Unit for treating biological process liquids with disposable flow path elements

Abstract

A first unit (1) for treating a biological process liquid comprises a first side face (2), a second side face (3) and a front face (4) meeting the two side faces. The front face comprises: a plurality of valves (7) adapted to receive one or more legs (8) of the disposable flow path (6) and to act on the one or more legs (8) of the disposable flow path (6); optionally, one or more pumps (10) adapted to receive the one or more legs of the disposable flow path and to act on the one or more legs of the disposable flow path; optionally, one or more sensors (11) adapted to receive and measure one or more parameters in one or more legs of the disposable flow path; wherein the plurality of valves and optional pumps and sensors are vertically offset from each other to give a slope of at least 3.0 degrees from a horizontal plane (h) to one or more legs of the disposable flow path received by the valves and optional pumps and sensors.

Description

[0001] This application is a divisional application of the PCT patent application "Unit for processing biological process liquids using disposable flow path elements" (application number: 201680071381.X, applicant: Stofan Sweden AB), which entered the Chinese national phase on June 6, 2018. Technical Field

[0002] This invention relates to apparatus for treating biological process liquids, and more particularly, to apparatus for filtering biological process liquids using disposable flow paths. The invention also relates to a method of installing disposable flow paths on a device for filtering biological process liquids. Background Technology

[0003] Cross-flow filtration (“CFF”, also known as “tangential flow filtration” (TFF)) systems are used in industrial applications such as manufacturing process separation, waste treatment plants, and water purification systems, where they can extend the life of the filter membrane by removing and / or preventing the accumulation of contaminants and promoting consistency of the filtration process over time.

[0004] The most commonly used CFF / TFF membrane processes are microfiltration and ultrafiltration. These processes can be pressure-driven and depend on “membrane flux,” which is defined as the flow rate per unit membrane area per unit time through a microfiltration or ultrafiltration membrane. At low pressures, transmembrane flux is proportional to pressure. Therefore, by varying the transmembrane pressure differential and the average pore diameter, the membrane can act as a selective barrier by allowing certain components of the mixture to pass through while retaining others. This results in two phases: a permeate phase and a retentate phase, each enriched with one or more of the components of the mixture. The retentate stream is recirculated in the flow loop and pumped through the membrane again in a continuous manner. Such CFF / TFF systems are used to significantly reduce the volume of the sample solution when the permeate stream is withdrawn from the system. Thus, the sample solution becomes concentrated when the system is driven in concentration mode.

[0005] CFF / TFF systems offer several advantages: Automatic purging and cleaning occur due to the flow direction of the fluid sample, which is substantially parallel to the membrane surface, allowing for higher flux and throughput typically achievable with such systems compared to corresponding normal flow filtration systems. Furthermore, the majority of the sample flows continuously above the membrane surface, thus hindering clogging and fouling in these systems. Due to these and other advantages, CFF / TFF systems are commonly used in industrial and / or biotechnological processes.

[0006] In automated CFF / TFF systems, buffer solutions and other system processing solutions need to be circulated through filters and other system components before or after the separation process for equilibration. Ideally, such circulation and equilibration of buffer solutions and other system processing solutions are performed automatically without manual intervention.

[0007] Filtration systems are critical components in the pharmaceutical and biotechnology industries for purifying liquids used in biological processes. Due to the high value of the purified liquids, extensive research has focused on improving all aspects of filtration systems. These systems encompass a wide range of applications, including microfiltration, ultrafiltration, tangential or cross-flow filtration, and constant-volume percolation. Generally, in these systems, the liquid to be filtered is forced through a flow path to a porous membrane sheet or porous hollow fiber column. These sheets or membranes are commercially available and utilize molecules or particles of varying pore sizes, smaller than the average membrane or column pore size, to pass through the membrane or hollow fiber wall along with, for example, solvents and be collected as filtrate. Percolate streams are left behind. In many filtration pathways (such as those incorporated into ultrafiltration or other tangential flow filtration devices), percolate is repeatedly recycled to improve filtration efficiency and increase the yield of filtrate or percolate. Each of these streams contains valuable products with a total recovery potential of up to 1-5%. Examples of such systems can be found in U.S. Patent 6,607,669 to Schick, published August 19, 2003; U.S. Patent 7,270,744 to Petersen, published September 18, 2007; U.S. Patent 6,461,513, published April 3, 2014; and International Patent Publication WO2014 / 051503, which are hereby incorporated in their entirety by reference.

[0008] The quantitative recovery of valuable concentrated bioprocess liquids after purification and / or concentration is an area of ​​interest. Once the major purification and / or concentration processes are complete, a significant amount of residual bioprocess liquid remains in the flow path of the filtration system. Many strategies have been applied to facilitate the recovery of this residual liquid. Unfortunately, none of these methods have resulted in the efficient and quantitative recovery of all residual liquids.

[0009] Furthermore, during the start-up of this process, air needs to be removed from the flow path, which is not adequately addressed by existing technologies.

[0010] Therefore, further development is needed to ensure the complete recovery of valuable bioprocess liquids and complete air removal during start-up. This need applies to filtration systems, as well as other bioprocess systems, such as, for example, chromatography systems and bioreactors. Summary of the Invention

[0011] One aspect of the invention is to provide a unit for processing biological process liquids that allows for complete recovery of the liquids and facilitates the removal of air from the system. This is achieved using the first unit as defined in claim 1.

[0012] The advantage lies in the improved release of the single-use flow path mounted on the unit before processing the flow path. It is always advantageous to release the flow path while it is in a controlled position (i.e., mounted on the unit) compared to releasing the loose flow path after it has been removed from the unit and the tubing manually directed to the release point. The latter procedure is incompatible with the constraints of standard operating procedures required in GMP manufacturing and biopharmaceutical production environments.

[0013] A second aspect of the invention is to provide an apparatus for treating biological process liquids that allows for complete recovery of the liquids and facilitates the removal of air from the system. This is achieved using the apparatus as defined in the claims.

[0014] A third aspect of the invention is to provide a method for installing a disposable flow path on a unit for processing liquids in a biological process. This is achieved using the method as defined in the claims.

[0015] A fourth aspect of the invention is to provide a method for tangential flow filtration of a biological process fluid. This is achieved using the method as defined in the claims.

[0016] Furthermore, suitable embodiments of the invention are described in the dependent claims. Attached Figure Description

[0017] Figure 1 The first unit of the present invention is shown (front view).

[0018] Figure 2 The alternative first unit of the present invention is shown in perspective view—a) left side + front, b) right side + front.

[0019] Figure 3 It shows how to use, for example, with Figure 2 The three flow path components used together by the unit (with schematic diagrams showing slopes not shown) are: a) supply flow path, b) residual flow path, and c) permeate flow path.

[0020] Figure 4 The device of the present invention is shown (front view).

[0021] Figure 5 A schematic diagram of slope calculation is shown.

[0022] Figure 6 A portion of the flow path leg with a hose barb connector is shown.

[0023] Figure 7 Different types of guides are shown: a) Colored lines (side view).

[0024] b) Raised (protruding) line (side view).

[0025] c) Stud (side view and front view).

[0026] d) Lug (side view).

[0027] e) Recess (side view).

[0028] Figure 8 A processor with a graphical user interface is shown.

[0029] limited To more clearly and concisely describe and point out the subject matter of the claimed invention, the following defines specific terms used in the following description and appended claims.

[0030] The singular forms “a,” “an,” and “the” include multiple referents unless the context clearly indicates otherwise. Approximate language used throughout the specification and claims can be applied to modify any quantitative expression that may be permissibly changed without causing a change in the essential function it relates to. Therefore, values ​​modified by terms such as “about” are not limited to the specified precise values. Thus, unless otherwise indicated, the numerical parameters set forth in the following specification and appended claims are approximate values ​​that may vary depending on the desired properties sought to be obtained from embodiments of the invention. At least each numerical parameter should be interpreted based on the number of significant figures reported and by applying common rounding techniques.

[0031] Any directional terms used herein (such as “top,” “bottom,” “above,” “below,” “up,” “down,” “high,” “low,” and “height”) refer to the arrangement as they appear in the figures. Connection references (e.g., link, attachment, coupling, connection, etc.) are to be interpreted broadly and may include intermediate parts between connections of elements and relative movement between elements. In this regard, a connection reference does not necessarily mean that two elements are directly connected and fixed relative to each other. Furthermore, the various elements discussed with reference to the various embodiments are interchangeable to create entirely new embodiments within the scope of the invention. Detailed Implementation

[0032] In the Figure 1-2In one aspect shown, the invention discloses a first unit 1 for treating liquids in biological processes, which may be, for example, a filtration unit, such as a tangential flow filtration unit or a terminal filtration unit. Alternatively, the first unit may be a chromatography unit or a bioreactor unit. The first unit includes a first side 2, a second side 3, and a front 4 that meets the two sides. Suitably, the front and, optionally, the sides, may be vertically oriented. The first unit may, for example, include a filter element 5 on one of the sides or be adapted to receive the filter element 5. The filter element may be fluidly connected to a single-pass flow path 6. The first unit (particularly the front 4) includes: i) A plurality of valves 7 adapted to receive and act on one or more legs 8 of a disposable flow path, which may be at least partially attached to the front, for example by being received by a valve. The valves may be, for example, pinch valves, and the disposable flow path may, for example, comprise multiple segments of flexible tubing 8 connected by connectors 9 (e.g., hose hook connectors). These connectors may be, for example, two-way or three-way connectors, such as Y-type or T-type connectors. In a tangential flow filtration system, the disposable flow path may, for example, comprise a supply line, a permeate loop, and a permeate loop or line, wherein the permeate loop and permeate loop / line are suitably fluidly connected to the filter element 5. The filter element may, for example, be one or more flat sheet membrane capsules in a hollow fiber cartridge or cassette retainer. The flow path may also include additional legs for system venting, air removal, and / or cleaning. The flow path is disposable, meaning it is intended for single use, and comprises low-cost plastic and / or elastomer components suitable for pre-sterilization, for example, by gamma irradiation. It may include, for example, one or more flexible tubing segments, such as non-braided tubing for low-pressure applications and braided tubing for applications requiring higher pressure. Tubing segments may be connected by hose hook connectors (e.g., straight connectors, Y-type or T-type connectors) and secured, for example, by cable ties or clamps (such as Oetiker clamps (Oetiker+Partner AG) or BarbLock fittings (St Gobain)). The inner diameter of the tubing may be, for example, 5-25 mm, such as 10-25 mm. The flow path may suitably include sanitary or sterile connectors, for example, as described in US6,679,529, US2009 / 0015005, or US2015 / 0061282 (hereinincorporated by reference in its entirety), to allow aseptic connection of the pre-sterilized flow path to pre-sterilized filter elements, canisters, bags, additional flow paths, etc. Examples of flow path components are shown in... Figure 3As shown in the diagram. The disposable flow path may also include at least one air outlet leg 31 and / or at least one discharge leg 33, wherein the air outlet leg may be configured to allow air to flow out of the system / flow path and may be located at a high / top position of the flow path. The air outlet leg may be further equipped with a sterilization-grade filter 32 to prevent contamination of the flow path. The discharge leg may be configured to allow system / flow path discharge and may be located at a low / bottom position of the flow path.

[0033] ii) Optionally, one or more pumps 10 are adapted to receive one or more legs of the disposable flow path and act on one or more legs of the disposable flow path. The pumps may be, for example, peristaltic pumps or pump drivers for disposable pump heads. In the latter case, the disposable pump head may form part of the disposable flow path and be received by the pump driver on the front side.

[0034] iii) Optionally, one or more sensors 11 are adapted to receive and measure one or more parameters of one or more legs of a single flow path. The sensors may be, for example, pressure sensors or flow rate sensors, but they may also include, for example, pH, conductivity, or concentration sensors.

[0035] Multiple valves, along with optional pumps and sensors, are offset perpendicularly to each other to give one or more legs (such as all legs) of the disposable flow path received by the valves, optional pumps, and sensors a slope of at least 3 (e.g., at least 4) degrees from the horizontal plane h. The slope may be defined as the angle α between the straight line from one end 23 of leg 8 to the opposite end 24 of the leg and the horizontal plane h. Suitably, the slope of one or more legs may be 3.0–10.0 degrees from the horizontal plane, such as 3.0–8.0 or 4.0–6.0 degrees. The slope allows for efficient discharging of the system, which is necessary for the recovery of valuable materials after treatment (e.g., filtration runs, chromatographic runs, or cell cultures). This also minimizes the amount of liquid discarded using the disposable flow path after use, promotes incineration of the flow path, and reduces the amount of potentially biohazardous material to be disposed of as waste. Furthermore, the slope also facilitates the removal of air from the system. The slope is particularly important when using flow paths with multi-segment tubes 8 connected by hose barb couplings 9, as the lower inner diameter of the hose barb couplings causes stagnant pools and can trap air bubbles. Hose barb couplings are particularly desirable for braided tubes and other types of tubes that do not conform to welded or molded connections. We have found that slopes greater than 3 degrees dramatically improve discharge, especially when using connectors, and when used to counteract any slack in the legs of flexible flow paths. The volume of the flow path should be kept generally as low as possible to minimize stagnant volume, thus allowing for high concentration factors and low volumes of the process fluid. For this reason, slopes can suitably be up to 10.0 degrees or up to 8.0 or 6.0 degrees, where higher slopes result in longer legs. However, short branch legs connecting longer legs may require higher slopes, for example, around 90 degrees.

[0036] like Figure 2 As shown, one or both of sides 2 and 3 may also include multiple valves 7 and optional pumps 10 / sensors 11, which are adapted to receive one or more flow path legs 8 in an inclined configuration.

[0037] In the Figure 1 , Figure 2 and Figure 7In some embodiments shown, the first unit also includes a guide 12 on the front (and optionally one or both sides) between the valve and any optional pump and sensor for mounting a disposable flow path. The guides may be substantially linearly related to a slope of at least 3.0 degrees (e.g., at least 4.0, or 3.0–10.0, 3.0–8.0, or 4.0–6.0) from the horizontal plane. They may include visually and / or tactilely distinguishable lines (e.g., colored lines 13 or raised lines 14), along which the legs of the disposable flow path may be arranged. The guides may also include means for constraining the disposable flow path with the desired slope, such as studs 15, lugs 16, and / or recesses 17 adapted to receive the disposable flow path. The legs of the disposable flow path may be suitably aligned with the guides, and if the guides include constraining means, this minimizes any slack in the legs of the flexible flow path. During use, single-use systems for treating biological process liquids require frequent installation and removal of flow paths. This is greatly facilitated by the presence of guides.

[0038] In the Figure 8 In some embodiments shown, the first unit (or device 30 discussed below) further includes a processor 17 with an optical display 18. A graphical user interface 25 on the optical display shows the outline of a front face 4 with a valve 7, an optional pump 10, and a sensor 11, and a flow path 6, wherein one or more legs 8 of the flow path have a slope of at least 3.0 degrees (e.g., at least 4.0, or 3.0-10.0, 3.0-8.0, or 4.0-6.0) from the horizontal plane h. The graphical user interface with a visual slope helps the user understand the orientation of the flow path legs. Furthermore, it facilitates programming methods for venting / recovery and / or air removal with regard to appropriate flow direction. This is particularly important for venting / recovery methods, where the venting flow direction in the flow path may be opposite to the pumping flow direction during the main process operation.

[0039] In the Figure 4 In some embodiments shown, the first unit is adapted to be juxtaposed against the second unit 19 from a first side. The first unit may also be adapted to be juxtaposed against the third unit 20 from a second side. At least one of the second and third units may be adapted to receive a can, such as a flexible bag 21, 22, fluidly connected to a disposable flow path. One of the second and third units may be adapted, for example, to receive a supply / residue can or bag 21, while the other of the second and third units may be adapted, for example, to receive a permeate can or bag 22. Alternatively, one of the second and third units may be adapted to receive both a supply / residue can or bag and a permeate can or bag. The other of the second and third units may be adapted, for example, to receive a filter element, such as a cassette holder for a flat plate filter cartridge.

[0040] In the Figure 4 In the second aspect shown, the invention discloses an apparatus 30 for treating biological process liquids. The apparatus may typically be a filtration apparatus (such as a tangential flow filtration apparatus), but it may also be, for example, a chromatography apparatus. The apparatus includes a first unit 1 as discussed above, and at least one of a second unit 19 and a third unit 20 arranged side-by-side by a first side and / or a second side. The apparatus may also include one or more of a filter element 5, a supply / permeate tank or bag 21, and a permeate tank or bag 22, all of which may be fluidly connected by a disposable flow path 6 described above. The disposable flow path may include a permeate loop received by a permeate pump and fluidly connected to a permeate inlet and a permeate outlet on the filter element. The permeate loop may also suitably be fluidly connected to the supply / permeate tank or bag (e.g., to the supply / permeate tank or bag outlet and the supply / permeate tank or bag inlet). Furthermore, the disposable flow path may include a permeate line or permeate loop fluidly connected to at least a permeate outlet on the filter element. The permeate line / loop can be received by a permeate pump and fluidly connected to a permeate tank or bag.

[0041] In a third aspect, the invention discloses a method for mounting a disposable flow path on a first unit as described above, comprising receiving the disposable flow path in a valve and optionally a pump and a sensor, wherein one or more (such as all) legs of the disposable flow path have a slope of at least 3.0 (such as at least 4.0) degrees from the horizontal plane. Suitably, one or more legs have a slope of 3.0-10.0, 3.0-8.0, or 4.0-6.0 degrees from the horizontal plane. The disposable flow path may be supplied pre-sterilized, for example by gamma irradiation. The flow path may be equipped with sanitary connectors for aseptic connection to a filter element, a supply / exhaust tank or bag, and a permeate tank or bag. Alternatively, the flow path may include multiple tubing segments for aseptic welding to tubing extending from the filter element, the supply / exhaust tank / bag, and / or the permeate tank / bag.

[0042] In a fourth aspect, the present invention discloses a method for tangential flow filtration of biological process liquids, comprising the following steps: a) Provide the equipment as described above; b) Circulate the liquid from the supply / leakage tank or bag through the leakage loop and filter element in a single-use flow path and return it to the supply / leakage tank or bag; c) The permeate from the filter element is conveyed through a permeate line or permeate loop through a single-use flow path to a permeate tank or bag or outlet.

[0043] The method may also include step a'), before or during step b), allowing any remaining air to flow out through an air outlet leg that passes through a disposable flow path. The air outlet leg may be a branch of the flow path located at a higher position and may include a sterilization-grade filter to prevent contamination of the flow path.

[0044] In some embodiments, the method includes a step d) following step c) to release a disposable flow path. The release may be performed, for example, via a release leg of the disposable flow path. This leg may be, for example, a branch of the flow path located at a lower position, and may be connected to a release container. Following the release step d), the method may further include a step e) to discard the disposable flow path. This may be accomplished, for example, by incineration.

[0045] This written description uses examples to disclose the invention (including the best mode) and also enables those skilled in the art to practice the invention (including making and using any device or system and performing any incorporated method). The patentable scope of the invention is defined by the claims and may include other examples that may occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that are not significantly different from the literal language of the claims, or if they include equivalent structural elements that are not significantly different from the literal language of the claims. Any patent or patent application mentioned herein is hereby incorporated in its entirety by reference as if it were incorporated independently.

Claims

1. A first unit (1) for processing biological process liquids, comprising a first side (2), a second side (3), and a front surface (4) joining the two said sides; said front surface comprising: - Multiple valves (7) adapted to receive and act on multiple legs (8) of a single flow path (6); - Optionally, one or more pumps (10) are adapted to receive and act on multiple legs of the one-time flow path; - Optionally, one or more sensors (11) are adapted to receive and measure one or more parameters in one or more legs of the disposable flow path; in - The plurality of valves, and optionally the pump and sensor, are vertically offset from each other to give one or more legs of the one-time flow path received by the valves, and optionally the pump and sensor, a slope of at least 3.0 degrees from the horizontal plane (h). The disposable flow path includes one or more flexible tubes, and the inner diameter of the flexible tube is 5-25 mm, optionally 10-25 mm.

2. The first unit according to claim 1, characterized in that, The valve, along with optional pumps and sensors, is arranged to give one or more legs of the one-time flow path a slope of 3.0-10.0 degrees from the horizontal plane, such as 3.0-8.0 degrees.

3. The first unit according to claim 1 or claim 2, characterized in that, The valve, along with an optional pump and sensor, is arranged to give all legs of the one-time flow path a slope of at least 3.0, such as at least 4.0 degrees, from the horizontal plane.

4. The first unit according to claim 1 or claim 2, characterized in that, The first unit is also adapted to receive a filter element (5) fluidly connected to the disposable flow path.

5. The first unit according to any of the preceding claims, characterized in that, The plurality of valves includes one or more pinch valves.

6. The first unit according to any of the preceding claims, characterized in that, The one or more pumps include peristaltic pumps.

7. The first unit according to any of the preceding claims, characterized in that, The first unit also includes a guide (12) on the front side between the valve and optionally the pump and sensor for mounting the one-time flow path, wherein the guide is substantially linearly related to a slope of at least 3, such as at least 4 degrees, from the horizontal plane.

8. The first unit according to claim 7, characterized in that, The guide includes visually and / or tactilely distinguishable lines (13, 14).

9. The first unit according to claim 7 or claim 8, characterized in that, The guide includes a stud (15), a lug (16), and / or a recess (17) adapted to receive the one-time flow path.

10. The first unit according to any of the preceding claims, characterized in that, The first unit also includes a processor (17) having an optical display (18), wherein a graphical user interface (25) on the optical display shows the outline of the front of the flow path having valves, optional pumps and sensors, and wherein one or more of the flow paths, such as all legs, have a slope of at least 3 degrees from the horizontal plane.

11. The first unit according to any of the preceding claims, characterized in that, The first unit is a tangential flow filtering unit.

12. The first unit according to any of the preceding claims, characterized in that, The first unit is a chromatographic unit.

13. The first unit according to any of the preceding claims, characterized in that, The first unit is a bioreactor.

14. The first unit according to any of the preceding claims, characterized in that, The first unit is adapted to be placed side by side against the second unit (19) from the first side.

15. The first unit according to claim 14, characterized in that, The first unit is adapted to be placed side by side with the third unit (20) against the second side.

16. The first unit according to claim 14 or claim 15, characterized in that, At least one of the second and third units is adapted to receive a can, such as a flexible bag (21, 22), with fluid connected to the disposable flow path.

17. The first unit according to any of the preceding claims, characterized in that, The first unit also includes a one-time flow path received by the plurality of valves, as well as optional pumps and sensors.

18. The first unit according to claim 17, characterized in that, The leg of the flow path is aligned with the guide.

19. The first unit according to claim 17 or claim 18, characterized in that, The disposable flow path includes at least one air outlet leg (31) and / or at least one discharge leg (33).

20. An apparatus for treating biological process liquids, comprising a first unit according to any of the preceding claims and at least one of a second unit and a third unit juxtaposed by the first side and / or the second side.

21. The device according to claim 20, characterized in that, The device also includes one or more of a filter element, a supply / permeate tank or bag (21), and a permeate tank or bag (22).

22. The device according to claim 20 or claim 21, characterized in that, The device also includes a one-time flow path having one or more legs having a slope of 3-10, such as 3-8 degrees, from the horizontal plane.

23. The device according to claim 22, characterized in that, The disposable flow path provides a fluid connection between the filter element and at least one of the supply / permeate tank or bag and the permeate tank or bag.

24. A method of mounting a disposable flow path on a first unit according to any one of claims 1 to 16, comprising receiving the disposable flow path in the valve and optionally in a pump and a sensor, wherein one or more of the disposable flow path, such as all legs, have a slope of at least 3, such as at least 4 degrees, from the horizontal plane.

25. The method according to claim 24, characterized in that, The disposable flow path includes at least one air outlet leg (31) and / or at least one discharge leg (33).

26. The method according to claim 24 or claim 25, characterized in that, The leg of the flow path is aligned with the guide.

27. The method according to any one of claims 24 to 26, characterized in that, The disposable flow path is pre-disinfected.

28. A method for tangential flow filtration of a biological process liquid, comprising the following steps: a) Provide the device according to claim 23; b) The liquid from the supply / leakage tank or bag is circulated through the leakage loop of the disposable flow path and the filter element and returned to the supply / leakage tank or bag; c) The permeate from the filter element is conveyed through the permeate line or permeate loop through the disposable flow path to the permeate tank or bag or outlet.

29. The method according to claim 28, characterized in that, The method includes step a', which involves allowing residual air to flow out of the air outlet leg that passes through the one-time flow path, before or during step b).

30. The method according to claim 28 or claim 29, characterized in that, The method includes step d) following step c), which releases the one-time flow path.

31. The method according to claim 30, characterized in that, The method includes step e) after step d), which discards the one-time flow path.

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