Continuous flow reactor for viral inactivation

Abstract

To provide a continuous flow reactor capable of securing a sufficient residence time required for viral inactivation.SOLUTION: A continuous flow reactor 100 comprises a plurality of interwoven flow paths that are in fluid communication to form a single continuous flow reactor tube 110 having a single flow path, wherein each of the plurality of interwoven flow paths includes a plurality of turns 114 that are in different, non-parallel planes, and the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, and further wherein the plurality of turns may include a repeated pattern of turns.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] The present disclosure generally relates to apparatus and processes for continuous flow reactors. More particularly, the present disclosure relates to apparatus and processes for a continuous flow reactor having at least two turns on a single longitudinal axis, each turn being disposed in a different non-parallel plane.

Background Art

[0002] The present invention is in the field of production of biological products such as proteins, which is typically carried out in a bioreactor (fermenter) for culturing eukaryotic cells to produce a target protein. Accordingly, various techniques are established, such as fed-batch or continuous or perfusion fermentation. Prior to use, the product needs to be purified. Among the purification steps, virus inactivation is essential, especially when the product is intended for use in humans.

[0003] Currently, virus inactivation at low pH is carried out in a batch reactor. The material to be inactivated (i.e., the liquid potentially containing live virus) is introduced into the batch reactor. The material to be inactivated is brought to pH ≦ 4 with an acidic solution and left for the required time. Virus inactivation is achieved by contacting the virus with the acidic solution for a time that depends on the particular product and process. All of the contents of the batch reactor are inactivated with substantially the same residence time. Furthermore, the virus reduction achieved within each batch is substantially the same.

Summary of the Invention

[0004] In one aspect, a continuous flow reactor is provided. The continuous flow reactor includes a plurality of intertwined flow paths that are in fluid communication to form a single continuous flow reactor tube having a single flow path.

[0005] In another aspect, each of the plurality of intertwined flow paths includes a plurality of turns in different non-parallel planes.

[0006] In a further aspect, the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, the second pattern includes a predetermined number of turns, and the predetermined number of turns within the first pattern is the same as or different from the predetermined number of turns within the second pattern.

[0007] In one aspect, the plurality of turns includes a repeating pattern of turns.

[0008] In another aspect, the pattern of turns is repeated after eight bends.

[0009] In a further aspect, each of the plurality of turns includes an angle of from about 100° to about 200°.

[0010] In one aspect, each of the plurality of turns includes an angle of from about 135° to about 140°.

[0011] In another aspect, the plurality of turns follows a three-dimensional path that includes a flow direction that changes by about 45° at the turn center.

[0012] In a further aspect, the plurality of intertwined flow paths is made from at least one of a flexible alloy and a shape memory alloy.

[0013] In one aspect, the plurality of intertwined flow paths includes from about 19.6 to about 39.2 turns per meter. 3

[0014] In another aspect, the plurality of intertwined flow paths includes internal structures.

[0015] In a further aspect, the plurality of intertwined flow paths includes a weft-like pattern and a warp-like pattern.

[0016] In one aspect, the plurality of intertwined flow paths includes a plurality of bends, and each bend is rotated relative to the other at an angle about the longitudinal axis of the plurality of intertwined flow paths.

[0017] In another aspect, the angle around the longitudinal axis of the intertwined flow paths is from about 25 degrees to about 60 degrees.

[0018] In one aspect, a continuous flow reactor is provided. The continuous flow reactor includes at least one flow path on a single longitudinal axis, includes a plurality of turns, and at least two of the plurality of turns are in different non-parallel planes.

[0019] In another aspect, the plurality of turns includes a first pattern that is repeated a predetermined number of times.

[0020] In a further aspect, the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, the second pattern includes a predetermined number of turns, and the predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern.

[0021] In one aspect, each of the plurality of turns is separated from each other by a bend having an angle smaller than the angle of the plurality of turns.

[0022] In another aspect, each of the bends includes an angle of less than about 135°, and each of the plurality of turns includes an angle of about 135° to about 140°.

[0023] In a further aspect, at least one flow path includes four flow paths intertwined with each other.

[0024] In one aspect, a method for virus inactivation in a continuous flow reactor is provided. The method includes a process flow to the continuous flow reactor at a flow rate having a Reynolds number of about 187 to about 333 and a Dean number of about 105 to about 212, and at least one virus inactivation compound or solution, and contacting the process flow with the at least one virus inactivation compound or solution in the continuous flow reactor.

[0025] In another aspect, a process for the continuous low pH inactivation of a production stream of virus is provided.

[0026] Additional features and advantages of the various embodiments will be described in part in the following description, become apparent in part from the description, or can be learned by practice of the various embodiments. The objectives and other advantages of the various embodiments are realized and attained by the elements and combinations particularly pointed out in the description herein.

[0027] This disclosure, in some of its aspects and embodiments, can be more fully understood from the detailed description and the accompanying drawings.

Brief Description of the Drawings

[0028]

Figure 1A

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DETAILED DESCRIPTION OF THE INVENTION

[0029] Throughout this specification and the drawings, like reference numerals identify like elements.

[0030] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide an explanation of various embodiments of the present teachings.

[0031] Viral safety is required for protein therapeutics produced in mammalian cells, and viral removal procedures are highly regulated. Viruses can be inactivated by adding compounds or solutions to the process stream. Such compounds or solutions can include at least one of solvents, detergents, pasteurization (heating), and pH reduction (acid). Low pH is a very effective method used in monoclonal antibody purification processes, consistently removing more than 4 log(10) of large enveloped viruses, including endogenous retroviruses. The American Society for Testing and Materials (ASTM) standard for the pH-based retrovirus inactivation process defines the following low pH virus inactivation conditions: pH ≤ 3.6, ≥ 15 °C, ≥ 30 minutes in the system-specific buffer at the specified pH, providing a ≥ 5 log reduction value (LRV).

[0032] Referring to FIGS. 1A-1E, to inactivate viruses, in the process stream, the process stream can be introduced into a continuous flow reactor, such as a continuous virus inactivation (CVI) reactor 100. Some exemplary process streams non-limitingly include bioreactor effluents, anion exchange chromatography effluents, cation exchange chromatography effluents, effluents from aqueous two-phase extraction, effluents from precipitation reactions, effluents from membrane filtration steps, and effluents from ultrafiltration steps.

[0033] In one example shown in FIG. 1A, the CVI reactor 100 can be configured or designed to minimize and / or reduce pressure drop and axial dispersion. Thus, the CVI reactor 100 is defined as a flow having a Reynolds (Re) number of less than 2000 and can operate at a low Reynolds (Re) number defined as Re = ρvd / μ, where ρ is density, v is average velocity, d is tube diameter, and μ is dynamic viscosity. For example, the calculation of the Re number can be based on a process flow having a temperature of 25° C., ρ = 1000 kg m−3, and μ = 8.9E−4 Pa·s. However, laminar flow, characterized by a parabolic velocity profile, can cause axial dispersion where fluid elements at the center of the tube move faster than those near the wall, resulting in a broad residence time distribution (RTD). As shown in FIGS. 1B, 2A, and 2B, to reduce and / or at least partially eliminate axial dispersion, the CVI reactor 100 includes a flow path or channel 112 having at least two turns or curves 114, such as turns 114A and 114B, that are disposed on a single longitudinal axis LX but in different non-parallel planes (e.g., plane A and plane B). This particular design can promote radial mixing and generate a secondary flow that reduces axial dispersion.

[0034] The radius of curvature (ROC) of the turn or curve 114 can be determined as a function of the Dean number (D) and the ratio of the turn length to the length of the annular shape L DT )(D = Re√(d / 2R), where d is the inner tube diameter and R is the radius of curvature of the flow path), and L DT = 0.322 × d c 0.31 × Re 0.59 × d i 0.76 (where d i is the inner diameter and d c is the coil diameter in meters)).

[0035] Reactor design Figures 1A - 1E illustrate an exemplary CVI reactor 100. The CVI reactor 100 can include a main body 102 and a continuous flow reactor tube 110 within the main body 102.

[0036] As shown in Figure 1A, the CVI reactor 100 can include multiple rows of continuous flow reactor tubes 110, for example, at least 5 rows of continuous flow reactor tubes 110. In this exemplary CVI reactor 100, the number of turns within each row of the continuous flow reactor tubes 110 can depend on the outer diameter and / or inner diameter of the reactor tubes 110. For example, reactor tubes 110 with a relatively large diameter can include fewer turns than reactor tubes 110 with a relatively small diameter. In one example, when the continuous flow reactor tubes 110 include a ROC from about 0.3 cm or less to about 2 cm or more, for example, from about 1.05 cm, each row of the continuous flow reactor tubes 110 can include 16 turns for a total of about 320 turns or more. The parameters of the CVI reactor 100 can correspond to a Dean number of about 50 or more, for example, about 100 or more, for example, a Dean number of about 100 - about 500.

[0037] In one example, before introducing a process stream and at least one virus inactivation compound or solution into the CVI reactor 100, the combination of the process stream and the virus inactivation compound or solution can include a flow rate having a Reynolds number of about 187 - about 333 and a Dean number of about 105 - about 212.

[0038] The CVI reactor 100 can include about 50 turns or more, for example about 100 turns or more. For example, the CVI reactor can include about 320 turns. Referring to FIGS. 1B and 1C, in order to accommodate about 320 turns in a small design, as shown in FIG. 1C, the flow path 112 within the CVI reactor 100 can be horizontally arranged in a plurality of stacks 180, for example, from two stacks 180 to ten or more stacks 180, for example five stacks 180. In one example, the flow path 112 within each of the stacks 180(a)-180(e) in the stack 180 can include from about 28 turns or less to about 68 turns or more. For example, each of the stacks 180(a)-180(e) in the stack 180 can include 64 turns. In one example, each stack 180 can be connected to its adjacent lower stack 180 by a 180° turn 185. In an example where the CVI reactor 100 includes five stacks 180, the continuous flow reactor tubes 110 within each of the five stacks 180 can be connected to each other by four 180° vertical turns 185.

[0039] Referring to FIG. 1B, in one example, each layer 180 within the CVI reactor 100 can include a depth L7. The depth L7 can be a distance capable of accommodating the continuous flow reactor tube 110. At a minimum, the depth L7 can be the distance from the center of the first octagram in the first layer 180(a) to the center of the second octagram in the second layer 180(b). For example, the depth L7 can be defined as a function of the diameter of the continuous reactor tube 110 or the length L3 (shown in FIG. 3C) of the intertwined continuous flow reactor tubes 110. In one example, the depth L7 can be from about 6.06 times (i.e., 6.06*d) the size of the diameter of the continuous flow reactor tube 110 or less to about 7.84 times (i.e., 7.84*d) the size of the diameter of the continuous flow reactor tube 110. For example, L7 can be from about 3.85 cm or less to about 5 cm or more, for example, about 4.7 cm. In one example, the distance L8 can be from the bottom of the tubular flow path 112 in the first layer to the top of the tubular flow path 112 in the second layer directly below the first layer. The distance L8 can also be defined as a function of the diameter of the continuous reactor tube 110. In one example, the distance L8 can be from about 0.23 times (i.e., 0.23*d) the size of the diameter of the continuous flow reactor tube 110 to about 0.70 times (i.e., 0.7*d) the size of the diameter of the continuous flow reactor tube 110. For example, L8 can be from about 0.15 cm (1.5 mm) to about 0.5 cm (5 mm), for example, starting from about 0.425 cm (4.25 mm).

[0040] Referring to FIG. 1D, in one example, the CVI reactor 100 can include a body or footprint dimension L (shown as S1 in FIG. 1D) × W (shown as W1 in FIG. 1D) × H (shown as H1 in FIG. 1D) of about 20×4.5×15 to about 40×9×30 cm, such as about 27×5.8×23.5 cm, and can accommodate a flow path 112 length of about 442.6 cm to about 7000 cm, such as about 1770.43 cm, and can approximately provide a flow rate of about 300 ml to about 800 ml, such as about 560.68 ml. The body of the CVI reactor 100 can include a first side portion 124 and a second side portion 126. In one example, the first side portion 124 can include at least one groove or depression 124A, and the second side portion 126 can include at least one protrusion 126A. The at least one depression 124A and the at least one protrusion 126A can be arranged such that when two CVI reactors 100 are arranged in contact with each other, they can be removably fixed to each other.

[0041] The distance from the center of the inlet point to the outlet point of the reactor, shown as H2, can be about 5 cm or less to about 200 cm or more, such as about 15 cm to about 25 cm, such as about 23.5 cm. The CVI reactor 100 can also include a length from the bottom of the reactor to the handle, shown as H3. The length of H3 can be about 23 cm to about 30 cm, such as about 27.2 cm. In one example, the flange 195 can extend from the bottom of the CVI reactor 100 by about 0.1 to about 1 cm, such as about 0.67 cm. Further, the flange 195 can include a radius of about 0.3 cm to about 2 cm, such as about 1.1 cm.

[0042] In one example, the continuous flow reactor tube 110 can include one or more internal structures. The internal structures can include, for example, without limitation, diffusers, catchers, distributors, catalysts, mixers, redistributors, and collectors. One or more of these internal structures can be arranged anywhere within the continuous flow reactor tube 110 and can be arranged in any manner.

[0043] In one example, the CVI reactor 100 can include sampling ports (not shown in the figures) disposed anywhere along the length of the continuous flow reactor tube 110. For example, the sampling ports can be disposed approximately midway between the start and end of the continuous flow reactor tube 110. The sampling ports can be used to extract samples of the mixed process stream and the virus inactivation compound or solution to determine, for example, the pH level or consistency of the mixture, and / or any other characteristics of the mixture. To adjust the pH level, the CVI reactor 100 can include an auxiliary input port. The auxiliary input port enables the user to add any necessary additional virus inactivation compound or solution or process stream.

[0044] In one example, relatively small or relatively large reactors can be used to accommodate relatively small or relatively large volumes of process stream, and the reactor tubes within the relatively small or relatively large reactors include an inner diameter and a radius of curvature of 2* that are substantially similar to those of reactor 100.

[0045] Figures 2A - 3D illustrate an exemplary continuous flow reactor tube 110 that can operate at low Re. The continuous flow reactor tube 110 can include a tubular flow path 112 that includes turns or curves 114 and bends 116. At least two of the turns or curves 114 are disposed on a single longitudinal axis LX, but are disposed in different non - parallel planes, such as plane A and plane B. Depending on the number of paths used to form the continuous flow reactor tube 110, the turns can be in two or more different non - parallel planes, such as about 6 - about 13 different planes, such as 8 different planes. Further, at least two of the turns are arranged such that the planes corresponding to at least two turns can intersect each other, as shown, for example, in FIGS. 2B and 3B. The turns can also form a pattern that may or may not be repeated after a given number of turns. For example, as shown in FIG. 2D, which shows a cross - section of a single path along its longitudinal axis, a single path can include a pattern 150 that is repeated at least twice (see also FIG. 2A). Each flow path can include from about 4 turns to about 128 turns or more of alternating turns, such as from about 16 to about 32 turns. Each turn 114 can include an angle of from about 110° to about 280°, such as from about 135° to about 140°. In one example, the first turn can include an angle (such as an angle of about 135°) that is less than the angle of the second turn (such as an angle of about 140°). Further, as shown in FIGS. 2A, 2B, and 3A, each flow path can also include from about 8 to about 64 or more bends 116, such as from about 8 to about 16 bends 116. Each bend 116 can include an angle of from about 15° to less than about 135°, such as from about 30° to about 90°, such as an angle of about 45°. In one example, each pattern 150 can be repeated after about 4 or more bends, such as after about 8 bends.

[0046] In another example not shown in the figures, the path of the continuous flow reactor tube 110 can include two or more different patterns, which may or may not be repeated. When the continuous flow reactor tube 110 includes a plurality of intertwined flow paths, each path of the continuous flow reactor tube 110 can include substantially the same pattern. Alternatively, or additionally, each path of the continuous flow reactor tube 110 can include different patterns. Further, each path of the continuous flow reactor tube 110 can include the same number of repeating patterns (e.g., two similarly repeating patterns), or can include more or fewer than two repeating patterns. For example, the second path can include two similarly repeating patterns or three similarly repeating patterns.

[0047] As described above, the intertwined tubular flow paths of the weave design consist of alternating 135° - 140° turns with 45° bends at the center of each turn, as shown in FIG. 2B. The inner diameter of the flow path can be from about 0.3 cm or less to about 1 cm or more, for example about 0.6 cm to about 0.7 cm, for example about 0.635 cm. Further, the minimum radius of curvature of the 130 - 140° turns can be from about 0.3 cm to about 2 cm, for example about 1.05 cm, determined for an ID of 0.635 cm.

[0048] In one example, as shown in FIG. 2E, the continuous flow reactor tube 110 can include a first flow path having a plurality of turns 114 that form a first pattern that can be repeated a predetermined number of times, for example, 2 times, and a second flow path that is substantially linear or includes a meandering pattern between the turns of the first flow path. As can be seen from FIG. 2C, the pattern of the turns 114 in the first flow path forms a top view having an octagonal star. As shown in FIG. 3A, when the continuous flow reactor tube 110 includes a plurality of flow paths, for example, 4 flow paths, each of the 4 flow paths can be substantially the same and can include turns and patterns that can be woven together and / or arranged to occupy the space formed within each turn in each flow path. Thus, as shown in FIGS. 2C and 3B, the top view of the continuous flow reactor tube 110 having one flow path or four or more flow paths substantially looks like an octagonal star.

[0049] Referring to FIGS. 2F and 2G, each of the turns 114 in the continuous flow reactor tube 110 can include a vertical L1 center-to-center distance of about 1 cm to about 2 cm, for example, about 1.5 cm, between the turns. Further, each of the turns 114 can include a horizontal L2 center-to-center distance of about 1 cm to about 2 cm, for example, about 1.63 cm, between the turns. Further, each of the turns 114 can include an end-to-end distance L3 of about 3 cm to about 4 cm, for example, about 3.85 cm. The radius of each turn 114 in the continuous flow reactor tube 110 can be substantially constant. For example, referring to FIG. 2G, the radii R1 and R2 can be within 0.05 cm of each other, for example, within about 0.02 cm of each other, to prevent a substantial difference in the Dean number between alternating turns. For example, R1 can be about 1.10 cm and R2 can be about 1.12 cm.

[0050] In one example, the plurality of flow paths can be woven together such that the plurality of turns form a multi-axis three-dimensional flow path. Such a multi-axis three-dimensional flow path can be arranged to form the overall shape of a sheet (as shown in FIGS. 4A - 4C), a prism (not shown in the figures), a cylinder (as shown in FIG. 3A), a cone (not shown in the figures), and / or a sphere (not shown in the figures).

[0051] In one example, when the flow paths of the continuous flow reactor tubes 110 are intertwined to form a sheet-like structure, the first flow path and the second flow path can include turns that form a weft-like pattern, as shown in FIG. 4A. Alternatively, the first flow path and the second flow path can include turns that form a warp-like pattern, as shown in FIG. 4B. Further, in another example, as shown in FIG. 4C, the first flow path can include turns that form a weft-like pattern, and the second flow path can include turns that form a warp-like pattern.

[0052] Material and Design of the Continuous Flow Reactor Tube The continuous flow reactor according to the present invention can be made of any suitable inert material, such as glass, synthetic material, or metal. In another example, the continuous flow reactor tube 110 can be made of at least one flexible alloy material and / or shape memory alloy material. For example, as shown in FIG. 3A, the intertwined flow paths of the continuous flow reactor tube 110 can be made of a shape memory alloy material or a flexible material. Such materials can enable the user of the continuous flow reactor tube 110 to change the shape of the tube and / or operate its flow rate as needed without the need to design a new reactor. For example, if it is necessary to heat the continuous flow reactor tube 110 in a high-temperature bath, but the available high-temperature bath cannot accommodate the rectangular continuous flow reactor tube 110, the user can change the shape of the continuous flow reactor tube 110 to circular to better fit inside the high-temperature bath. Further, by using a flexible alloy material or a shape memory alloy material for the continuous flow reactor tube 110, the user may be able to change the density of the turns per square meter of the reactor. This enables a single reactor to be used for multiple purposes. Depending on the purpose of the reactor, the user can straighten some of the turns or add additional turns to the continuous flow reactor tube 110. In one example, the density of 135° - 140° turns per unit volume of the reactor can be from about 19.6 turns / m 3 to about 39.2 turns / m 3 and can be.

[0053] Details Regarding the Intertwined Flow Paths Figures 3A - 3D show an exemplary design in which the continuous flow reactor tubes 110 can include a plurality of intertwined flow paths that are in fluid communication to form a single flow path. For example, FIG. 3A shows four paths (Paths 1 - 4) that are in fluid communication with each other to form a single flow path 112. This design can enable a smaller design than a linear pattern of stacking flow paths side - by - side by reducing the necessary distance between the flow paths and the void space below the flow paths. FIG. 3A also shows an enlarged view of the weave pattern of the four flow paths. In this example, Paths 1 - 4 are connected by curved connections such as flow path connectors 160, as shown in FIG. 3D, to avoid straight lines within the flow path.

[0054] In one example, as shown in FIGS. 3A and 3D, the flow path connector 160 can be a tube that appears to have two convex end regions and a central concave region, thereby forming a shape like an “m”. Referring to FIG. 3D, the slope between the convex region and the concave region can be at an angle of about 30 degrees to about 60 degrees, for example, an angle of about 45°. Further, each radius R3 of the convex region is about 0.3 cm to about 0.9 cm, for example, about 0.65 cm, and the radius R4 of the concave region is about 0.2 cm to about 0.8 cm, for example, about 0.52 cm. Further, as can be seen from FIGS. 3B and 3D, the distance L4 from the center of one end of the flow path connector 160 to the center of the second end of the flow path connector 160 can be about 2 cm to about 4 cm, for example, about 2.96 cm.

[0055] Referring to FIG. 3C, as described above, the four flow paths form a top view and a bottom view of an octagonal star. Referring to FIG. 3C, the octagonal star includes at least two vertically parallel tubes, two horizontally parallel tubes, and the flow path connector 160. Each turn 114 can include an end - to - end distance L3 of about 3 cm to about 4 cm, for example, about 3.85 cm. Further, the distance L5 between each pair of parallel tubes is about 1 cm to about 2 cm, for example, about 1.65 cm. Further, the distance L6 between the end of the flow path connector 160 and the tube inlet 170 or the tube outlet 175 can be about 0.5 cm to about 1.5 cm, for example, about 1.1 cm.

[0056] A plurality of reactors connected in series In one example, as shown in FIG. 5, in addition to the CVI reactor 100 having a plurality of layers 180, a plurality of CVI reactors 100 can be connected in series with each other to enable changes to the path length and incubation time. This can be achieved by one or more flanged connectors. In one example, at least two tubular CVI reactors 100, for example at least six or more in-line tubular CVI reactors 100, can be connected to each other. In this particular example, the tubular flow paths 112 at each end of the CVI reactor 100 can extend partially from the CVI reactor 100 (extension portion 190). The extension portion 190 can also include a flange 195 as shown in FIG. 1D. The connector 200 can include a horizontal 180° turn and / or can be in the shape of a "U". One end of the connector can be connected to the tubular flow path 112 or the flange 195 of the first CVI reactor 100, and the second end of the connector can be connected to the tubular flow path 112 or the flange 195 of the adjacent in-line tubular CVI reactor 100.

[0057] The connector 200 can be connected to each tubular flow path 112 or flange 195 by a clamp 210 or other fastening means such as screws, adhesives, etc., and / or integral connectors such as threaded male / female terminals, high-speed connection / disconnection terminals, etc. In one example, a gasket can be disposed between the end of the tubular flow path 112 or flange 195 and each end of the connector 200.

[0058] Examples Example 1 As shown in FIGS. 1A, 1C, and 1D, the curvature of the flow within the CVI reactor 100 generated Dean vortices that induced mixing while operating in the laminar flow regime. The 45° bends at the center of the turns further increased mixing by changing the direction of the Dean vortices generated by the turns. Referring to FIG. 6, the left image shows the centerline velocity of the centerplane flow path, and the right image shows every centerplane of the 16 135° - 140° turns and 7 45° bends of the woven flow path. As seen in FIG. 6, the profile, which is the centerline velocity measured at the centerplane of the flow path, changed with length even though it was operating in the laminar flow regime characterized by a fully developed parabolic velocity profile of the flow. The characteristic parabolic velocity profile was seen at the inlet of the flow path shown in FIG. 6 where the flow path is straight. As the flow path transitioned to the woven flow path with alternating turns and bends, the centerline velocity profile changed dynamically with length.

[0059] To further analyze the velocity profile of the woven design, as shown in FIGS. 7 and 8, the axial velocity profile and Dean vortices were measured at 45° intervals from the start of the alternating turns, or approximately every 0.9 cm along the flow path. In FIG. 8, the upper image includes a velocity heat map and an overview of the planes numbered 1 - 13 where the axial velocity and radial velocity were measured along the flow path. The inlet velocity was 5.26E - 02 m s -1 and resulted in a maximum velocity of 1.052E - 01 m s -1 for fully developed laminar flow. The velocity heat map ranged from 0 to 1.052E - 01 m s -1 . The lower image is an overview of the flow path, and the velocity profile (upper) and radial velocity / Dean vortices (lower) were measured at every 45° from the start of the turns along the flow path, or at approximately 0.9 cm intervals, at the 13 planes located at the inlet.

[0060] The average / inlet velocity of 5.26E - 02 m s -1 at each plane of FIG. 8 was predicted, and is shown in the table and graph of FIG. 9. The characteristic value of the laminar flow in the pipe for the maximum velocity was twice the average velocity (2*v avg ). Here, the v avgis 5.26E-02 m s -1 and 2*v avg is 1.052E-01 m s -1 At the inlet, before the curvature in the flow path, the maximum velocity reached the characteristic maximum value. However, in the radial plane within the woven flow path, the maximum velocity was lower than the characteristic value. This indicates that the flow path reduces the maximum velocity and thus decreases the axial dispersion.

[0061] For further analysis, the horizontal and vertical centerline velocity profiles in the radial plane of Figure 8 are shown in Figure 10. The characteristic symmetric parabolic laminar flow velocity profile was again seen at the inlet, but as the flow moved through the bend, the profile widened and became asymmetric.

[0062] Example 2 The pulse tracer experiment using the CVI woven reactor consisted of first flushing the JIB with Milli-Q water (Barnstead Nanopure Water Purification System, Thermo Scientific, Waltham, MA, USA), followed by a 13 ml pulse injection of 50 mg / ml riboflavin, and finally being chased with Milli-Q water via the P-970 system pump on an AKTA Pilot (GE Healthcare, IL, USA). The absorbance of the tracer at the outlet was measured at a wavelength of 372 nm using a UV flow cell on the AKTA Pilot (GE Healthcare). The absorbance vs. time results obtained from the pulse tracer experiments at four flow rates of 20, 30, 40, 50, and 100 ml / min are shown in Figure 11.

[0063] Laminar flow occurs at Reynolds numbers (Re) less than 2000. The Re for the flow in the pipe is defined by Equation 1 below, where ρ is the density, v is the average velocity, d is the pipe diameter, and μ is the kinematic viscosity.

Number

[0064] For the case of steady motion of an incompressible fluid in a curved pipe, the intensity of the secondary flow is characterized by the Dean number (D), a dimensionless parameter given by Equation 2, where d is the inner diameter of the pipe and R is the radius of curvature of the flow path.

Number

[0065] The RTD of the reactor can be represented as having a single E-curve with an area under the curve, and can be defined by Equation 3, where C is the concentration of the tracer at the outlet and t is time.

Number

[0066] Axial dispersion is characterized by the mean residence time defined by Equations 4 and 5, respectively,

Number

Number

[0067] Table 1 below shows the Reynolds number (Re), Dean number (D), and dispersion (σ 2 ) for the pulse tracer experiment shown previously in Figure 11. These values are important for characterizing the mixing efficiency of our design as relatively low dispersion values close to the dispersion of the injection pulse, indicating that the woven design reactor approaches mixing close to plug flow despite operating in the laminar flow regime with Re < 2000. The lowest possible value of dispersion is 0.1 minutes at a maximum flow rate of 100 ml / min 2 .

Table 1

[0068] The E-curve can be expressed in dimensionless form, E(θ), as described in Equation 6 (where θ is dimensionless time and [Number] ). The dispersion can be expressed in dimensionless time by dividing the dispersion by the square value of the mean residence time. [Number] The dimensionless E-curve of the experimental data in Figure 11 is shown in Figure 12 below. The higher the symmetry around one of the dimensionless RTD curves, the closer the reactor is to being preformed as a plug flow reactor.

[0069] As can be seen in Figure 12, the dimensionless residence time distribution curve, E(Θ), at 20 ml / min is slightly narrower than that at a flow rate of 30 ml / min. This is a characteristic of secondary flow within the range of Dean numbers D ≤ 40 - 60 where the flow is unidirectional. At higher Dean numbers D ≥ 60, the Dean vortices become stable as a pair of generated vortices.

[0070] From the foregoing description, one of ordinary skill in the art can understand that the present teachings can be implemented in various forms. Therefore, although these teachings have been described in relation to specific embodiments and examples thereof, the true scope of the present teachings should not be so limited. Various changes and modifications can be made without departing from the scope of the teachings of this specification.

[0071] The scope of the present disclosure should be construed broadly. The present disclosure is intended to disclose equivalents, means, systems, and methods for achieving the devices, activities, and mechanical operations disclosed herein. For each device, article, method, means, mechanical element, or mechanism disclosed, the present disclosure also intends to encompass its disclosure and teach equivalents, means, systems, and methods for implementing many of the aspects, mechanisms, and devices disclosed herein. Further, the present disclosure relates to coatings and many of its aspects, features, and elements. Such devices may be dynamic in their use and operation, and the present disclosure intends to encompass equivalents, means, systems, and methods of use of the devices and / or articles of manufacture, and many of its aspects consistent with the description and spirit of the operations and functions disclosed herein. The claims of the present application should likewise be construed broadly

[0072] The description of the invention in many embodiments herein is illustrative in nature and, accordingly, variations that do not depart from the gist of the invention are intended to be within the scope of the invention. Such variations should not be regarded as a departure from the spirit and scope of the invention

Claims

1. A continuous flow reactor comprising a plurality of intertwined flow paths that are in fluid communication to form a single continuous flow reactor tube having a single flow path.

2. The continuous flow reactor according to claim 1, wherein each of the plurality of intertwined flow paths includes a plurality of turns in different non-parallel planes.

3. The continuous flow reactor according to claim 2, wherein the plurality of turns includes at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, the second pattern includes a predetermined number of turns, and the predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern.

4. The continuous flow reactor according to claim 2, wherein the plurality of turns includes a repeating pattern of turns.

5. The continuous flow reactor according to claim 4, wherein the pattern of turns is repeated after bending eight times.

6. The continuous flow reactor according to claim 2, wherein each of the plurality of turns includes an angle of about 100° to about 200°.

7. The continuous flow reactor according to claim 2, wherein each of the plurality of turns includes an angle of about 135° to about 140°.

8. The continuous flow reactor according to claim 2, wherein the plurality of turns follows a three-dimensional path including a flow direction that changes by about 45° at the center of the turn.

9. The continuous flow reactor according to claim 1, wherein the plurality of intertwined flow paths are made of at least one of a flexible alloy and a shape memory alloy.

10.

11. A plurality of intertwined flow paths are 1 m 3 The continuous flow reactor according to claim 1, comprising from about 19.6 to about 39.2 turns per meter. The continuous flow reactor according to claim 1, wherein the plurality of intertwined flow paths includes an internal structure.

12. The continuous flow reactor according to claim 1, wherein the plurality of intertwined flow paths includes a weft-like pattern and a warp-like pattern.

13. The continuous flow reactor according to claim 1, wherein the plurality of intertwined flow paths includes a plurality of bends, and each bend is rotated relative to each other at an angle around the longitudinal axis of the plurality of intertwined flow paths.

14. The continuous flow reactor according to claim 13, wherein the angle around the longitudinal axis of the intertwined flow paths is about 25 degrees to about 60 degrees.

15. A continuous flow reactor including at least one flow path on a single longitudinal axis and including a plurality of turns, wherein at least two of the plurality of turns are in different non-parallel planes.

16. ​ ​ The continuous flow reactor according to claim 15, wherein a plurality of turns include a first pattern that is repeated a predetermined number of times.

17. The continuous flow reactor according to claim 15, wherein a plurality of turns include at least a first pattern and a second pattern different from the first pattern, the first pattern includes a predetermined number of turns, the second pattern includes a predetermined number of turns, and the predetermined number of turns in the first pattern is the same as or different from the predetermined number of turns in the second pattern.

18. The continuous flow reactor according to claim 15, wherein each of the plurality of turns is separated from each other by a bent portion having an angle smaller than the angle of the plurality of turns.

19. The continuous flow reactor according to claim 18, wherein each of the bent portions includes an angle of less than about 135°, and each of the plurality of turns includes an angle of about 135° to about 140°.

20. The continuous flow reactor according to claim 15, wherein at least one flow path includes four flow paths woven together with each other.

21. Introducing a process stream and at least one virus inactivating compound or solution into the continuous flow reactor at a flow rate having a Reynolds number of about 187 to about 333 and a Dean number of about 105 to about 212; Contacting the process stream and at least one virus inactivating compound or solution in the continuous flow reactor; A method for inactivating a virus in a continuous flow reactor, comprising:

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