Continuous flow reactor for virus inactivation

Abstract

To provide a continuous flow reactor for viral inactivation.SOLUTION: There is provided a continuous flow reactor 100 that includes a plurality of interwoven flow paths in fluid communication to form a single continuous flow reactor tube 110 having a single flow path, wherein each of the interwoven flow paths comprises a plurality of turns 114 that are in different, non-parallel planes, and wherein the plurality of turns include at least a first pattern and a second pattern different from the first pattern, and wherein the first pattern and the second pattern include a predetermined number of turns respectively, and wherein the predetermined number of turns in the first pattern is same or different from the predetermined number of turns in the second pattern.SELECTED DRAWING: Figure 1A

Description

[Technical field]

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

[0002] The present invention is in the field of production of biological products such as proteins, which is usually carried out in bioreactors (fermenters), for example, where eukaryotic cells are cultured to produce the protein of interest. Thus, various techniques are established, such as fed-batch or continuous or perfusion fermentation. Before use, the product needs to be purified. Among the purification steps, in particular when the product is intended for human use, the inactivation of viruses is essential.

[0003] Currently, virus inactivation at low pH is carried out in a batch reactor. The material to be inactivated (i.e., liquid potentially containing active virus) is introduced into the batch reactor. The material to be inactivated is brought to a pH of ≦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 period that depends on the particular product and process. The entire 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 that includes a plurality of interwoven flow channels in fluid communication to form a single continuous flow reactor tube having a single flow channel.

[0005] In another aspect, each of the plurality of interwoven flow paths includes a plurality of turns that lie 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 including a predetermined number of turns and the second pattern including 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.

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

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

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

[0010] In one embodiment, each of the plurality of turns comprises an angle of about 135° to about 140°.

[0011] In another embodiment, the multiple turns follow a three-dimensional path that includes a flow direction change of approximately 45° at the center of the turn.

[0012] In a further aspect, the plurality of interwoven channels are fabricated from at least one of a flexible alloy and a memory alloy.

[0013] In one embodiment, the plurality of interwoven channels is 1 m 3 Contains approximately 19.6 to 39.2 turns per hit.

[0014] In another aspect, the plurality of interwoven channels comprises an internal structure.

[0015] In a further aspect, the plurality of interwoven channels comprises a weft-like pattern and a warp-like pattern.

[0016] In one aspect, the plurality of interwoven flow channels includes a plurality of bends, each bend being rotated relative to one another at an angle about a longitudinal axis of the plurality of interwoven flow channels.

[0017] In another embodiment, the angle of the interwoven channels about the longitudinal axis is between about 25 degrees and about 60 degrees.

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

[0019] In another embodiment, 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 including a predetermined number of turns and the second pattern including 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 one another by a bend having an angle that is less than the angle of the plurality of turns.

[0022] In another embodiment, each of the bends comprises an angle of less than about 135°, and each of the plurality of turns comprises an angle of between about 135° and about 140°.

[0023] In a further embodiment, the at least one channel comprises four channels interwoven with each other.

[0024] In one aspect, a method of virus inactivation in a continuous flow reactor is provided, the method comprising: a process stream into a 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 inactivating compound or solution; and contacting the process stream with the at least one virus inactivating compound or solution in the continuous flow reactor.

[0025] In another aspect, a process is provided for continuous low pH viral inactivation of a product stream.

[0026] Additional features and advantages of various embodiments will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the various embodiments. The objectives and other advantages of the various embodiments will be realized and attained by means of the elements and combinations particularly pointed out in the description herein.

[0027] The present disclosure, in some aspects and embodiments thereof, can be more fully understood from the detailed description and the accompanying drawings. [Brief description of the drawings]

[0028] [Figure 1A] FIG. 1 is a perspective view of a continuous flow reactor showing its casing and exemplary reactor tubes according to one example of the present disclosure. [Figure 1B] FIG. 1B is a partial perspective view of the continuous tubular reactor of FIG. 1A according to an example of the present disclosure. [Figure 1C] FIG. 1B is a rear view of the continuous tubular reactor of FIG. 1A according to an example of the present disclosure. [Figure 1D] 1B shows a perspective view, a front view, and a side view of the continuous flow reactor of FIG. 1A according to an example of the present disclosure. [Figure 2A] FIG. 1 is an isometric view of an exemplary continuous flow reactor tube having a single run according to one example of the present disclosure. [Figure 2B] 2B shows the continuous flow reactor tube of FIG. 2A having turns that are on a single longitudinal axis but in different non-parallel planes according to one example of the present disclosure. [Figure 2C] FIG. 2B is a top view of the exemplary continuous flow tube of FIG. 2A according to one example of the present disclosure. [Figure 2D] FIG. 2B is a cross-sectional view along a longitudinal access of the tube of FIG. 2A according to an example of the present disclosure. [Figure 2E] 2B is a continuous flow reactor tube of FIG. 2A having a first flow path having turns and a second path that is substantially straight, according to an example of the present disclosure. [Figure 2F]FIG. 2B is a side view of the exemplary continuous flow tube of FIG. 2A according to one example of the present disclosure. [Figure 2G] FIG. 2C is a detailed view of region A of the side view of the exemplary continuous flow tube of FIG. 2F according to one example of the present disclosure. [Figure 3A] FIG. 2 is an isometric view of an exemplary continuous flow tube having four runs according to one example of the present disclosure. [Figure 3B] FIG. 3B is a top view of the exemplary continuous flow tube of FIG. 3A according to one example of the present disclosure. [Figure 3C] FIG. 3B is a bottom view of the exemplary continuous flow tube of FIG. 3A according to one example of the present disclosure. [Figure 3D] FIG. 3B is a detailed view of a connection point between a first flow path and a second flow path of the exemplary continuous flow tube of FIG. 3A according to one example of the present disclosure. [Figure 4A] 1 illustrates a first flow channel and a second flow channel having a weft-like pattern according to one example of the present disclosure. [Figure 4B] 1 illustrates a first flow channel and a second flow channel having a warp thread pattern according to one example of the present disclosure. [Figure 4C] 1 illustrates a first flow channel having a warp-like pattern and a second flow channel having a weft-like pattern according to one example of the present disclosure. [Diagram 5] 1 shows multiple continuous flow reactors connected together according to an example of the present disclosure. [Figure 6] 13 illustrates the centerline velocity of a woven channel for an inlet velocity of 5.26E-02 m s-1 according to an example of the present disclosure. [Figure 7] 13 illustrates flow path and axial velocity contours along a weave flow path according to an example of the present disclosure. [Figure 8] 8 illustrates details of the weave design planar velocity contour and Dean vortex / radial velocities of FIG. 7 according to an example of the present disclosure. [Figure 9] 9 illustrates the maximum velocities calculated using an inlet velocity of 5.26E-01 m s-1 estimated for each of the radial planes of FIG. 8 according to an example of the present disclosure. [Figure 10A] 9 illustrates horizontal and vertical centerline velocities in a radial plane at positions 1-3 of FIG. 8 according to an example of the present disclosure. [Figure 10B] 9 illustrates horizontal and vertical centerline velocities in a radial plane at locations 4-7 of FIG. 8 according to an example of the present disclosure. [Figure 10C] 8 illustrates horizontal and vertical centerline velocities in a radial plane at locations 8-11 of FIG. 8 according to an example of the present disclosure. [Figure 10D] 8 shows horizontal and vertical centerline velocities in a radial plane at locations 12-13 of FIG. 8 according to an example of the present disclosure. [Figure 11] Graph showing waveform pulse tracer experimental data of absorbance at 372 nm versus time (min) for four flow rates of 20, 30, 50, 100 ml / min (linear velocities of 1.05E-02, 1.58E-02, 2.63E-02, and 5.26E-02 m / s, respectively). [Figure 12] 1 is a graph showing dimensionless E-curves for Weave Pulse Tracer experiments at 20, 30, 50, and 100 ml / min. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Like reference numbers identify like elements throughout the specification and drawings.

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

[0031] Viral safety is required for protein therapeutics produced in mammalian cells, and virus 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 (heat), and pH reduction (acid). Low pH is a highly effective method used in monoclonal antibody purification processes, consistently removing >4 log(10) of large enveloped viruses, including endogenous retroviruses. The American Society for Testing and Materials (ASTM) standard for pH retrovirus inactivation processes specifies the following low pH virus inactivation conditions: pH ≤ 3.6, ≥ 15°C, for ≥ 30 minutes in a system-specific buffer at the specified pH, providing ≥ 5 log reduction value (LRV).

[0032] 1A-1E, to inactivate viruses, a process stream can be introduced into a continuous flow reactor, such as a continuous virus inactivation (CVI) reactor 100. Some exemplary process streams include, but are not limited to, bioreactor effluent, anion exchange chromatography effluent, cation exchange chromatography effluent, effluent from an aqueous two-phase extraction, effluent from a precipitation reaction, effluent from a membrane filtration process, and effluent from an ultrafiltration process.

[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 can operate at low Reynolds (Re) numbers, defined as flows having a Re number less than 2000 and 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 Re number calculation can be based on a process stream having a temperature of 25° C., ρ=1000 kg m−3, and μ=8.9E-4 Pa·s. However, laminar flows, as characterized by a parabolic velocity profile, can cause axial dispersion, where fluid elements in the center of the tube move faster than elements near the wall, resulting in a wide residence time distribution (RTD). 1B, 2A, and 2B, to reduce and / or at least partially eliminate axial dispersion, the CVI reactor 100 can include a flow path or channel 112 that is disposed on a single longitudinal axis LX but has at least two turns or curves 114, such as turns 114A and 114B, that are in different non-parallel planes (e.g., plane A and plane B). This particular design can create secondary flows that promote radial mixing and reduce axial dispersion.

[0034] The radius of curvature (ROC) of a turn or curve 114 is determined by the Dean number (D) and the ratio of the turn length to the length of the torus (L DT ) (D = Re√(d / 2R), where d is the inner diameter of the tube 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 (In the formula, d i is the inside diameter, and d c is the coil diameter in meters).

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

[0036] As shown in FIG. 1A, the CVI reactor 100 can include multiple rows of continuous flow reactor tubes 110, for example, at least five rows of continuous flow reactor tubes 110. In this exemplary CVI reactor 100, the number of turns within each row of continuous flow reactor tubes 110 can depend on the outer diameter and / or inner diameter of the reactor tubes 110. For example, a relatively large diameter reactor tube 110 can include fewer turns than a relatively small diameter reactor tube 110. In one example, where the continuous flow reactor tubes 110 include an ROC from about 0.3 cm or less to about 2 cm or more, for example from about 1.05 cm, each row of 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, a Dean number of about 100 or more, for example, a Dean number of about 100 to about 500.

[0037] In one example, prior to introducing the process stream and at least one viral inactivating compound or solution into the CVI reactor 100, the combination of the process stream and the viral inactivating compound or solution can include a flow rate having a Reynolds number of about 187 to about 333 and a Dean number of about 105 to 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. With reference to FIGS. 1B and 1C, to accommodate about 320 turns in a compact design, the channels 112 in the CVI reactor 100 can be arranged horizontally in multiple stacks 180, for example, two layers 180 to ten or more layers 180, for example, five layers 180, as shown in FIG. 1C. In one example, the channels 112 in each layer 180(a)-180(e) in the stacks 180 can include about 28 turns or less to about 68 turns or more. For example, each layer 180(a)-180(e) in the stacks 180 can include 64 turns. In one example, each layer 180 can be connected to its adjacent lower layer 180 by a 180° turn 185. In one example where the CVI reactor 100 includes five layers 180, the continuous flow reactor tubes 110 in each of the five layers 180 may be connected to each other by four 180° vertical turns 185.

[0039] Referring to FIG. 1B, in one example, each layer 180 in the CVI reactor 100 can include a depth L7. The depth L7 can be a distance that can accommodate the continuous flow reactor tubes 110. At a minimum, the depth L7 can be a distance from the center of a first eight-pointed star in the first layer 180(a) to the center of a second eight-pointed star in the second layer 180(b). For example, the depth L7 can be defined as a function of the diameter of the continuous reactor tubes 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 the size of the diameter of the continuous flow reactor tubes 110 (i.e., 6.06*d) or less to about 7.84 times the size of the diameter of the continuous flow reactor tubes 110 (i.e., 7.84*d). For example, L7 can be from about 3.85 cm or less to about 5 cm or more, such as about 4.7 cm. In one example, the distance L8 can be from the bottom of the tubular channels 112 in the first layer to the top of the tubular channels 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 the size of the diameter of the continuous flow reactor tube 110 (i.e., 0.23*d) to about 0.70 times the size of the diameter of the continuous flow reactor tube 110 (i.e., 0.7*d). For example, L8 can be from about 0.15 cm (1.5 mm) to about 0.5 cm (5 mm), such as from about 0.425 cm (4.25 mm).

[0040] 1D, in one example, the CVI reactor 100 can include body or footprint dimensions 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, e.g., about 27×5.8×23.5 cm, and can accommodate a channel 112 length of about 442.6 cm to about 7000 cm, e.g., about 1770.43 cm, approximately providing a flow rate of about 300 ml to about 800 ml, e.g., about 560.68 ml. The body of the CVI reactor 100 can include a first side 124 and a second side 126. In one example, the first side 124 can include at least one groove or recess 124A, and the second side 126 can include at least one protrusion 126A. The at least one recess 124A and the at least one protrusion 126A can be positioned such that when two CVI reactors 100 are placed in abutment with one another, they can be removably secured to one another.

[0041] The distance between the center of the inlet point of the reactor to the outlet point, shown as H2, can be from about 5 cm or less to about 200 cm or more, such as from 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 from 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. Additionally, 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 internals. The internals can include, for example, diffusers, catchers, distributors, catalysts, mixers, redistribution, and collectors, to name a few. One or more of these internals can be located 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 a sampling port (not shown) located anywhere throughout the length of the continuous flow reactor tube 110. For example, the sampling port can be located approximately midway between the beginning and end of the continuous flow reactor tube 110. The sampling port can be used to extract samples of the mixed process stream and virus inactivating 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 allows the user to add any required additional virus inactivating compound or solution or process stream.

[0044] In one example, smaller or larger reactors can be used to accommodate smaller or larger volumes of process streams, with the reactor tubes in the smaller or larger reactors comprising substantially similar inner diameters and 2* radii of curvature as reactor 100.

[0045] 2A-3D show an exemplary continuous flow reactor tube 110 capable of operating at low Re. The continuous flow reactor tube 110 can include a tubular flow passage 112 including 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 in different non-parallel planes, e.g., plane A and plane B. Depending on the number of passes used to form the continuous flow reactor tube 110, the turns can be in two or more different non-parallel planes, e.g., about 6 to about 13 different planes, e.g., 8 different planes. Furthermore, at least two of the turns are disposed such that the planes corresponding to at least two turns can intersect with each other, e.g., as shown 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, a single pass can include a pattern 150 that is repeated at least twice, as shown in Fig. 2D, which shows a cross-section of a single pass along its longitudinal axis (see also Fig. 2A). Each flow path can include about 4 turns to about 128 turns or more alternating turns, for example, about 16 to about 32 turns. Each turn 114 can include an angle of about 110° to about 280°, for example, about 135° to about 140°. In one example, a first turn can include an angle (such as an angle of about 135°) that is smaller than the angle of a second turn (such as an angle of about 140°). Furthermore, as shown in Figures 2A, 2B, and 3A, each flow path can also include about 8 to about 64 or more bends 116, for example, about 8 to about 16 bends 116. Each bend 116 can include an angle of about 15° to less than about 135°, for example, an angle of about 30° to about 90°, for example, an angle of about 45°. In one example, each pattern 150 can be repeated after about 4 or more bends, for example, after about 8 bends.

[0046] In another example not shown in the figure, the paths of the continuous flow reactor tube 110 can include two or more different patterns that may or may not be repeated. When the continuous flow reactor tube 110 includes multiple interwoven flow paths, each path of the continuous flow reactor tube 110 can include a substantially similar pattern. Alternatively, or additionally, each path of the continuous flow reactor tube 110 can include a different pattern. Furthermore, each path of the continuous flow reactor tube 110 can include a similar number of repeating patterns (e.g., two similarly repeating patterns) or can include more or less than two repeating patterns. For example, a second path can include two similarly repeating patterns or can include three similarly repeating patterns.

[0047] As discussed above, the interwoven tubular flow paths of the woven design consist of alternating 135°-140° turns with a 45° bend at the center of each turn, as shown in FIG. 2B. The inner diameter of the flow path can be about 0.3 cm or less to about 1 cm or more, such as about 0.6 cm to about 0.7 cm, e.g., about 0.635 cm inner diameter. Additionally, the minimum radius of curvature of the 130-140° turns can be about 0.3 cm to about 2 cm, e.g., about 1.05 cm, determined for an ID of 0.635 cm.

[0048] In one example, as shown in FIG. 2E, a continuous flow reactor tube 110 can include a first flow path having a plurality of turns 114 forming a first pattern that can be repeated a predetermined number of times, for example, twice, and a second flow path that can be substantially straight or include a serpentine pattern between the turns of the first flow path. As can be seen in FIG. 2C, the pattern of turns 114 in the first flow path forms a top view with an eight-pointed star. As shown in FIG. 3A, when the continuous flow reactor tube 110 includes multiple flow paths, for example, four flow paths, each of the four flow paths can include turns and patterns that are substantially the same and can be interwoven and / or arranged to occupy the space formed within each turn in each flow path. Thus, as shown in FIG. 2C and FIG. 3B, a top view of a continuous flow reactor tube 110 having one flow path or four or more flow paths looks substantially like an eight-pointed star.

[0049] 2F and 2G, each of the turns 114 in the continuous flow reactor tube 110 can include a vertical L1 center-to-center distance between the turns of about 1 cm to about 2 cm, e.g., about 1.5 cm. Additionally, each of the turns 114 can include a horizontal L2 center-to-center distance between the turns of about 1 cm to about 2 cm, e.g., about 1.63 cm. Additionally, each of the turns 114 can include an end-to-end distance L3 of about 3 cm to about 4 cm, e.g., 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 or less of each other, e.g., within about 0.02 cm of each other, to prevent substantial differences in Dean numbers between alternating turns. For example, R1 can be about 1.10 cm and R2 can be about 1.12 cm.

[0050] In one example, multiple channels can be interwoven such that multiple turns form a multi-axial three-dimensional channel. Such multi-axial three-dimensional channels can be arranged to form the overall shape of a sheet (as shown in Figures 4A-4C), a prism (not shown), a cylinder (as shown in Figure 3A), a cone (not shown), and / or a sphere (not shown).

[0051] In one example, when the flow channels of the continuous flow reactor tube 110 are interwoven to form a sheet-like structure, the first and second flow channels can include turns forming a weft-like pattern, as shown in Figure 4A. Alternatively, the first and second flow channels can include turns forming a warp-like pattern, as shown in Figure 4B. Yet, in another example, the first flow channels can include turns forming a weft-like pattern and the second flow channels can include turns forming a warp-like pattern, as shown in Figure 4C.

[0052] Materials and Design of Continuous Flow Reactor Tubes The continuous flow reactor according to the present invention may be made from any suitable inert material, for example, glass, synthetic material, or metal. In another example, the continuous flow reactor tube 110 may be made from at least one flexible alloy material and / or memory alloy material. For example, as shown in FIG. 3A, the interwoven flow passages of the continuous flow reactor tube 110 may be made from a memory alloy material or a flexible material. Such a material may allow the user of the continuous flow reactor tube 110 to change the shape of the tube and / or manipulate its flow rate as needed without the need to design a new reactor. For example, if the continuous flow reactor tube 110 needs to be heated in a high temperature bath, but the available high temperature bath cannot accommodate the rectangular continuous flow reactor tube 110, the user may change the shape of the continuous flow reactor tube 110 to a circular shape to better fit within the high temperature bath. Additionally, the use of a flexible alloy material or a memory alloy material for the continuous flow reactor tube 110 may allow the user to change the density of turns per square meter of the reactor. This allows a single reactor to be used for multiple purposes. Depending on the reactor purpose, users 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 reactor volume is approximately 19.6 turns / m 3 ~Approx. 39.2 turns / m 3 It could be.

[0053] Details on interwoven flow paths 3A-3D show an exemplary design in which a continuous flow reactor tube 110 can include multiple interwoven channels that are in fluid communication to form a single flow channel. For example, FIG. 3A shows four channels (channels 1-4) that are in fluid communication with each other to form a single flow channel 112. This design can allow for a more compact design than a linear pattern that stacks channels side-by-side by reducing the distance required between the channels and the void space below the channels. FIG. 3A also shows a close-up view of the woven pattern of the four channels. In this example, channels 1-4 are connected by curved connections, such as channel connectors 160, as shown in FIG. 3D, to avoid straight lines in the channels.

[0054] In one example, as shown in FIG. 3A and FIG. 3D, the flow connector 160 may 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 inclination between the convex region and the concave region may be at an angle of about 30 degrees to about 60 degrees, for example, about 45 degrees. Furthermore, the radius R3 of each of the convex regions may be about 0.3 cm to about 0.9 cm, for example, about 0.65 cm, and the radius R4 of the concave region may be about 0.2 cm to about 0.8 cm, for example, about 0.52 cm. Furthermore, as can be seen from FIG. 3B and FIG. 3D, the distance L4 from the center of one end of the flow connector 160 to the center of the second end of the flow connector 160 may be about 2 cm to about 4 cm, for example, about 2.96 cm.

[0055] Referring to FIG. 3C, the four channels form a top view and a bottom view of an eight-pointed star, as described above. Referring to FIG. 3C, the eight-pointed star includes at least two vertical parallel tubes, two horizontal parallel tubes, and a channel connector 160. 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. Furthermore, the distance L5 between each parallel tube can be about 1 cm to about 2 cm, for example about 1.65 cm. Furthermore, the distance L6 between the end of the channel 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] Multiple reactors connected in series In one example, in addition to the CVI reactor 100 having multiple layers 180, as shown in FIG. 5, multiple CVI reactors 100 can be connected to each other in series to allow for modifications to path length and incubation times. This can be accomplished by one or more flanged connectors. In one example, at least two tubular CVI reactors 100, such as 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 out of the CVI reactor 100 (extensions 190). The extensions 190 can also include flanges 195, as shown in FIG. ID. The connectors 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 passage 112 or flange 195 of the first CVI reactor 100, and a second end of the connector can be connected to the tubular flow passage 112 or flange 195 of the adjacent in-line tubular CVI reactor 100.

[0057] The connector 200 may be connected to each tubular passage 112 or flange 195 by clamps 210 or other fastening devices such as screws, adhesives, etc., and / or integral connectors such as threaded male / female terminals, quick connect / disconnect terminals, etc. In one example, a gasket may be disposed between an end of the tubular passage 112 or flange 195 and each end of the connector 200.

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

[0059] To further analyze the velocity profile of the woven design, axial velocity contours and Dean vortices were measured at 45° intervals from the start of alternate turns, or approximately every 0.9 cm along the flow path, as shown in Figures 7 and 8. In Figure 8, the top image includes a velocity heat map and an overview of the planes where axial and radial velocities were measured along the flow path and are numbered 1 to 13. The inlet velocity was 5.26E-02 m s -1 and 1.052E-01 m s for fully developed laminar flow. -1 The velocity heatmap shows a maximum velocity of 0 to 1.052E-01 m s -1 The bottom image is an overview of the flow channel, where the velocity contours (top) and radial velocity / Dean vortex (bottom) were measured at 13 planes located at the inlet, every 45° from the start of the turn along the flow channel, or at intervals of approximately 0.9 cm.

[0060] Average inlet velocity for each plane in Figure 8: 5.26E-02 m s -1 The maximum velocity of the pipe is predicted and shown in the table and graph of Figure 9. The characteristic value of laminar flow in the pipe with the maximum velocity is twice the average velocity (2*v avg ) where the inventors' v avgis 5.26E-02m s -1 and 2*v avg is 1.052E-01m s -1 At the inlet, the maximum velocity reached the characteristic maximum before any curvature in the channel. However, in the radial plane in the woven channel, the maximum velocity was lower than the characteristic value. This indicated that the channel reduces the maximum velocity and therefore the axial dispersion.

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

[0062] Example 2 Pulsed tracer experiments with 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 chasing with Milli-Q water via a 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 an AKTA Pilot (GE Healthcare). The absorbance versus time results from the pulsed 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. Re for flow in a 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 steady motion of an incompressible fluid in a curved pipe, the strength of the secondary flow is characterized by a dimensionless parameter, the Dean number (D), given by Equation 2, where d is the inner pipe diameter and R is the radius of curvature of the flow passage.

number

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

number

[0066] The axial dispersion is calculated by the mean residence time, which is defined by Equation 4 and Equation 5, respectively.

number

number

[0067] Table 1 below shows the Reynolds number (Re), Dean number (D), and dispersion (σ 2 ) are shown. These values ​​are important to characterize the mixing efficiency of our design as the relatively low dispersion values ​​approaching the dispersion of the injected pulse, and show that the woven design reactor approaches mixing close to plug flow, despite operating in the laminar flow regime at Re<2000. When possible, the lowest values ​​of dispersion are achieved at 0.1 min−1 for the highest flow rate of 100 ml / min. 2 It is. [Table 1]

[0068] The E-curve is expressed by Equation 6, where θ is the dimensionless time and

number

number

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

[0070] From the foregoing description, those skilled in the art can appreciate that the present teachings can be implemented in a variety of forms. Thus, although these teachings have been described with reference 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 herein.

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

[0072] The description of the invention in its many embodiments herein is merely exemplary in nature and, thus, 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 considered as departures from the spirit and scope of the invention.

Claims

1. 1. A method for viral inactivation in a continuous flow reactor comprising: The continuous flow reactor comprises: a plurality of interwoven flow paths in fluid communication to form a single continuous-flow reactor tube having a single flow path; each of the plurality of interwoven flow paths includes a plurality of turns that lie in different non-parallel planes; the plurality of interwoven channels includes a plurality of bends; the bends are rotated relative to one another at an angle about a longitudinal axis of the plurality of interwoven channels; the continuous flow reactor tube is configured to provide a flow rate having a Reynolds number of 187 to 333 and a Dean number of 105 to 212; introducing a process stream and at least one virus inactivating compound or solution into said continuous flow reactor; contacting the process stream with at least one virus inactivating compound or solution in said continuous flow reactor; A method comprising:

2. The radius of curvature (ROC) of the turn of the flow channel is determined by the Dean number (D) and the ratio of the turn length to the length of the annular shape (L ＤＴ ) as a function of The method of claim 1.

3. The continuous flow reactor parameters correspond to a Dean number of 50 or greater. The method of claim 1.

4. The parameters of the continuous flow reactor correspond to a Dean number of 100 or more. The method according to claim 3.

5. The parameters of the continuous flow reactor correspond to a Dean number of 100 to 500. The method according to claim 4.

6. The flow rate of the continuous flow reactor tube has a Reynolds number of 187 to 333 and a Dean number of 105 to 212. The method of claim 1.

7. The radius of curvature of each turn of the flow path is determined to be less than or equal to 0.05 cm from each other when preventing differences in Dean numbers between alternate turns. The method of claim 1.

8. The radius of curvature of each turn of the flow path is determined to be less than or equal to 0.02 cm from each other when preventing differences in Dean numbers between alternate turns. The method of claim 7.

9. The Dean number is D≧60. The method of claim 1.

10. 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; The method of claim 1.

11. The multiple turns include a repeating pattern of turns, The method of claim 1.

12. The repeating pattern of turns is repeated after eight bends. The method of claim 11.

13. each of the plurality of turns includes an angle between 100° and 200°; The method of claim 1.

14. The method of claim 1, wherein each of the plurality of turns comprises an angle of 135° to 140°. The method of claim 13.

15. The plurality of interwoven channels are fabricated from at least one of a flexible alloy and a memory alloy; The method according to any one of claims 1 to 14.

16. Multiple interwoven channels, 1 m 3 Includes 19.6 to 39.2 turns per hit. The method according to any one of claims 1 to 15.

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