GB2631765A

GB2631765A - Viral inactivation reactor and method

Info

Publication number: GB2631765A
Application number: GB2310763.4A
Authority: GB
Inventors: Koziol Krzysztof; Skordos Alex
Original assignee: Cranfield University
Current assignee: Cranfield University
Priority date: 2023-07-13
Filing date: 2023-07-13
Publication date: 2025-01-15
Also published as: WO2025012303A1; GB202310763D0

Abstract

Viral inactivation apparatus and method for the inactivation of live virus species. A fluid flow bioreactor 11 is provided having an elongate flow channel 12 comprising at least one wall capable of allowing passage of radiation into the flow channel and a length section 52 positioned between at least a first turn 51a and a second turn 51b of the flow channel 12; wherein the length section 52 of the flow channel 12 comprises at least one fluid flow deflector 53 provided to create turbulent fluid flow. The bioreactor is adapted to control fluid flow characteristics of a solution containing suspended viral particles for irradiation by a suitable radiation source to produce inactive viral species suitable for vaccine synthesis. The present bioreactor configuration is advantageous to control administration of irradiation dosage to create inactivated viral species reliably and efficiently at 100% effectiveness whilst preserving structural integrity of the viral species to provide an effective inactivated vaccine.

Description

Viral Inactivation Reactor and Method

Field of invention

The present concept relates to apparatus and method for viral inactivation and in particular, 20 although not exclusively, to apparatus and method for vaccine manufacture by irradiating live virus within a batch or continuous flow bioreactor.

Background

A variety of different types of vaccines have been developed, providing immune systems response to germ infection. Examples include viral vector vaccines, proxoid vaccines, subunit, recombinant, polysaccharide and conjugate vaccines, messenger RNA vaccines, live-attenuated vaccines and inactivated vaccines. Live vaccines are used extensively and are based on a live, weakened (or attenuated) form of the germ that causes diseases. As these vaccines are similar to natural infection, they invoke a strong immune response with just one or two doses providing lifetime protection against diseases. However, these vaccines are unsuitable for people with weakened immune systems and long-term health problems and organ transplant patients. Such vaccines are also required to be kept cool and can be challenging to store and transport.

Inactivated vaccines are based on a killed version of a germ and typically are more suited 5 to those groups of people indicated above. These inactivated viruses, being based on a structurally altered and non-live form of the original germ, create a less profound immune response. Accordingly, inactivated vaccines typically require several doses over time (booster shots) in order to achieve continued immunity against disease. These vaccines are typically easier to store and transport. Methods of viral inactivation include irradiation, chemical inactivation, low-energy electron irradiation, heat and/or high-pressure inactivation.

US 2013/0236358 Al describes a system and method for virus inactivation involving dissolving carbon dioxide into biological or other sensitive substances for a prescribed 15 treatment time to achieve inactivation of at least 80% of the target virus.

US 10,434,201 B2 describes a method continuous virus inactivation to produce a product stream involving segmenting a fluid flow and exposing segments of the stream to virus-inactivating conditions such as sustained low pH, detergents, UV or thermal treatment.

Similarly US 2021/0388308 Al describes a continuous flow reactor to inactivate live viral species for example via the use of solvents, detergents, pH reduction or heating.

US 2021/0380914 Al describes a viral inactivation device that includes a tubular flow path having alternating turns to form a serpentine pattern between an inlet and an outlet. Viral 25 inactivation is achieved by mixing with a low pH solvent.

However, there is a continued need for improved apparatus and methods for viral inactivation.

Summary of the Invention

It is an objective of the present concept to provide an efficient and an effective system for viral inactivation. It is a further specific objective to provide a viral inactivation system to allow batchwise and/or continuous synthesis of inactive viral species synthesised directly from a live virus.

It is a further specific objective to provide apparatus and method that is scalable for both batchwise and continuous production of vaccines that may be stored, transported and suitable for administration to a large demographic. It is a further specific objective to provide a reliable viral inactivation system and method to kill a live virus effectively and reliably whilst preserving structural integrity of the virus during processing. It is a further specific objective to provide apparatus, system and methods of viral inactivation suitable for a variety of different types of virus/germ so as to create vaccines suitable to prevent a variety of different human and animal diseases.

The objectives are achieved by providing viral inactivation apparatus and method in which a reactor is specifically configured with an elongate flow pathway suitable to allow the through-flow of a solution containing a live virus whilst allowing the live virus to be exposed to radiation introduced into the flow channel through at least one channel wall. The present concept is specifically advantageous to provide an efficient and reliable viral inactivation process in which all viral species at a molecular level, are subjected to irradiation uniformly so as to output 100% inactivated virus species. The present reactor and method of inactivation is configured specifically for scalability and to be suitable for use with a variety of different types of virus/germ.

According to a first aspect of the present concept there is provided a viral inactivation reactor comprising: a reactor body configured to be irradiated with radiation having an internal elongate flow channel defined by at least one wall, a fluid flow inlet and outlet provided in fluidic communication with the flow channel; the wall capable of allowing passage of radiation into the flow channel; the flow channel comprising at least one first turn at a first position along the length of the channel, a second turn at a second position along the length of the channel and a length section positioned in a fluid flow direction between the first and second turns wherein the length section comprises at least one fluid flow deflector to provide a change of direction and/or to create turbulence at a fluid when flowing through the channel.

Optionally, the inactivation mechanism may comprise exposing at least a region of the reactor to ionising and/or non-ionising radiation. Optionally, the radiation may comprise electromagnetic radiation including any one or a combination of gamma, x-ray and/or low energy electron (LEE) irradiation. Preferably, the present bioreactor, apparatus and method is configured for and compatible for use with x-ray radiation.

The reactor is configured specifically via the design of the main body housing and in particular the elongate channel wall(s) to produce a vial species that is fully inactivated in which all live virus species receive a desired and uniform irradiation dose. The bioreactor is compatible for both irradiation of viral species when stationary within the elongate channel, such as batchwise production or when flowing through the channel, such as continuous, semi-continuous or repeated batch production.

Optionally, the reactor comprises a plurality of turns and respective length sections positioned in a fluid flow direction between the inlet and outlet. Optionally, the reactor comprises a plurality of flow deflectors provided at each of the length sections, the deflectors positioned in-series in a flow direction along each length section. The deflectors are configured specifically to disrupt liquid and particulate flow within the elongate flow channel so as to disrupt laminar flow. The elongate flow channel is particularly advantageous to increase the residence time of viral species and facilitate uniform and desired irradiation dosage effective for 100% viral inactivation.

Optionally, the flow deflectors may comprise any one of a combination of: at least one internal baffle positioned within the flow channel; a bend at the flow channel; an increase or decrease in a cross-sectional area of the flow channel; a valve or body provided internally at the flow channel. Optionally, and in specific implementations only, the flow deflectors define a zigzag or serpentine flow pathway extending between the turns.

Optionally, a width of the channel is greater than a depth of the channel at a cross section of the channel, where an orientation of the depth is aligned with and/or parallel to a direction of a beam of radiation incident at the reactor. Optionally, at a cross section of the reactor/channel, a thickness of the wall is in a range 0.05 to 2mm, 0.05 to 1.5mm, 0.05 to 1.2mm, 0.05 to 1.0mm, 0.1 to 0.4mm, 0.5 to 1.5mm. Optionally, at a cross section of the reactor/channel body a depth of the channel is in a range 1 to 15mm, 2 to 15mm, 5 to 15mm or 5 to 12mm. Optionally, the at least one deflector comprises a plurality of bends and the bends comprise an internal radius in a range 5 to 120°, 60 to 110° or 80 to 100°.

Advantageously, the reactor comprises a reactor body material that is appropriately transmissive of radiation whilst providing sufficient structural integrity to withstand fluid flow pressure (internally within the elongate channel) and external forces such as structural mounting. Optionally, the reactor body may comprise a material being any one or a combination of a resin; a thermoset resin; a polystyrene; a liquid crystal polymer; a polyurethane; a polyethylene; a polyester; a polycarbonate; a HP engineering resin; a silicone; a polyvinyl chloride (PVC); a polyamide; acrylonitrile butadiene styrene (ABS); polymethyl methacrylate (PIVEVIA); polypropylene; polymethyl pentene; an elastomer; a cellulose or cellulose based material; a fluorinated alkylene or alkane; a fluorinated ethylene-polypropylene (FEP); a polytetrafluoroethylene (PTFE); an acetal.

Optionally, the reactor may comprise a coating provided at at least one internal surface of the channel, the coating comprising any one or a combination of: a resin; a thermoset resin; a polystyrene; a liquid crystal polymer; a polyurethane; a polyethylene; a polyester; a polycarbonate; a HP engineering resin; a silicone; a polyvinyl chloride (PVC); a polyamide; acrylonitrile butadiene styrene (ABS); polymethyl methacrylate (PMMA); polypropylene; polymethyl pentene; an elastomer; a cellulose or cellulose based material; a fluorinated alkylene or alkane; a fluorinated ethylene-polypropylene (FEP); a polytetrafluoroethylene (PTFE); an acetal. Accordingly, the bioreactor may comprise a hybrid material construction comprising a first material type to form the body of the bioreactor and a second material type to provide the coating. The body and coating, as applied are configured specifically to withstand rigorous sterilisation techniques optionally involving internal liquid boiling, solvent cleaning, exposure to extreme high and low pH solvents including acidic and alkali cleaning processing.

Optionally, the reactor body may be provided as a layer optionally having a generally 5 planar configuration. Optionally, the flow channel at the at least one length section comprises an inclined and declined section relative to a general plane of the layer.

Optionally, the reactor comprises a plurality of layers interconnected in internal fluidic communication via the respective inlets and outlets, the layers arranged as an assembly, a block or stack. The layers may be interconnected as a modular construction. Optionally, the layers may be formed integrally to provide a single unitary reactor body having an internal elongate flow channel that extends in the x-y and z planes through the body. The channel preferably comprises a series of turns and length sections at respective layers. Preferably the channel extends from an external surface region, through the reactor body including an inner or core region, to be output at a further external surface or region. Optionally, where the layers are assembled to form a modular construction, each of the layers are interconnected in fluidic communication to define a single internal flow channel extending through each of the layers of the block or stack. Each of the layers may comprise integral interconnections, ports, valves, flanges etc as will be appreciated to provide the sealed fluidic communication between neighbouring layers of the assembly.

Optionally, the layers may be configured for interconnection using suitable connecting valves, conduits, pipes or tubing to provide an interconnected layer assembly.

According to a further aspect of the present concept there is provided modular viral inactivation apparatus comprising: a plurality of modular units, each unit comprising a viral inactivation reactor as claimed and described herein; each of the units arranged as an assembly, block or stack and interconnected in internal fluidic communication to provide a single elongate flow channel extending from the inlet of an initial unit to the outlet of a subsequent or final unit wherein a plurality of units are positioned in fluidic communication between the initial and further or final units.

Optionally, according to a further aspect of the present concept there is provided viral inactivation apparatus comprising: a viral inactivation reactor as claimed and described herein; a fluid supply reservoir connected in fluidic communication with the flow channel to provide a supply into the flow channel of a solution containing a live virus; a filtration unit having a filter to separate components of the solution based on size, the filtration unit provided in fluidic communication with the flow channel; a fluid flow pump to drive fluid flow through the channel; and at least one sensor to monitor at least one characteristic of the solution at the apparatus.

Optionally, the apparatus may further comprise any one or a combination of: a membrane filter; an ultrafiltration membrane. The filtration unit may be part of or configured as a concentrating unit to increase the concentration of viral species within a solution prior to administration of the solution into the bioreactor.

Optionally, the apparatus may comprise any one or a combination of a temperature sensor; a pressure sensor; a flow rate/velocity sensor; a solution concentration sensor; a fluid volumetric sensor; a biological sensor; a chemical sensor; an electrochemical sensor. The sensor may be positioned at, proximal or remote relative to the bioreactor. Optionally, at least one sensor may be provided at the bioreactor and at least one sensor may be provided at a position within a fluid flow network within which the bioreactor is interconnected in fluidic communication. Preferably, each of the sensors is coupled for electronic data transmission with a suitable control unit as described in claim herein. In particular, the present apparatus may comprise a fluid control unit to control at least one characteristic of the apparatus and/or a fluid introduced into, flowing through and/or output at the apparatus. Optionally, the fluid control unit comprises any one or a combination of: a processor; a memory storage utility; a data library; fluid flow control software provided at the memory storage utility; a user interface utility having a data and/or command input interface; a wired or wireless communication utility for wired or wireless data transfer to and/or from the apparatus. Optionally, the reactor may further comprise at least one access port provided at a wall of the reactor to allow access or communication to the internal channel. Optionally, at least one sensor may be mounted and/or is positioned at the at least one access port to monitor a characteristic of a solution flowing internally within the flow channel.

According to a further aspect of the present concept there is provided a method of viral 5 inactivation comprising: introducing a solution containing at least one live virus into a reactor, the reactor comprising an elongate internal flow channel having a plurality of turns and respective length sections positioned in a fluid flow direction between respective upstream and downstream turns, the length sections comprising at least one fluid flow deflector to provide a change of direction and/or to create turbulence at the solution; passing a flow of the solution through the channel; irradiating the solution within the channel with radiation to inactivate a live virus present within the solution; and outputting from the channel inactivated virus created from the live virus.

Optionally, the method comprises: filtering and/or concentrating the solution prior to the 15 step of introducing the solution into the reactor to increase a concentration of the live virus in the solution.

Optionally, the method comprises controlling and/or changing any one or a combination of: a solution flow rate through the channel; a concentration of the live virus within the solution prior to introducing the solution into the reactor; a temperature of the solution; a pressure of the solution; a pH of the solution; a flow direction of the solution within the channel optionally being a forward and/or reverse flow direction.

Optionally, the method of viral inactivation may be a continuous process comprising a 25 continuous supply of solution containing the live virus into the reactor and a continuous output from the reactor of the inactivated virus.

Optionally, the inactivation method may be implemented as a batch process comprising in order: the step of introducing the solution into the reactor; terminating the flow of the solution introduced into the reactor; irradiating the fluid within the reactor; and outputting the inactivated virus.

According to a further aspect of the present concept there is provided an inactivated virus manufactured using: the viral inactivation reactor as claimed and described herein; the modular viral inactivation apparatus as claimed and described herein; the viral inactivation apparatus as claimed and described herein; the method of viral inactivation as claimed and described herein.

According to a further aspect of the present concept there is provided a vaccine comprising the inactivated virus as claimed and described herein.

Brief description of drawings

A specific implementation of the present invention will now be described, by way of example only, and with reference to the accompanying drawings in which: Figure 1 is a schematic view of a system for inactivation of virus species using x-ray radiation; Figure 2 is a perspective view of a modular flow bioreactor formed from interconnected layers to provide a single elongate flow pathway extending internally through the 20 bioreactor; Figure 3 is a plan view of one layer of the bioreactor of figure 2; Figure 4 is a perspective view of the bioreactor layer of figure 3; Figure 5 is a cross-sectional view through A--A of the modular bioreactor of figure 2; Figure 6 illustrates a cross-sectional view through a fluid flow bioreactor having internal baffles to disrupt laminar flow according to a further specific embodiment.

Detailed description of preferred embodiment of the invention The present concept provides a fluid flow bioreactor suitable for viral inactivation by irradiation for the subsequent manufacture of vaccines. Referring to figure 1, the present system 10 comprises a fluid flow bioreactor indicated generally by reference 11 comprising an elongate internal flow channel 12 through which a fluid is capable of flowing. Bioreactor 11 is specifically adapted to allow the through-flow of a solution including suspended viral species/particles. In particular, reactor 11 comprises a fluid flow inlet 45 and corresponding outlet 46. At least one temperature sensor 34 is provided at reactor 11 preferably in fluidic communication with internal flow channel 12. System 10 further comprises connecting conduits 18 to create and maintain a fluid flow network within which reactor 11 is positioned. A suitable x-ray radiation emitter 13, configured to provide incident x-ray radiation 30 is positioned proximate to an external face (62, figure 5) of bioreactor 11 so as to introduce radiation through the walls of the bioreactor 11 and into internal flow channel 12.

System 10 further comprises a supply reservoir 14 containing a supply volume of a solution 23 containing live virus species. Reservoir 14 is connected in fluidic communication to a filtration unit indicated generally by reference 15 comprising a filter 17 (optionally implemented as a membrane filter). A filtered fluid collection vessel 27 collects the filtered solution 16 for delivery into bioreactor 11. A spectrophotometer 28 provides spectroscopic analysis of filtered solution 16 for concentration determination and analysis of other characteristics of the solution and/or live virus. A plurality of peristaltic pumps 20 drive fluid flow from initial reservoir 14 into and through bioreactor 11 for onward fluidic flow to a collection vessel 22 coupled to outlet 46. A fluid control unit indicated generally by reference 19 provides local and/or remote control of the various fluid flow, supply and output characteristics in real-time. Control unit 19 and system 10 is configured for both batchwi se and continuous viral inactivation processing. Control unit 19 comprises at least one processor (CPU/MCU) 35; a data storage utility 41 including data libraries upload and download data storage modules etc; a data collection utility 36 (optionally implemented as software); a control utility 37 (optionally implemented as software); wireless/wired communication components and protocols 38 for the wired or wireless transmission of data 39, 42 at control unit 19; and user interface 40 for real-time control parameter, status and data monitoring by a user.

In operation, solution 23 containing the live virus is processed through filtration unit 15 for direct flow filtration in which retentate 24 containing live virus particles 47 is filtered and concentrated to provide filtered solution 16. Permeate 25 may then be dispensed 26 as waste or for onward processing. Filtered solution 16 is then delivered into bioreactor 11 via inlet 45 whilst monitoring fluid pressure via sensors 21. As solution 16 follows along elongate flow channel 12, radiation 30 incident at channel 12, is effective to inactivate virus 47. The flow, solution and particle characteristics are monitored in real-time via sensors 21, 34 and optional additional sensors such as pH, flow rate, biological, chemical or electrochemical sensors (not shown) that supply real-time data to control unit 19. The processed solution 31 collected at vessel 22 contains inactivated virus species 48. Species 48 may then be extracted for sampling 43 and proto vaccine synthesis 44. Control unit 19 is adapted via wired or wireless connection 32 for the real-time control of the various operational characteristics and components of system 10 including in particular pumps 20, sensors 21, 34 and radiation emitter 13.

Referring to figure 2, reactor 11 comprises a modular construction formed from a plurality of interconnected layers 50, including by way of example a first layer 50a, a second layer 50b, a third layer 50c etc to form a bioreactor assembly, stack or block. Each layer is interconnected at each respective inlet and outlet 45, 46 so as to provide a continuous elongate flow channel extending through each layer and through subsequent layers in-series. The flow channel 12 at each layer 50, comprises a series of channel turns 51 including in particular a set of first turns 51a and a set of second turns 51b. Each turn 51a, 51b is formed as a 180° bend (internal radius of bend) so as to return the fluid flow through 180°. Length sections 52 extend between the spatially and positionally separated turns 51a, 51b so as to provide meandering elongate flow channel 12 extending between each inlet 45 and outlet 46. Each length section 52 is configured with fluid flow disrupters/deflectors. According to the specific implementation, the disrupters/deflectors are formed as bends 53, with each bend comprising an approximate internal radius of 90°.

According to the specific implementation, four bends 53 are arranged in-series, in a fluid flow direction between each turn 51a, 51b. As illustrated in figure 3, the series of bends 53 create a serpentine or zigzag fluid flow section 54 between respective turns 51a, 51b.

Referring to figure 4, each layer 50 is formed as a generally planar structure in which turns 51 are provided at opposite ends of each plate-like layer 50 with respective length sections 52 defining the lateral sides of the plate-like body. Accordingly, each layer 50 extends generally in the x-y plane such that flow channel 12 at each layer similarly extends in the x-y plane having main length sections 52 orientated with the x axis with the flow path at each turn 51 extending in the y axis. According to the specific implementation, the fluid flow disrupters at each length section 52 further comprise deflection in the z axis via respective inclined sections 52a and corresponding declined sections 52b. Sections 52a 10 and 52b are advantageous to further disrupt laminar flow between turns 51.

Referring to figure 5, bioreactor 11 comprises a plurality of walls 55 having respective internal surfaces 59 that define internal flow channel 12. At the cross section A--A through bioreactor 11 of figure 2, the stack of layers 50 provide a series of channels 12a, 12b, 12c... 12f (when viewed in cross section A--A) extending in the z axis. When orientated with bioreactor external surface 62 proximal to radiation emitter 13, radiation 30 travels sequentially through layer 50a and in contact with virus species 47 (suspended in solution 16 and flowing 56 through the external most channel 12a). Radiation 30 continues to penetrate each subsequent layer 501), 50c through each respective channel section 12b, 12c...121 Accordingly, live virus species 47 are irradiated to generate inactivated viral species 48.

According to the specific implementation, a wall thickness t is configured to provide sufficient structural strength and integrity to maintain the cross section of channel 12 whilst solution 16 is introduced at a desired pressure. Thickness I is also adapted to minimise radiation attenuation through the layers 50. According to the specific implementation, wall 55 comprises a polystyrene material and thickness t may be in a range 0.6 to 0.1mm. According to this specific implementation, a depth d of channel 12 in the z axis (figure 2) may be in a range 8 to 12mm.

As illustrated in figure 5, bioreactor 11 comprises at least one access port 61 to positionally mount sensor 34 for monitoring one or more characteristics of solution 16 and/or species 47, 48.

Figure 6 illustrates a further specific implementation of the present concept in which the fluid flow deflectors arc implemented as internal baffles 58. Baffles 58 are formed as projections extending inwardly from channel internal surface 59 towards a central region 64 of channel 12. Baffles 58 are orientated perpendicular to the fluid flow path 57 so as to disrupt laminar flow and create internal fluid flow turbulence -as provided similarly by bends 53 (figures 3 and 4). Optionally, and according to further implementations, the flow deflectors may be orientated parallel and/or oblique relative to fluid flow direction 56, 57.

According to a further specific implementation, at least one coating 60 is provided at channel internal surface 59. Optionally, coating 60 is provided at all, a majority or selected 15 regions of channel internal surface 59 and may be formed from the same or a different material to that of bioreactor walls 55.

The configuration of bioreactor 11, comprising turns 51, and specifically configured length sections 52 with laminar flow deflectors (bends 53 and/or baffles 58), is advantageous to enable the accurate and uniform inactivation (via irradiation dosage) to the live virus species 47 resident within channel 12. Moreover, the bioreactor 11 is effective for killing viral infectuosity whilst preserving viral species structural integrity. By providing an elongate flow channel having turns, straight sections and multiple layers provides an enhanced reactor residence time of species 47. This in turn, provides extended irradiation exposure that has been found to be significant for effective and reliable inactivation and to allow scaling of inactivated virus production of both batchwi se and continuous processing.

Further characteristics of reactor 11 that contribute to the uniform and effective killing of live virus species 47 whilst preserving structural integrity, include the choice of bioreactor material to provide sufficient irradiation (x-ray) transmission through each walls 55 of reactor 11 as illustrated in figure 5. Layer thickness t is also configured specifically to facilitate radiation transmission into the body of reactor 11 (figure 2) and each layer 50.

Corresponding considerations also apply to the determination of channel depth d. In particular, and according to the specific implementation, bioreactor 11 comprises polystyrene walls 55 with the wall thickness t of 0.8mm and a channel depth doflOmm. The reactor 11 may be implemented with a flow of velocity of 0.17mm/sec, a production rate of 6.2x109 virus/h, based on a gradual decrease in radiation intensity through the depth of reactor 11. In particular, an attenuation at each channel section 12a, 12b, 12c... 12f (figure 5) may be 22%, 41%, 57%...99% (where reactor 11 comprises nine layers 50).

As indicated, the present bioreactor 11 is particularly advantageous to control the irradiation dose exposure of each of the live virus species/particles 47 within solutions 16. This is achieved by the passive mixing provided by bends 53 and/or baffles 58. According to further specific implementations, active mixing may be induce using pressure gradients, electrical potentials etc as will be appreciated. Such configurations provide both multi-plane mixing in both x-y and x-z planes (referring to figure 4). Additionally, via turns 51 and length sections 52, bioreactor 11 is suitable to create a passive mixing geometry and velocity inversion of the virus particles 47 between initial inlet 45 and final output 46. The inventors through particle tracking simulations (Ansys k-epsilon modelling) have confirmed suitable/desirable particle perturbance flow profiles. This shows each particle of viral species within solution is stimulated to undergo non-laminar flow through channel 12. This in turn, ensures each viral species encounters a uniform radiation dose whilst also ensuring 100% of live virus species/particles 47 are inactivated as they exit reactor 11 via output 46.

The choice of material of bioreactor 11 (to form walls 55) include consideration of dose 25 radiation transmission/absorption (kGy), yield strength (MPa), density (kg/m3), Young's Modulus E (GPa) and fatigue strength at 107 cycles (MPa).

Where the bioreactor 11 comprises a channel 12 with internal coating 60, coating 60 is adapted specifically via the choice of material, to comprise a high-water contact angle, to be non-toxic, to prevent agglomerate formation and to be suitable for a wide range of solvents, solutions and viral species. In particular, coating 60 is selected to be compatible with a variety of different types of cleaning techniques and processes including water or solvent exposure, heating and boiling. The bioreactor 11 may be manufactured using 3D printing such as stereolithography, fused deposition modelling and the like.

In order to achieve standard titer virus stocks, system 10 is configured to concentrate purified virus particles at filtration unit 15. In particular, the ultra-filtration type and/or pre-selected pore size of filter 17 (nanometrc scale) is suitable to concentrate desired viral species for collection at vessel 27. Accordingly, via initial testing, concentration increases from 106 to 1010 were observed with an increased production rate of 10%. Spectrophotometer 28 may be used to detect the concentration and to allow through-flow or recirculation 66 through filtration unit 15 as necessary to achieve the desired concentration.

System 10 further comprises suitable temperature regulation components and control (not shown) to maintain a desired temperature range of the solution 16 in the fluid network between reservoir 14 and 22. The temperature control unit (not shown) is configured to maintain solution temperature in a range 0 to 4°C. Suitable cooling components may include heatsink (passive heat exchanger), liquid cooling (active heat exchanger) and refrigeration/cryogenic cooling technologies, as will be appreciated.

Claims

Claims 1. A viral inactivation reactor comprising: a reactor body configured to be irradiated with radiation having an internal elongate flow channel defined by at least one wall, a fluid flow inlet and outlet provided in fluidic communication with the flow channel; the wall capable of allowing passage of radiation into the flow channel; the flow channel comprising at least one first turn at a first position along the length of the channel, a second turn at a second position along the length of the channel and a length section positioned in a fluid flow direction between the first and second turns wherein the length section comprises at least one fluid flow deflector to provide a change of direction and/or to create turbulence at a fluid when flowing through the channel.
2. The reactor as claimed in claim 1 comprising a plurality of turns and respective 15 length sections positioned in a fluid flow direction between the inlet and outlet.
3. The reactor as claimed in claims 1 or 2 comprising a plurality of flow deflectors provided at each of the length sections, the deflectors positioned in-series in a flow direction along each length section.
4. The reactor as claimed in any preceding claim wherein the flow deflectors comprise any one of a combination of: * at least one internal baffle positioned within the flow channel; * a bend at the flow channel; * an increase or decrease in a cross-sectional area of the flow channel; * a valve or body provided internally at the flow channel.
5. The reactor as claimed in claims 3 or 4 wherein the flow deflectors define a zigzag or serpentine flow pathway extending between the turns.
6. The reactor as claimed in any preceding claim wherein a width of the channel is greater than a depth of the channel at a cross section of the channel, where an orientation of the depth is aligned with and/or parallel to a direction of radiation to be incident at the reactor.
7. The reactor as claimed in any preceding claim wherein at a cross section of the 5 channel, a thickness of the wall is in a range 0.05 to 2mm, 0.05 to 1.5mm, 0.05 to 1.2mm, 0.05 to 1.0mm, 0.1 to 0.4mm, 0.5 to 1.5mm.
8. The reactor as claimed in any preceding claim wherein at a cross section of the reactor body a depth of the channel is in a range 1 to 15mm, 2 to 15mm, 5 to 15mm or 5 to 10 12mm.
9. The reactor as claimed in any preceding claim wherein the at least one deflector comprises a plurality of bends and the bends comprise an internal radius in a range 5 to 120°, 60 to 110° or 80 to 100°.
10. The reactor as claimed in any preceding claim wherein the reactor body comprises a material being any one or a combination of: a resin; a thermoset resin; a polystyrene; a liquid crystal polymer; a polyurethane; a polyethylene; a polyester; a polycarbonate; a HP engineering resin; a silicone; a polyvinyl chloride (PVC); a polyamide; acrylonitrile butadiene styrene (ABS); polymethyl methacrylate (PMMA); polypropylene; polymethyl pentene; an elastomer; a cellulose or cellulose based material; a fluorinated alkylene or alkane; a fluorinated ethylene-polypropylene (FEP); a polytetrafluoroethylene (PTFE); an acetal.
11. The reactor as claimed in any preceding claim further comprising a coating provided at at least one internal surface of the channel, the coating comprising any one or a combination of a resin; a thermoset resin; a polystyrene; a liquid crystal polymer; a polyurethane; a polyethylene; a polyester; a polycarbonate; a HP engineering resin; a silicone; a polyvinyl chloride (PVC); a polyamide; acrylonitrile butadiene styrene (ABS); polymethyl methacrylate (PMMA); polypropylene; polymethyl pentene; an elastomer; a cellulose or cellulose based material; a fluorinated alkylene or alkane; a fluorinated ethylene-polypropylene (FEP); a polytetrafluoroethylene (PTFE); an acetal.
12. The reactor as claimed in any preceding claim wherein the reactor body is provided as a layer optionally having a generally planar configuration.
13 The reactor as claimed in claim 12 wherein the flow channel at the at least one length section comprises an inclined and declined section relative to a general plane of the layer.
14. The reactor as claimed in claims 12 or 13 comprising a plurality of layers interconnected in internal fluidic communication via the respective inlets and outlets, the layers arranged as a block or stack.
15. The reactor as claimed in claim 14 wherein the channels of each of the layers are interconnected in fluidic communication to define a single internal flow channel extending through each of the layers of the block or stack.
16. Modular viral inactivation apparatus comprising: a plurality of modular units, each unit comprising a viral inactivation reactor as claimed in any one of claims 1 to 15; each of the units arranged as a block or stack and interconnected in internal fluidic communication to provide a single elongate flow channel extending from the inlet of an initial unit to the outlet of a subsequent or final unit wherein a plurality of units are positioned in fluidic communication between the initial and further or final units.
17. Viral inactivation apparatus comprising: a viral inactivation reactor as claimed in any one of claims 1 to 15, a fluid supply reservoir connected in fluidic communication with the flow channel to provide a supply into the flow channel of a solution containing a live virus; a filtration unit having a filter to separate components of the solution based on size, the filtration unit provided in fluidic communication with the flow channel; a fluid flow pump to drive fluid flow through the channel; and at least one sensor to monitor at least one characteristic of a solution at the apparatus.
18. The apparatus as claimed in claim 17 wherein the filter comprises any one or a combination of: * a membrane filter; * an ultrafiltration membrane.
19. The apparatus as claimed in claims 17 or 18 wherein the at least one sensor comprises any one or a combination of a temperature sensor; a pressure sensor; a flow rate/velocity sensor; a solution concentration sensor; a fluid volumetric sensor; a biological sensor; a chemical sensor; an electrochemical sensor.
20. The apparatus as claimed in any one of claims 17 to 19 further comprising a fluid control unit to control at least one characteristic of the apparatus and/or a fluid introduced into, flowing through and/or output at the apparatus.
21. The apparatus as claimed in claim 20 wherein the fluid control unit comprises any one or a combination of: a processor; a memory storage utility; a data library; fluid flow control software provided at the memory storage utility; a user interface utility having a data and/or command input interface; a wired or wireless communication utility for wired or wireless data transfer to and/or from the apparatus.
22. The apparatus as claimed in any one of claims 17 to 21 further comprising at least one access port provided at a wall of the reactor to allow access or communication to the internal channel.
23. The apparatus as claimed in claim 22 when dependent on claim 19 wherein the at least one sensor is mounted and/or is positioned at the at least one access point to monitor a characteristic of a solution flowing internally within the flow channel.
24. A method of viral inactivation comprising: introducing a solution containing at least one live virus into a reactor, the reactor comprising an elongate internal flow channel having a plurality of turns and respective length sections positioned in a fluid flow direction between respective upstream and downstream turns, the length sections comprising at least one fluid flow deflector to provide a change of direction and/or to create turbulence at the solution; passing a flow of the solution through the channel; irradiating the solution within the channel with radiation to inactivate a live virus present within the solution; and outputting from the channel inactivated virus created from the live virus.
25. The method a claimed in claim 24 further comprising: filtering and/or concentrating the solution prior to the step of introducing the solution into the reactor to increase a concentration of the live virus in the solution.
26. The method as claimed in claims 24 or 25 further comprising controlling and/or changing any one or a combination of: * a solution flow rate through the channel; * a concentration of the live virus within the solution prior to introducing the fluid into the reactor; * a temperature of the solution; * a pressure of the solution; * a pH of the solution; * a flow direction optionally being a forward and/or reverse flow direction.
27. The method as claimed in any one of claims 24 to 26 wherein the method is a continuous process comprising a continuous supply of solution containing the live virus into the reactor and a continuous output from the reactor of the inactivated virus
28. The method as claimed in any one of claims 24 to 26 wherein the method is a batch process comprising in order: * the step of introducing the solution into the reactor; * terminating the flow of the solution introduced into the reactor; * irradiating the fluid within the reactor; and * outputting the inactivated virus.
29. An inactivated virus manufactured using: the viral inactivation reactor of any one of claims 1 to 15; the modular viral inactivation apparatus of claim 16; the viral inactivation apparatus of any one of claims 17 to 23; the method of viral inactivation of any one of claims 24 to 28.
30. A vaccine comprising the inactivated virus of claim 29.