are connected with each other, optionally wherein the permeate and/or waste stream channel of at least one filtration unit is connected with a common input port of at least one further filtration unit.

9. The modular filtration system according to claim 1, characterised in that the filtration modules include at least one sensor for measuring at least one parameter selected from the group consisting of feed pressure, retentate pressure, permeate pressure, temperature, pH, conductivity, viscosity, flow, permeate pressure, protein concentration, turbidity.

10. The modular filtration system according to claim 1 any of the preceding claims, characterised in that each filtration unit is configured to receive a filter cassette comprising one or a plurality of membrane filters.

11. The modular filtration system according to claim 10, characterised in that each filter cassette is held in a filter cassette holder and received together with the filter cassette holder in a matching receptacle of the respective filtration unit.

12. The modular filtration system according to claim 10, characterised in that each filter cassette bears machine readable information on it, including at least one of: batch number, type and specifics of the filter membrane(s), date of manufacture, use-by date, maximum operating pressure, link to further information.

13. The modular filtration system according to claim 10, characterised in that at least some of the filtration units are provided with machine readable information, including unit ID codes.

14. The modular filtration system according to claim 1 characterised in that the at least one control unit is a central control unit comprising control software and a user interface assisting a user in setting up desired experiments.

15. The modular filtration system according to claim 14, characterised in that the user interface provides access to pre-defined setups.

16. The modular filtration system according to claim 14, characterised in that the user interface is installed on a mobile device.

17. A method of using the automated modular filtration system according to claim 14 for performing a plurality of filtration processes concurrently, the method comprising loading a filter cassette into each filtration unit.

18. The method according to claim 17, characterised in that the method further comprises the following steps: performing a flux test; measuring a flux value for each filter cassette; and comparing the measured flux value with a flux value specified by the manufacturer of the filter cassette or an expected flux value.

19. The method according to claim 17, characterised in that machine-readable information about at least one filter cassette is submitted to the control software of the central control unit, the machine-readable information preferably including at least one of a batch number, type and specifics of filter membrane(s), date of manufacture, use-by date, maximum operating pressure, link to further information.

20. The method according to claim 19, characterised in that a user is prompted to provide the machine readable information of a filter cassette which is to be used in a specific filtration unit to the control software of the central control unit.

21. The method according to any of claims 17, characterised in that machine-readable information about at least one filtration unit is submitted to the control software of the central control unit, the machine-readable information including a unit ID code.

22. The method according to any of claims 19, characterised in that the control software uses submitted information for at least one of: associating a filter cassette to a filtration unit; providing appropriate setups based on the loaded filter cassettes; emitting a warning if a wrong or inappropriate filter cassette is loaded; emitting a warning if a filter cassette is reused; considering the information in controlling the experiments and/or in the evaluation of the experiments.

23. The method according to any of claims 17, characterised in that the filtration processes in the filtration units are started concurrently.

24. The method according to any of claims 17, characterised in that after completion of the filtration processes the filter cassettes are removed from the filtration units and fluid connections are automatically or semi-automatically established to bridge spaces of the removed filter cassettes.

25. The method according to any of claims 17, characterised in that an automated cleaning process is triggered after removal of the filter cassettes, the automated cleaning process using at least one of the system fluids supplied via at least one of the second input ports of the filtration modules.

26. The method according to any of claims 17, characterised in that fluid output from the filtration process of one filtration unit is routed to at least an input of a filtration process in another filtration unit.

27. A method of performing a plurality of filtration processes concurrently using an automated modular filtration system according to claim 1, the method comprising: executing filtration processes in the individual filtration units independently from other individual filtration units of the filtration system, providing a first type of fluids to the first input ports of the filtration modules, the fluids of the first type being process fluids specific to the respective filtration processes executed in the individual filtration units, providing a second type of fluids to the second input ports of the filtration modules, the fluids of the second type being system fluids not specific to the respective filtration processes executed in the individual filtration units, forwarding the system fluids from one filtration module to an adjacent filtration module of the filtration system via inter-module connections established by the second input and exit ports, outputting unused system fluids through the exit ports of the filtration modules, and jointly controlling the filtration processes executed in the individual filtration units by at least one control unit.

28. The method according to claim 27, characterised in that for controlling the filtration processes executed in the individual filtration units a distributed control architecture is used including dedicated local unit controllers, distinct from the control unit, in each individual functional filtration unit.

Description

[0048] Further features and advantages of the invention will become apparent from the following description and from the accompanying drawings to which reference is made. In the drawings:

[0049] FIG. 1 shows the basic components of an embodiment of the modular filtration system according to the invention;

[0050] FIG. 2 shows a specific arrangement of an embodiment of the modular filtration system according to the invention;

[0051] FIG. 3 shows a fluid diagram of an embodiment of a filtration unit of a filtration module of the modular filtration system according to the invention;

[0052] FIG. 4 shows the system fluid path of two connected filtration modules of an embodiment of the modular filtration system according to the invention;

[0053] FIG. 5 shows an example of a possible input connection scheme for process fluids of the arrangement of the modular filtration system of FIG. 4;

[0054] FIG. 6 shows an example of a possible output connection scheme for harvested retentate material, samples of retentate fluid, permeate fluid and waste of the arrangement of the modular filtration system of FIG. 4;

[0055] FIG. 7 shows a variant of the scheme for harvested retentate material, samples of retentate fluid, permeate fluid and waste stream collection of the arrangement of the modular filtration system of FIG. 4;

[0056] FIG. 8 shows one of a number of possible assembly sequences of a filter cassette according to a first embodiment;

[0057] FIG. 9 shows a filter cassette according to the first embodiment in an upright position;

[0058] FIG. 10 shows a filter cassette according to a second embodiment;

[0059] FIG. 11 shows an assembly sequence of a filter cassette according to a third embodiment;

[0060] FIG. 11 a shows a detail of a cross section of the assembled filter cassette of FIG. 11; and

[0061] FIG. 12 shows an assembly sequence of a filter cassette according to a fourth embodiment.

[0062] The following description relates to preferred embodiments of a modular tangential flow filtration system according to the invention. However, the invention is not limited to these embodiments. A person skilled in the art will understand that certain features are optional or may be replaced by other appropriate features.

[0063] FIG. 1 is a schematic representation of a filtration module 10 including a number of individual filtration units 12, in particular tangential flow filtration (TFF) units. Each filtration unit 12 is part of a fully self-contained tangential flow system designed particularly to carry out ultrafiltration or diafiltration processes. Although four is a preferred number, the filtration module 10 may include more or less than four filtration units 12 as one set. Each set of filtration units 12 forms a filtration module 10, i.e. a pre-assembled structure, which is used as the smallest common physical unit for configuring a filtration system according to the specific needs of a customer. In FIG. 2 an example configuration is shown with four filtration modules 10, each including four filtration units 12, resulting in a total of 16 individual filtration units 12.

[0064] Each filtration unit 12 is controlled by a central control unit 14 which is connected to the array of filtration modules 10. The main software of the central control unit 14 may be hosted by a stationary computer associated to the filtration system. It is also possible to have multiple control units for controlling the filtration processes in the filtration modules 10 of the system. In this case, independent filtration units 12 within the system are assigned to different control units as required, as such forming a fixed system resource that can be used flexibly by different operators.

[0065] In particular, the modular filtration system features a distributed control architecture where each individual functional filtration unit 12out of e.g. four within a single filtration module 10incorporates a dedicated local unit controller (not shown), distinct from the central control unit 14. This ensures that each single functional filtration unit 12 is independent except for power supply and a common data bus for communications. The common data bus is terminated by the central control unit 14 that runs the process recipes and issues commands to change operational mode and set control parameters (target pressure, flow rate, liquid addition volumes, sampling volumes, etc.). Between such instructions from the central control unit 14 the individual device operations are managed by the local controller. The central control unit 14 would normally be a PC executing the high level system software. However, it is not limited to a PC, it can be any device with sufficient capabilities to issue commands to distributed controllers according to a defined recipe process.

[0066] Because of this architecture each individual filtration unit 12 features a very high degree of autonomy. Failure of the central control unit 14 does not prevent the modular filtration system from continuing its operation until central controller functionality is restored. This robustness is critical as one example embodiment may have four filtration modules 10, each comprising four individual filtration units 12 connected to the central control unit 14, thus a total of 16 individual filtration units 12 and 16 experiments underway. The investment in preparation time and test samples in such experiments means that robustness of operations is essential for the utility of the systems; it increases the certainty of retaining valuable samples which are derived from costly bioreactor run and also ensure development timelines can be met and the use of the system continues to give the right balance between risk and gain.

[0067] In addition, this control architecture enables process customization and control, by the operator, using the graphical user interface of the central control unit 14. The operator can rerun a previously performed process recipe or design a new one, either from scratch or by modifying a previously defined one. Using the filtration system software, the user can design or modify the recipe for a process by composing it from recipe steps and also by changing the parameters of these recipe steps. The recipe steps are taken from a fixed toolbox of permitted recipe steps.

[0068] Each recipe step makes an operational change to the local unit controller on an individual filtration unit 12; such as providing an instruction, e. g for the change of a set point or to add/remove liquid; or performing process flow control, e. g. a delay, a branch, a repeat or a condition; or prompting the user to perform a manual action, e. g. change an item of disposable labware.

[0069] This control architecture enables approaches such that the operator has complete control in customizing the process performed, within the operation limits of the system. Additionally, the recipe for the process can be customised individually for each individual filtration unit 12, both in terms of which steps run, and the values (set points etc.) used.

[0070] The setup of the individual filtration units 12 is substantially identical, including several input and exit ports. A diagram representing an individual UF/DF filtration unit 12 is provided in FIG. 3. The input ports include first ports 16 for a first type of fluids, hereafter referred to as process fluids. The process fluids are specific to the filtration process executed in the respective filtration unit 12 and may include protein solutions (feeds), buffer solutions, etc. The input ports further include second ports 18 for a second type of fluids, hereafter referred to as system fluids. The system fluids are not specific to the filtration process executed in the respective filtration unit 12 and may provide pH calibration, other calibration and/or automated cleaning.

[0071] The actual filtration is performed in each filtration unit 12 by one or more single use membrane filters arranged in a filter cassette 20. The setup of the filter cassette 20 and loading of a filter cassette 20 into a filtration unit 12 will be explained further below. The filtration unit 12 further includes well-known components like peristaltic pumps 22, valves 24, and a load cell 26. A range of sensors 28 may be employed for measuring one or more of the following parameters: feed pressure, retentate pressure, temperature, pH, conductivity, viscosity, flow, permeate pressure, protein concentration, turbidity.

[0072] As can be seen in FIG. 4, which shows two filtration modules 10 connected to a modular filtration system, each filtration module 10 includes a set of system fluid input ports 30 and a corresponding set of system fluid exit ports 32. The lines 34 leading from the system fluid input ports 30 to the system fluid exit ports 32 (not shown in FIG. 3) branch off to the individual filtration units 12 so that the system fluids are supplied to each filtration unit 12 of the filtration module 10. The system fluid exit ports 32 of the first filtration module 10a are connected (via tubing or directly) to the system fluid input ports 30 of the second filtration module 10b. Further, each individual filtration unit 12 of the filtration modules 10 has a process fluid input line 36 which is accessible via a connector. In FIG. 4 the input lines 36 are labelled 1, 2, 3, 4, according to the respective filtration unit 12a, 12b, 12c, 12d of the filtration module 10.

[0073] The fluid input ports 30 may be connections at a tee or manifold or other tubing connection located at or upstream of a filtration unit 12. Similarly, the exit ports 32 may also be connections at a tee or manifold or other tubing connection located at or downstream of a filtration unit 12. If the respective filtration module 10 is the last module in the fluid supply path then the last filtration unit 12 in that module may not have exit ports to avoid a tubing dead leg.

[0074] FIG. 5 shows a possible input connection scheme of the arrangement of the two filtration modules 10. The system fluid input ports 30 of the first filtration module 10a are connected to an NaOH reservoir 38, a buffer solution reservoir 40 for calibration and a lab supply reservoir 42, which may contain a cleaning fluid, for example. These system fluids are provided to the second filtration module 10b via the connections between the system fluid exit ports 32 of the first filtration module 10a and the system fluid input ports 30 of the second filtration module 10b. More filtration modules 10 could be supplied with the system fluids in the same manner.

[0075] In the example configuration of FIG. 5 the input line 44 of the first filtration unit 12a of the first filtration module 10a is connected to both a first protein solution reservoir 46 (Feed 1) and reservoir 48 of a first variant of a first diafiltration buffer solution (DF1 A). The input line 50 of the second filtration unit 12b of the first filtration module 10a is connected to both a second protein solution reservoir 52 (Feed 2) and a reservoir 54 of a second variant of the first diafiltration buffer solution (DF1 B). The input line 56 of the third filtration unit 12c of the first filtration module 10a is connected to both a third protein solution reservoir 58 (Feed 3) and a reservoir 60 of a third variant of the first diafiltration buffer solution (DF1 C). The input line 62 of the fourth filtration unit 12d of the first filtration module 10a is connected to both a fourth protein solution reservoir 64 (Feed 4) and to the reservoir 60 of the third variant of the first diafiltration buffer solution (DF1 C). It is to be noted that one DF1C reservoir supplies both the third filtration unit 12c and the fourth filtration unit 12d of the first filtration module 10a at the same time.

[0076] In the second filtration module 10b of the example configuration shown in FIG. 5 the four filtration units 12a, 12b, 12c, 12d are connected to fifth, sixth, seventh and eighth protein solution reservoirs 66, 68, 70, 72 (Feed 5, Feed 6, Feed 7, Feed 8), respectively, while the buffer solution of a single reservoir 74, namely a fourth variant of the first diafiltration buffer solution (DF1 D), is fed to all four filtration units 12a, 12b, 12c, 12d at the same time.

[0077] It is readily apparent that other combinations of individual and/or shared supplies of certain solutions to the filtration units 12 are possible. The reservoirs may be flexible bags or other suitable containers which can preferably store enough solution for all the experiments executed in the whole filtration system which require the respective solution, so that the reservoirs do not have to be exchanged during running experiments.

[0078] Similar to the variable input connection scheme the output connection scheme of the filtration system is also variable. FIGS. 6 and 7 show two different variants of individually and/or jointly collecting the permeate and/or waste streams of the filtration units 12. Respective channels 76 of the filtration units 12 lead into a common tank 77, or they are connected with each other.

[0079] The central control unit 14 includes a control software and a user interface for assisting the user in setting up the desired experiments. The user may also access a library of pre-defined setups or load pre-defined setups from other sources. According to the chosen setups, the user is instructed how to connect the ports of the filtration modules 10 to the system fluids and process fluids reservoirs. If possible, the user interface suggests that certain process reservoirs are used for more than one experiment as described above. The user may set further parameters like temperature, etc. via the user interface. The user interface may be installed on a mobile device like a tablet or a laptop computer to facilitate the setup procedure for the user.

[0080] Before the experiments are started, a flux test is performed (while an optional sanitation may be performed before or after the flux test). The membranes of the filter cassettes 20 of each filtration unit 12 are flushed with water, and the normalised water permeability (NWP) of the membranes is measured to obtain flux and pressure baselines. The filtrate flux is the rate the liquid passes through the filter membranes, and may also be called the permeate flow rate. Therefore, the NWP is the amount of water that will flow through the membranes at a specific driving force (TMP). It is to be noted that the water flux test is not performed because the membranes may not have been cleaned appropriately (with pores being still partially clogged). Rather, for each experiment a new single use filter cassette 20 is employed which may be pre-sterilised, e.g. by chemicals, gamma-irradiation, gas or autoclaving. (It is also possible that the whole filtration unit 12 and even the whole filtration unit flow path including tubing etc. is pre-sterilised). The measured pre-use flux value is used to compare with the value specified by the manufacturer to determine any deviations. The deviations may indicate a damage or be (automatically) considered in controlling the experiment and in the evaluation of the experiment, depending on the magnitude of the deviations.

[0081] In operation, all processes are started at the same time, so that the different processes in the individual filtration units 12 all run simultaneously. Thus, it is possible to effectively perform a number of related experiments, for example running the same protein solution (feed) against different diafiltration buffer solutions, or running different protein solutions against the same buffer solution, or combinations thereof.

[0082] It is preferable to control the temperature between the filtration modules 10 of the system to allow exploration of different operating temperatures and to avoid variation in the experiments executed over a period of timetemperature being known to have significant effects on protein stability, degradation, viscosity etc. The temperature is controlled by the central control unit 14 with the aid of temperature sensors and appropriate heating/cooling means.

[0083] After the product collection (harvest) is completed, the samples and the filter cassettes 20 are removed by the user. A fluid connection is automatically, semi-automatically or manually established to bridge the space of each removed filter cassette 20. By simply pressing a button an automated cleaning process is started. For performing the cleaning process no user interaction is necessary. The automated cleaning process uses one or more cleaning fluids supplied via the system fluid input ports 30 of the filtration modules 10. After the cleaning process and insertion of new filter cassettes 20 the filtration units 12 are ready for the next set of experiments.

[0084] The control software also evaluates the results of the experiments and displays the information of the analysis on the mobile device and/or on the stationary computer associated to the filtration system.

[0085] As indicated before, each filtration unit 12 is configured to receive a single use filter cassette 20 including one or a plurality of membrane filters, membrane filter layers or membrane filter stacks. Each filter cassette 20 is used for only one filtering process. The user may choose between a number of different filter cassette types with different filter properties such as membrane pore size, material of the membranes, flow channel design, spacer, etc. However, the filter cassettes 20 all have the same outer profile characteristics so that each type of filter cassette 20 matches a given filter cassette holder of the filtration units 12.

[0086] Each filter cassette 20 bears information on it, preferably contained in a barcode, RFID tag or the like. The information may include one or more of the following: batch number, type and specifics of the filter membranes, date of manufacture, use-by date, maximum operating pressure, link to further information (e.g. web manual etc.). With an appropriate reading device the user is able to submit the relevant information to the control software of the central control unit 14. The control software may use the information for one or more of the following: providing appropriate setups based on the loaded filter cassettes 20; emitting a warning if a wrong or inappropriate filter cassette 20 is loaded; emitting a warning if a filter cassette 20 is reused; considering the information in controlling the experiments and/or in the evaluation of the experiments.

[0087] Possible structures for the filter cassettes 20 are illustrated in FIGS. 8 to 12. In particular, FIG. 8 shows the assembly sequence of a filter cassette 20 according to a first embodiment. In this embodiment a bottom plate 78 includes a permeate outlet channel 80. A supporting structure 82 (e.g. mesh) can be placed into the permeate outlet channel (port) 80 or be part of the inner surface of the bottom plate 78. A sealing structure 84 (e.g. gasket) and a membrane (not shown) are placed on the bottom plate 78. The membrane can be placed between two sealing structures 84, or only a one-sided sealing 84 or no additional structure is provided. A top plate 86 with feed and retentate ports 88, 90 is added. The inner surface of the top plate 86 consists of a spacer structure or a slot to place a spacer (e.g. mesh). A clamping structure 92 is provided for compression and sealing of the filter cassette 20. In FIG. 9 the three ports 80, 88, 90 of the filter cassette 20 can be seen. The permeate port 80 extends from the bottom plate 78, whereas the retentate and feed ports 88, 90 extend from the opposite top plate 86. All ports 80, 88, 90 feature Luer lock connections, although other connection types may be used as well, preferably low volume connection types, e.g. types in which the connection is only sealed by a sealing ring.

[0088] FIG. 10 shows a second embodiment with a permeate outlet 80 provided at one of the sides of the filter cassette 20.

[0089] In FIG. 11 the assembly sequence of a filter cassette 20 according to a third embodiment is shown. A bottom plate 78 with a sealing 84 is provided. A spacer 94 and a frame (optional) for protecting the membrane 96 are placed on the bottom plate 78 before the membrane 96 is inserted. A further spacer 94 and a further sealing 84 are placed on top of the membrane 96 before the filter cassette 20 is closed with a top plate 86 including all ports, i.e. the permeate, retentate and feed ports 80, 88, 90. Thus, in contrast to the first and second embodiments, here all the ports 80, 88, 90 are provided on the same side of the filter cassette 20. In the cross-sectional view of FIG. 11a the sealing of the membrane 96 can be seen in detail.

[0090] FIG. 12 depicts the assembly of a fourth embodiment of the filter cassette 20. Although the structure is very similar to that of the first embodiment, the ports 80, 88, 90 of the filter cassette 20 according to the fourth embodiment are all placed on the top side. This means that all outlet channels (permeate, retentate, feed) are formed in the top plate 86 of the filter cassette 20.

[0091] Of course, certain aspects of the embodiments described above may be combined in other ways. Moreover, individual illustrated parts of the construction may also be present as composite parts. Different positioning and a different number of ports 80, 88, 90 are possible.

[0092] Each type of filter cassette 20 has shape characteristics matching with corresponding characteristics of a common filter cassette holder. The filter cassette holder, in turn, includes shape characteristics matching with corresponding characteristics of a common filter cassette holder receptacle provided in each filtration unit 12.