Cartridge system for sterile mixing process

Abstract

The invention provides a frame (10) for holding and disposing a static mixing device (16) and flexible containers (11, 12, 13, 14) for liquid substrates, waste and liquid products. The frame includes a sealable region for holding the container, the flexible container and the mixing device. Other aspects relate to kits including a frame and one or more mating components, such as static mixing devices and flexible containers, apparatus for operating the frame in its assembled state, and methods including using the frame.

Description

Background Art

[0001] Process automation as well as scale-up and scale-down of hybrid processes are frequently addressed tasks in various biotechnological and medical fields.

[0002] Systems for producing mixed fluids or products based on a combination of two or more components require a source of liquid raw materials, supply lines, a chamber for mixing or reacting, and an outlet for harvesting the product. The chamber usually represents the core of such a system and can be, for example, large-volume (e.g., container) or miniaturized (e.g., in microfluidic methods). However, the system's setup, conditions, and the quality of the raw materials also play a decisive role in these processes.

[0003] An example of a discontinuous mixing system is a device for mixing, storing and homogenizing liquids disclosed in US7784997B2. The device includes a rigid container equipped with a non-invasive pump. The container includes a disposable bag having an orifice on the lower surface for liquid outlet and a plurality of orifices on the top of the bag for adding various liquids to produce a mixture. One of the upper orifices is used to return the liquid to the inside of the bag (with the aid of a pump) to achieve a closed-loop circulation. The system is disposable and avoids the cleaning and sterilization steps necessary for mixing using a rigid tank. The system is capable of processing bags with a volume of 25 to 3000 liters, but does not seem to be suitable for small-scale production (e.g., microliter or milliliter production).

[0004] EP1146959B1 discloses a device for the continuous production of encapsulated therapeutic compounds, which provides an example of a precisely controlled metering system. The device includes a lipid phase storage member, an aqueous phase storage member, and a pressurized transfer member, which is used to transfer these phases to a mixing device, which is preferably a static mixer. The device of EP1146959B1 also includes a premixing system. By means of a metering pump driven by a motor, these phases are transported from the member to the premixing and mixing chamber. Since this system is a continuous system, it can produce a larger amount of required products.

[0005] Despite these and other solutions for mixing systems and methods, the need for methods, devices and apparatus for producing small quantities of products that are fast, reliable and can be performed under standardized conditions has not been fully met. This is particularly true for applications in the field of personalized medicine.

[0006] Therefore, an object of the present invention is to provide a component, device, assembly and method for producing a mixed fluid or product based on a combination of two or more components, which are flexible in adapting to different types of products and can produce required products robustly, quickly and reliably. These components, equipment, assemblies and methods are also intended to provide a high-throughput method. Based on the following description of the present invention, the accompanying drawings and claims, other objects of the present invention will become apparent. Summary of the invention

[0007] In a first aspect, the present invention relates to a frame adapted to simultaneously hold (a) first and second flexible substrate containers, each of which includes an outlet port; (b) a flexible waste container, which includes an inlet port; (c) a flexible product container, which includes an inlet port; (d) a static mixing device, which includes at least a first and second inlet port and an outlet port; and (e) a conduit for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device, the outlet port of the second substrate container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet ports of the waste container and the product container. The frame is further characterized in that it includes a first sealable area for holding the first flexible substrate container, a second sealable area for holding the second flexible substrate container, and a member for holding the static mixing device. In addition, the frame has an operating orientation, and the first and second sealable areas and the member for holding the static mixing device are arranged so that in the operating orientation, the flow of fluid from the first and second substrate containers to the static mixing device and / or from the static mixing device to the waste container or product container is at least partially along the direction of gravity. The framework is particularly useful for small-batch aseptic manufacturing of sterile liquid products that require mixing of two fluid matrices, especially without the use of pumps.

[0008] In another aspect, the present invention provides a kit comprising a frame as described herein and any one of the following components: (a) a first and / or second flexible substrate container; (b) a flexible waste container; (c) a flexible product container; (d) a static mixing device; and / or (e) one or more conduits for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device, the outlet port of the second substrate container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet port of the flexible waste container and the flexible product container. The kit may also include a frame and all components (a) to (e) (including the first and second flexible substrate containers and all conduits for specific fluid connections). Alternatively, the kit may include components (a) to (e), but not a frame.

[0009] According to another aspect of the present invention, a flexible container is provided, which is suitable for use as a flexible matrix container, a flexible waste container or a flexible product container as described above. The container has an internal space for accommodating a fluid material, the internal space being surrounded by a flexible front wall and a flexible rear wall, each wall portion being made of a polymer material. In addition, the container also includes at least one inlet port or an outlet port for achieving fluid communication with the internal space. The flexible front wall and the flexible rear wall are connected to each other to form a sealing edge that substantially surrounds the internal space. The edge includes four corner regions so that the internal space has a square or rectangular overall shape when empty. The container is also characterized in that at least two through holes are provided in the sealing edge, wherein the first through hole is arranged in or near the first corner region of the edge, the second through hole is arranged in or near the second corner region of the edge, and the second corner region is adjacent to the first corner region. Other aspects of the present invention relate to an apparatus for aseptically filling a first and a second flexible matrix container assembled in a frame; an apparatus for mixing a first and a second liquid matrix, wherein these liquid matrices are contained in a first and a second flexible matrix container, which are assembled in a frame; and a method for mixing a first and a second liquid matrix, the method relying on the use of a frame in which the first and the second flexible matrix container are assembled.

[0010] Further aspects, preferred and optional features and embodiments are described in more detail below. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 A perspective view of the frame (10) is shown.

[0012] Figure 2 yes Figure 1 A front view of the frame (10) in FIG.

[0013] Figure 3 Shows Figure 2 A front view of the frame (10) in FIG. 1 (without its assembled parts).

[0014] Figure 4 yes Figure 1 A perspective view of the frame (10) in FIG. 1 (without its assembled parts).

[0015] Figure 5 A perspective view of the frame (50) is shown.

[0016] Figure 6 Shows Figure 5 A top view of the frame (50) is shown.

[0017] Figure 7 yes Figure 6 A top view of the frame (50) is shown without its assembled components.

[0018] Figure 8 A perspective view of the frame (80) is shown.

[0019] Fig. 9 yes Figure 8 A top view of the frame 80 in FIG.

[0020] Fig.10 Shows Figure 8 A perspective view of the frame (80) in FIG. 1 (without its assembled components).

[0021] Fig.11 yes Fig. 9 A top view of the frame (80) in FIG. 8 (without its assembled components).

[0022] Fig.12 A front view of the frame (120) is shown.

[0023] Fig.13 An example of a flexible container (1) is shown.

[0024] Fig.14 Shows Fig.13 A perspective side view of a flexible container (1) in FIG.

[0025] Fig.15 A front or user-facing elevation view of another example of a frame (150) with its assembled components is shown.

[0026] Fig.16 Shows Fig.15 A front view of the rear side of the frame (150) is shown.

[0027] Fig.17 Shows Fig.15 A front elevation view of the frame (150) is shown without its assembled components.

[0028] Fig.18 Shows Fig.17 A front view of the rear side of the frame (150) is shown.

[0029] Fig.19 Shows Fig.15 A perspective view of the front side of the frame (150) is shown.

[0030] Fig. 20 Shows Fig.19 A perspective view of the rear side of the frame (150) is shown.

[0031] Fig.21 Shows Fig.16 A detailed or enlarged view of a portion of the back side of the frame (150) is shown.

[0032] Fig. 22A perspective view of an exemplary static mixing device (162) is shown, which can be used with, for example, Fig.15 and Fig.16 The frame (150) or kit shown is used in combination.

[0033] Fig.23 Shows Fig. 22 A perspective view of a static mixing device (162) is shown.

[0034] Fig.24 A perspective view of the front side of another example of a frame (240) is shown.

[0035] Fig.25 Shows Fig.24 A perspective view of the rear side of the frame (240) is shown. DETAILED DESCRIPTION

[0036] In one aspect, the present invention provides a frame adapted to simultaneously hold (a) first and second flexible matrix containers, each of which includes an outlet port; (b) a flexible waste container, which includes an inlet port; (c) a flexible product container, which includes an inlet port; (d) a static mixing device, which includes at least a first and second inlet port and an outlet port; and (e) a conduit for fluidly connecting the outlet port of the first matrix container to the first inlet port of the static mixing device, the outlet port of the second matrix container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet port of the waste container and the product container. The frame is further characterized in that it includes a first sealable area for holding the first flexible matrix container, a second sealable area for holding the second flexible matrix container, and a member for holding the static mixing device. In addition, the frame has an operating orientation, and the first and second sealable areas and the member for holding the static mixing device are arranged so that in the operating orientation, the flow of fluid from the first and second flexible matrix containers to the static mixing device and / or from the static mixing device to the waste container or product container is at least partially along the anti-gravity direction.

[0037] The inventor finds that, for aseptic mixing of two kinds of fluid matrices in small batches or making two kinds of fluid matrices react to obtain sterile liquid products (such as liquid pharmaceutical products), this framework is particularly useful.For example, the mixing of two kinds of matrices or reaction can be driven by utilizing pressure (such as pressurized gas), and allow to perform the process that all parts that provide in contact with matrix or product can be disposable sterile supplies.In addition, this framework can be used for minimizing the dead volume that can cause lower product output (especially in the case of extremely small batches, such as in personalized medicine manufacturing) to the greatest extent.At least part of the anti-gravity flow of the fluid affected by the framework reduces the negative impact (such as bubble formation) of the gas that may be present in the matrix container or produce in the mixing process.Hereinafter, these and other unexpected effects and advantages will be described in further detail.

[0038] As used herein, a frame should be understood as a support structure or holder for specific components, providing their spatial layout. In this case, it should be understood by those skilled in the art that the expression "for" in "for holding" means that the frame is set for or suitable for a specific purpose.

[0039] Flexible substrate container (sometimes also referred to as substrate container in this article) is a container that is suitable for holding fluid substrate (especially liquid substrate, such as aseptic liquid as intermediate product in the preparation of injectable medicine). These flexible substrate containers can show high flexibility, are similar to infusion bag.Each substrate container comprises at least one outlet port, and this outlet port can be connected with static mixing device fluid by conduit.

[0040] Similarly, waste container and product container are respectively suitable for accommodating fluid waste or fluid product, and they also show flexibility.Each of these containers has at least one inlet port, and this inlet port can be connected to static mixing device by fluid (for example, by conduit) so that this container can receive waste or product from mixing device.In addition, product and at least some waste are normally liquid.In one embodiment, waste container and / or product container are non-flexible, and substrate container is flexible.

[0041] With respect to conduits, it should be understood that these conduits can have any structure (such as a tubular or pipe-like structure) that enables them to conduct fluid materials. At the same time, conduits should not be understood as requiring a specific minimum length. In fact, according to some embodiments, the length of the conduit can be very small (even relative to its outer diameter), which will minimize the internal volume and therefore minimize the potential dead zone associated with the conduit.

[0042] The frame may be adapted to hold any type of static mixing device.As used herein, a static mixing device may be any mixing device without movable parts.

[0043] As described above, the frame includes first and second sealable areas. As used herein, the sealable area of ​​the frame is a structure that is suitable for holding or accommodating or helping to accommodate an object (such as a flexible substrate container) and can be sealed against at least one counterpiece to enclose the object in a sealed space.

[0044] For example, sealable area can be shaped as a cavity. In this case, the cavity in the tray portion (tray portion) of this framework or this framework refers to a part of the surface, which can be recessed or sunken, and is shaped to receive one or more objects (such as substrate containers). Alternatively, even when there is no recess in the original flat portion of the framework, sealable area or cavity can be formed by a frame (such as being arranged on the frame or the circumferential frame (circumferential rim) extending from the frame). For avoidance of doubt, the statement of " cavity " does not require that the flexible container is fully adapted to the corresponding cavity; particularly when being filled with fluid substrate, the height of the flexible container may exceed the height of the cavity that keeps the container. In some preferred embodiments, the first and / or second sealable area is limited by the circumferential frame extending from the framework.

[0045] Alternatively, the circumferential frame is arranged to receive the mating piece in a sealed manner, and this mating piece has the cavity that is used to hold corresponding flexible substrate container.In some related embodiments, the first and second sealable areas have all represented the substantially flat zone of framework, and it has the circumferential frame that extends from framework and is suitable for receiving the mating piece in a sealed manner, and this mating piece has the cavity that is used to hold corresponding flexible container at least in part.As those skilled in the art will appreciate, the structure or shape of the sealable area and the structure or shape of the mating piece can change the contribution degree of the overall shape of the sealed space of the closed flexible substrate container.

[0046] In a related embodiment, the frame can be designed to include a tray portion. In this case, a tray portion can be broadly understood as a relatively flat structure, which is optionally interrupted by an opening and is designed to hold one or more objects. Such a tray or tray portion can include a first and a second sealable area in the form of a cavity. As described above, the cavity can be formed by a recess provided in an originally flat portion of, for example, the tray portion of the frame, and / or it can be formed by a frame provided on or extending from the tray. The frame and optionally the tray portion of the frame can also include a component for holding a static mixing device. The component can also be shaped as or include a cavity or a groove, but other structures (such as a frame or a clip) can also be used.

[0047] According to this aspect of the present invention, the framework has an operating orientation. In other words, the framework is configured to keep a specific assembly in a specific orientation, in which the process of mixing two substrates or reacting two substrates to obtain a product is carried out. As mentioned above, the framework is configured to make the first and second sealable areas or cavities and the components for holding the static mixing device in its operating orientation be spatially arranged so that the flow of fluid from the first and second substrate containers to the static mixing device is at least partially carried out along the anti-gravity direction, or the flow of fluid from the static mixing device to the waste container or product container is at least partially carried out along the anti-gravity direction, or both situations exist. In this case, the statement "at least partially along the anti-gravity direction" should be understood as at least for a part of the corresponding flow path, the downstream end is in a higher position than the upstream end, and does not require the flow direction to be exactly opposite to the direction of gravity (that is, at an angle of 180 °).

[0048] It is obvious to those skilled in the art that (and in order to avoid doubt), the framework disclosed herein is not configured for the situation of microfluid or as a part of microfluid system or device.Microfluid refers to a system that uses a small channel with a size of ten to hundreds of microns to manipulate a very small amount of fluid. In addition, microfluid utilizes micro-scale fluid behavior different from "normal" or macrofluid behavior, because factors such as surface tension, energy dissipation and fluid resistance dominate in the system. On the contrary, the conduit (including the conduit that the outlet port of the first matrix container is connected to the first inlet port of a static mixing device, the outlet port of the second matrix container and the second inlet port of a static mixing device and the outlet port of a static mixing device are fluidly connected to the inlet port of a waste container and a product container) maintained by the framework is a non-microfluid conduit. For example, the internal diameter of these conduits is usually in the range of at least one millimeter or several millimeters (such as about 1 millimeter to about 10 millimeters). In addition, in some preferred embodiments, these conduits are flexible (for example, flexible tubes), and can be detachably connected (reversibly connectable) with the ports that they are suitable for fluid connection. These characteristics further distinguish the present invention from a microfluid system.

[0049] Therefore, static mixer is not a microfluid mixer, but is configured to mix fluid with macrofluid scale, even if this scale may be considered to be smaller than typical large-scale pharmaceutical manufacturing process.In some preferred embodiments, static mixer is suitable for mixing fluid with the total flow rate of about 10mL / minute to about 1000mL / minute.In other embodiments, static mixer is suitable for mixing fluid with the total flow rate of about 20mL / minute to about 600mL / minute or about 30mL / minute to about 300mL / minute respectively.

[0050] Similarly, with regard to size, according to some further embodiments, the shape and size of the first and second sealable areas are arranged to keep the internal volume range to be about 10mL to about 3000mL of a flexible substrate container. It is also preferred that the shape and size of the sealable areas are designed to keep the internal volume range to be about 50mL to about 1500mL of a flexible substrate container. The internal volumes of other preferred substrate containers are respectively about 300 ± 100mL, 500 ± 200mL, 1000 ± 300mL and 1500 ± 300mL. In some related embodiments, the internal volume range of the flexible product container is respectively about 50mL to about 4000mL, about 100mL to about 2000mL or about 300mL to about 2000mL.

[0051] In some preferred embodiments, the first and second flexible substrate containers are of different sizes.For example, the internal volume of the first substrate container can be greater than the internal volume of the second substrate container.In some embodiments, the internal volume of the first substrate container is about 1.5 to about 4 times than the internal volume of the second substrate container.Correspondingly, the shape and size of the first and second sealable areas are suitable for keeping the substrate containers of these different sizes.In some embodiments, the first and second sealable areas are basically similar or identical in height (or length, depends on the operating orientation of framework, as described below), and basically different in width.For example, the width of the first sealable area can be larger (such as large 1.5 times or more) than the width of the second sealable area.

[0052] In some further embodiments, the first and second sealable regions are positioned in close proximity to each other so as to minimize the size of the frame and the length of the conduit required for the liquid to flow from the substrate container to the static mixer, thereby reducing the dead volume of the flow path. Optionally, the first sealable region and the second sealable region are positioned adjacent to each other, and wherein the minimum distance between the first sealable region and the second sealable region is less than 10% of the width of the first sealable region.

[0053] In some embodiments, the frame also includes components for holding or fixing flexible product containers and / or flexible waste containers. For example, the components for holding these containers can be represented by cavities, and these cavities can be arranged in the tray portion of the frame. Alternatively or additionally, components such as hooks, protrusions, pins, etc. can be provided to hold or fix these containers. In some preferred embodiments, these components are suitable for allowing the corresponding containers to be detachably fixed to the frame. In this case, a detachable fixing method should be understood as a fixing method that a user can easily separate in a non-destructive manner (preferably without using tools).

[0054] In addition, there are various options for positioning the means for holding or securing the flexible product container and / or the flexible waste container. In some embodiments, the frame is configured to hold the product container and the waste container on the same side of the frame. In other embodiments, the two containers are secured on different sides of the frame. In some preferred embodiments, the frame has a front side facing the user in its operative position and a rear side opposite the front side, wherein the means for securing the flexible product container are disposed on the front side of the frame, and the means for securing the flexible waste container are disposed on the front side or the rear side of the frame. An advantage of this configuration is that the space provided by a frame of a given size for holding these containers is used more efficiently.

[0055] In this case, the front side or user-facing side should be understood broadly and independently of the operating orientation of the frame. For example, for a frame with a vertical operating orientation, the front side will also be oriented vertically, and for a frame with a horizontal operating orientation, the front side will also be oriented horizontally and is typically the upward side of the frame.

[0056] In some preferred embodiments, the frame is adapted for a vertical operating orientation. This means that any cavity provided for holding substrate containers and / or product containers and waste containers during operation may not be sufficient to hold the respective containers in place. Therefore, the first and second sealable areas may each include one or more members for securing the respective flexible substrate containers.

[0057] In some preferred embodiments, one or more members for fixing the flexible substrate container are arranged on the front side of the framework.Equally, these members can be members suitable for detachably fixing the corresponding container, as described in the above related content.These members can alternatively be shaped as hooks, projections or pins, and these hooks, projections or pins are arranged to be used to receive the flexible substrate container with through hole, and these through holes are positioned to match with hooks, pins or projections.The pin can be for example a barbed pin (barbed pin) or a snap-lock pin (snap-lock pin).

[0058] With regard to the operating orientation of the frame and the fixing of the flexible substrate container, the options and preferences disclosed herein should not only be interpreted as different individual disclosures, but also as their combinations. For example, it is obvious that the present invention will also provide a frame suitable for a vertical operating orientation, the frame having a first and a second sealable area, the first and the second sealable area being used to hold the first and the second flexible substrate container arranged on the front side of the frame, wherein the sealable areas each include a member for fixing the corresponding substrate container, and wherein the members are arranged on the front side of the frame so that the substrate container can be fixed to the front side of the frame.

[0059] In some embodiments, the pallet portion of this framework or this framework not only comprises the cavity for the first and second substrate containers, also comprises the cavity for the flexible product container or the cavity for flexible waste container or both.Relative to the size of whole framework, these embodiments need sizable pallet portion or pallet area.Due to these other cavities, the pallet portion can represent a part larger than any other part of framework in the framework.In some further embodiments, whole framework can be shaped as pallet.Alternatively, the pallet portion only comprises two cavities (that is, the cavity for two specific substrate containers) for container.In one embodiment, the pallet portion of framework only comprises the cavity for the first and second substrate containers, and alternatively comprises the cavity for the flexible product container.

[0060] In some embodiments, the first and second cavities that are used to keep the first and second substrate containers are all positioned in the larger groove of the tray portion. Because groove also can have the general shape of tray cavity in this case, two cavities that are used to keep two substrate containers separately can also be considered as the subcavity of larger cavity. But, need to be provided with independent sealable area or cavity for each in the two substrate containers, it can seal against another cavity in principle.

[0061] As mentioned above, the first and second sealable areas can be shaped as cavities.Although the cavity can be shaped as to hold and keep the first and second substrate containers in principle, the additional fixing of these containers may be useful for better processing.In some embodiments, the first and second cavities (or preferably each in the first and second cavities) comprise one or more members that are used to fix the corresponding flexible substrate container.This has brought extra advantages, and promptly when keeping the container, this framework can tilt, and container can not fall out from the cavity.In some embodiments, one or more members are suitable for detachably fixing the substrate container, so that allow to remove the container easily and losslessly after use.

[0062] According to some further embodiments, at least two members (such as two, three or four members) for fixing the flexible substrate container are arranged in one or more sealable areas or tray cavities. An advantage of these embodiments is that the corresponding container can be kept in its desired position more stably. Another advantage is that a specific spatial arrangement for each sealable area or cavity can be selected, which helps the user or operator to match each container with the correct sealable area or cavity.

[0063] For example, a fixing system can be adopted, which comprises a projection or a pin arranged in a sealable area or a cavity and a through hole arranged in the peripheral area of ​​the flexible container (i.e., at a distance from the inner chamber of the corresponding container). Advantageously, the position of the projection or the pin can match the position of the through hole of the container, but the spatial arrangement can be different for each sealable area or the cavity and the container of the matching. As mentioned above, in some embodiments, the member for fixing the flexible substrate container is shaped as a projection or a pin, and these projections or the pins are used to receive the flexible substrate container with a through hole, and these through holes are positioned to match the pins or the projection. In this particular case, the projection or the pin can be a snap-fit ​​pin (snap-fit ​​pin) (such as the pin with an arrow or a mushroom-shaped head).

[0064] The spatial arrangement of the means for securing can be used not only to ensure that the correct container is secured to the sealable area or inserted into the cavity, but also to facilitate its securing or insertion in the desired or correct orientation. Thus, in some embodiments, the means for securing the respective flexible matrix container is adapted to secure the container only when the respective flexible matrix container has the desired orientation.

[0065] In some embodiments, the flexible product container and / or the flexible waste container or only the flexible waste container is directly fixed to the frame itself by a fixing member. In other words, the frame does not include a cavity or a sealable area for holding the one or more containers. A fixing system similar to or similar to the system for holding the matrix container described herein can be used, for example, a system including a projection or a pin arranged on a non-recessed portion of the frame or frame portion, wherein a through hole is provided in the peripheral area of ​​the flexible container. In some embodiments, the fixing member on the frame can be arranged so that the flexible waste container is detachably fixed on the surface of the frame, relative to the fixing member provided for fixing the flexible matrix container and the product container. As described above, the member for fixing the flexible product container can be optionally arranged on the front side of the frame, and the member for fixing the flexible waste container can be arranged on the rear side of the frame.

[0066] Can adopt other technology to guarantee the correct operation of framework and the assembly that keeps thereof.For example, in some embodiments, this framework comprises identification tag.In some further preferred embodiments, the identification tag is radio frequency identification (RFID) tag.Equally preferred embodiment is, wherein a kind of substrate container or all two kinds of substrate containers all have identification tag (such as RFID tag).

[0067] As described above, the framework can be configured to operate in a specific operating orientation. In some preferred embodiments, the operating orientation is horizontal or substantially horizontal. In other preferred embodiments, the operating orientation is vertical or substantially vertical. As used herein, the horizontal orientation of the framework means in principle that its two larger dimensions are in a horizontal plane, while its smallest dimension is in a vertical plane. Vice versa, when the two larger dimensions of the framework are in a vertical plane and its smallest dimension is in a horizontal plane, the vertical orientation of the framework is given. However, the modified term "substantially" takes into account that a framework that can generally have a slightly flat or planar overall shape will not be completely flat or planar.

[0068] The frame, in particular a frame having a vertical operating orientation, may also include one or more members for fixing or maintaining it in its proper position and orientation. For example, the frame may include one or more through holes adapted to match protrusions or hooks provided by a device configured to operate a frame as defined herein or a kit comprising the frame.

[0069] Not only this framework can have operating orientation.As mentioned above, for container (such as flexible substrate container), orientation may also be important.In some further preferred embodiments, static mixing device also has operating orientation.This framework can be advantageously suitable for ensuring that static mixing device can only be installed on correct (that is, required) orientation.Especially, the member for keeping static mixing device can be suitable for keeping static mixing device only when static mixing device has required orientation.In order to avoid doubt, the required orientation of static mixing device is defined relative to framework.If this framework is also in operating orientation, the required orientation of static mixing device is identical with its operating orientation.

[0070] In some related embodiments, the desired orientation of the static mixing device is such an orientation that when the frame is in its operating orientation, the liquid flows out of the static mixing device through the outlet port of the static mixing device in a direction counter to gravity. It has been found that this upward or counter to gravity flow of the liquid in the static mixing device reduces unwanted mixing effects (such as the formation of bubbles).

[0071] As mentioned above, for other parts of fluid flow path (for example, between substrate container and static mixing device), at least part of anti-gravity flow also may be desirable.In some relevant embodiments, the first and second sealable areas or cavity and the member that is used to keep static mixing device are arranged to make the position of the outlet port of flexible substrate container on the operating orientation of framework lower with respect to the position of the corresponding inlet port of static mixing device.This structure will need at least some upward fluid flows.In this case, suppose that not only this framework itself is in the operating orientation, and substrate container and static mixing device are fixed in correct orientation.

[0072] For many processes that need to mix two liquid substrates, the optimal ratio between the substrates is not 1: 1. More typically, one of the substrates must be provided with significantly more amount and / or higher rate than other substrates. Therefore, the size of the two substrate containers can be different, so in some embodiments, the size of the first and second sealable areas or cavities is different. In this case, the size of the sealable area or cavity mainly refers to the size of the flexible container that it can maintain. The size difference of the sealable area or cavity is also reflected in the volume difference of the sealable area or cavity, or when covered by the first pairing (as further described below) The volume difference of the pressure chamber formed by the sealable area (this then requires the difference of at least one dimension of the sealable area). In some embodiments, relative to the volume of a smaller cavity or pressure chamber, the volume of one of the two cavities or pressure chambers is at least about 50% larger than the volume of another cavity or pressure chamber. According to an equally preferred embodiment, the length (that is, the maximum dimension) and width (that is, the second largest dimension) of one of the two cavities or sealable areas are greater than the length and width of another cavity or sealable area.

[0073] As already mentioned, the framework is particularly useful for pumpless aseptic preparation of sterile liquid products by mixing two fluid matrices in small batches or reacting two fluid matrices, wherein the fluid passes through a mixing device under pressure. The pressure can be provided, for example, by pressurized gas. For example, such pressure-driven systems are described in patent applications EP21206216 or WO 2023 / 079039A1, which are being filed concurrently, and the entire disclosure of the patent application is incorporated herein by reference.

[0074] If pressurized gas is to be used to drive fluid from a flexible matrix container through a conduit into a static mixing device, the sealable areas or cavities that hold the container must be tightly closed to form pressurizable chambers (e.g., by applying a lid or another type of mating piece to cover the sealable areas or cavities), and the pressurized gas must be introduced into these chambers in a controlled manner.

[0075] To this end, in some embodiments, the frame or its tray portion is provided with a first through hole disposed in a first sealable region and a second through hole disposed in a second sealable region. Likewise, the sealable region may be provided as a cavity. As used herein, a through hole should be understood as any opening in a sealable region through which the sealable region may be pressurized with gas from outside the frame when the rest of the sealable region is covered and sealed, regardless of the size and shape of the through hole. For example, Figure 3 As shown, the size of the through hole may not be much smaller than the size of the sealable area.

[0076] There are various options regarding the spatial arrangement of the first and second sealable areas or cavities relative to each other. In some embodiments, the first and second sealable areas or cavities are arranged to hold the flexible substrate container so that the outlet port of the first flexible substrate container and the outlet port of the second flexible substrate container are coaxially opposite. In some further embodiments, the outlet port of the first flexible substrate container and the outlet port of the second flexible substrate container are coaxially opposite at an angle of approximately 45° relative to the longitudinal center axis of the frame.

[0077] In some embodiments, the first and second sealable areas are arranged to keep the flexible substrate container so that the outlet port of the first flexible substrate container and the outlet port of the second flexible substrate container are coaxial and not relative. In one embodiment, the first and second sealable areas or cavity are arranged to keep the flexible substrate container so that when the framework is in its operating orientation, liquid flows out of the corresponding flexible substrate container along the anti-gravity direction through the outlet port of the corresponding flexible substrate container. When the operating orientation of the framework was vertical, these embodiments were especially advantageous.

[0078] The frame can also be adapted to hold the flexible product container only in a specific orientation. For example, this can be achieved by the construction of the member for holding the container. In some embodiments, the operating orientation of the frame is vertical and is also adapted to hold the product container in a vertical orientation, wherein its inlet port for receiving liquid from the static mixer is in a horizontal orientation or a vertical orientation, so that the liquid flows from the static mixer through the inlet port in the direction of anti-gravity. For example, if it is intended to dilute the liquid received from the static mixer with a liquid diluent, such a vertical orientation of the container and the inlet port may be advantageous; the liquid diluent is pre-filled in the product container to promote the mixing of various liquids on the product container. If it is intended to dilute the liquid received from the static mixer into the product container inline or subsequently, the horizontal orientation of the inlet port may be advantageous. In this case, "inline" refers to supplying the liquid diluent to the product container while the container also receives liquid from the static mixer; "subsequent" refers to supplying the liquid diluent after the product container no longer receives any liquid from the static mixer.

[0079] As mentioned above, it may be desirable to minimize the length of conduit (at least the length of those conduits arranged between substrate container and static mixing device). In addition, it is advantageous to find that these conduits are contained in the sealable area or cavity identical with corresponding substrate container. The advantage of these embodiments is that, when pressurized gas is used as the driving force of liquid, conduit will not be subject to any significant pressure difference during operation, because they are located in the pressurized area identical with the flexible substrate container connected with them. Another advantage is that, conduit does not need to be carried out high pressure sealing; If conduit is contained in sealable area or cavity, then can be sealed against the mixing device mechanically more stable than conduit. Therefore, in some embodiments, the first sealable area or cavity are shaped as at least partially to hold the conduit for the outlet port of the first substrate container being connected to the first inlet port fluid of static mixing device. In a related embodiment, the second sealable area or cavity are shaped as at least partially to hold the conduit for the outlet port of the second substrate container being connected to the second inlet port fluid of static mixing device; Or the first and second sealable areas or cavity are so shaped.

[0080] The framework can also include one or more components for holding conduits, which are used to connect the outlet port of the static mixing device to the inlet port fluid of the waste container and the product container. Similarly, these components can be optionally formed as grooves or cavities in the frame or the tray portion of the frame, and the conduit can be at least partially inserted into these grooves or cavities. As used in the case of retaining components, grooves and cavities can be used interchangeably. The method of keeping the conduit in the cavity is particularly suitable for short conduits. As mentioned above, it may be desirable to keep the conduit shorter so that the dead zone of the fluid is smaller; the dead zone can reduce product output, especially when manufacturing products in small batches. Alternatively or additionally, other retainers (such as clamps, clips, sleeves, etc.) can be provided.

[0081] In some embodiments, the frame also includes one or more members for holding a valve, which can be arranged in a conduit for connecting the outlet port of the static mixing device to the inlet port of the waste container or to the fluid of the product container. For example, one or two valves can be envisioned to control the flow of fluid from the static mixing device to the waste container and the product container. These valves can also help prevent backflow from the product container during or at the end of batch production. For example, a diverter valve can be used to initially introduce liquid into a conduit connected to the waste container, and once a stable mixing process is achieved, the diverter valve can introduce fluid into the product container. Alternatively, two valves (such as pinch valves or other stopcocks) can be used for this function, the first valve being arranged in the conduit or fluid path between the static mixing device and the waste container, and the second valve being arranged between the static mixing device and the product container. Similarly, a retainer or retaining member for such a valve (or multiple valves, as the case may be) can be configured as a groove or cavity in the frame or the tray portion of the frame, in which the valve is accommodated and maintained in place. Alternatively, one or more frames, clamps, clips or other structures can be used for this purpose, or even a combination of the two.

[0082] In some related embodiments, the frame is suitable for holding a Y-shaped piece or a T-shaped piece, wherein the Y-shaped piece or the T-shaped piece is arranged in a conduit that fluidly connects the outlet port of the static mixing device with the inlet ports of the waste container and the product container, so that the inlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the outlet port of the static mixing device, the first outlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the inlet port of the waste container, and the second outlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the inlet port of the product container.

[0083] In some further related embodiments, the one-way stopcock can be arranged downstream of the Y-piece or T-piece, i.e. in the conduit portion that fluidly connects the first outlet of the Y-piece or T-piece to the inlet port of the waste container and / or in the conduit portion that fluidly connects the second outlet of the Y-piece or T-piece to the inlet port of the product container. Preferably, a one-way stopcock is provided at both locations. In this case, a one-way stopcock should be understood as a one-way valve having an open state and a closed state and having no pressure reduction or flow regulation function. Preferably, the one-way stopcock can be operated to quickly switch from its closed state to its open state (especially in less than one second, or even in less than 0.5 seconds).

[0084] The one-way stopcock valve (or preferably each one-way stopcock valve) may include a member for mechanically operating the valve, wherein the member is preferably oriented in a direction corresponding to the rear side of the frame or is adapted to be operated from that direction. When viewed from the front, this configuration will allow the valve to be operated by an automatic operating device arranged at the rear of the frame (for example, when the frame is inserted into the device (which will be described in more detail below)). In one embodiment, the frame is adapted to or includes at least one member for holding or fixing the valve to the frame.

[0085] In some further embodiments, the check valve is arranged in a conduit or conduit portion, and this conduit or conduit portion is connected with the inlet port fluid of the waste container by the first outlet of the Y-shaped piece or the T-shaped piece.If this conduit or conduit portion also comprises a one-way stopcock as above, then the check valve is located at the downstream of the one-way stopcock.If intention is to remove residual gas or air from the flexible substrate container before starting the mixing process, this check valve may be advantageous.If the substrate container is oriented so that the corresponding outlet port is vertically oriented to allow fluid to flow out along the anti-gravity direction, then when the stopcock positioned at the waste container upstream is in its open state, it can be vented by squeezing this container gently, and this can push air or gas to the waste container.When no longer squeezing the substrate container to vent, the check valve can prevent any backflow of gas or air.The example of a possible suitable check valve comprises a duckbill valve, a ball valve, a swing valve, a piston valve, a butterfly valve and a tilting disc valve.In some preferred embodiments, the check valve is a duckbill valve.

[0086] In some further embodiments, the member for holding the static mixing device is itself formed as a groove or cavity in the frame or the tray portion of the frame. As described above, according to one of the preferred embodiments of this aspect of the invention, the frame in its operating orientation is arranged so that the liquid flows through the outlet port of the static mixing device in an upward or anti-gravity direction. Therefore, the cavity for holding the mixing device can be shaped and oriented to allow the mixing device to be inserted only in its required orientation, which is the operating orientation when the frame itself is also in its operating orientation. One or more additional members (such as clamps) for holding the mixing device can also be used.

[0087] According to some further preferred embodiments, this framework or its tray part comprise the circumferential gasket for each in the first and second sealable areas or cavity.Usually preferably adopt gasket to seal the first and second sealable areas or cavity against the mating piece, especially if the intention is to pressurize the cavity when keeping the corresponding substrate container and when covering with this mating piece.In principle, these gaskets can be pre-set on framework or its tray part or mating piece, and currently preferably gasket and framework are arranged together (that is, the framework comprising gasket is provided).Alternatively, a gasket can be set, and this gasket is shaped as respectively around the first sealable area or cavity and around the circumferential seal of the second sealable area or cavity.In another embodiment, each in the first and second sealable areas of this framework or cavity is separately arranged on the front side (for example, with respect to the user-facing side of framework) of the sealable area and the second circumferential gasket that is arranged on the rear side of framework around the sealable area is closed.As understood herein, circumferential gasket can be separately applicable to the front side or rear side of the first and second sealable areas or cavity and / or the sealable area. Furthermore, the one or more gaskets sealing the first and second sealable areas or cavities may also be shaped such that the gasket portion also seals the corresponding sealable area or cavity against a portion of the static mixing device (e.g., against one of the inlet ports). Alternatively, the inlet port of the static mixing device may be sealed against a hollow tubular structure disposed in the frame (e.g., in a circumferential frame defining the sealable area or cavity).

[0088] As mentioned above, it is usually desirable to minimize the dead volume, which can cause fluid loss and product yield reduction. Therefore, it is preferred to adopt a relatively short conduit between various containers and static mixing devices. For this purpose, according to some further preferred embodiments, the distance between the first and second sealable areas or cavities is relatively short (such as less than half the length of each sealable area or cavity). In this case, the length of the sealable area or cavity is its maximum dimension, and the distance should be understood as the shortest distance between the position on the profile of the first sealable area or cavity and the position on the profile of the second sealable area or cavity. Remember that the sizes of the two sealable areas or cavities can be different from each other, and the distance between the two sealable areas or cavities should be less than the length of the smaller one in the sealable area or cavity.

[0089] According to a preferred use of the frame, some further preferred embodiments provide that the frame is adapted to be insertable in its operative orientation into a device for aseptic mixing of two fluids, wherein the device comprises a pair of members for sealingly covering the first and second sealable areas and a member for applying pressure to the first and second flexible matrix containers when the first and second flexible matrix containers are fixed to or inserted into the first and second sealable areas. With regard to the device, which is part of the present invention and relates to one of the other aspects of the present invention, reference is made to the corresponding part described in detail below.

[0090] It should be understood by those skilled in the art that the present invention includes framework as above and the framework with the specific assembly in assembled state.In other words, in some embodiments, this framework keeps the first and second substrate containers, flexible waste container, flexible product container, static mixing device and the conduit for the outlet port of the first substrate container and the first inlet port of static mixing device, the outlet port of the second substrate container and the second inlet port of static mixing device and the outlet port of static mixing device and waste container and the inlet port fluid of product container are connected.In addition, in these embodiments, conduit can actually be assembled into the outlet port of the first substrate container and the first inlet port of static mixing device, the outlet port of the second substrate container and the second inlet port of static mixing device and the outlet port of static mixing device and waste container and the inlet port fluid of product container are connected.Therefore, for example, by filling flexible substrate container (unless pre-filled substrate container is assembled in framework) with the first and second substrates, the assembled framework can be used at any time.

[0091] In some preferred embodiments, the frame is adapted to be inserted into an apparatus for aseptically mixing two fluids as described above, wherein the pressure is applied by a pressurized gas contacting an outer surface of a first flexible matrix container and an outer surface of a second flexible matrix container, wherein the pressurized gas is provided to the surfaces via a first through hole provided in the first sealable region and a second through hole provided in the second sealable region. In other words, the apparatus is configured to pressurize the flexible matrix container from the outside via the through holes provided in the sealable region so as to drive the fluid out of the matrix container toward the static mixing device.

[0092] To this end, as described above, the rear side of the frame is preferably adapted to seal against the second counterpart by a circumferential gasket surrounding the first through hole and the second through hole, respectively. The circumferential gasket may be provided by the frame and arranged on its rear side, or the circumferential gasket may be provided by a surface of the second counterpart configured to contact the frame and arranged on this surface.

[0093] In some embodiments, the first and second mating parts can be connected or connected to each other in an articulated manner. In particular, if the framework has a vertical operating orientation, it can also include one or more members or structures configured to hold or detachably connect the framework to the predetermined position of the second mating part. For example, the framework can have two or more through holes, which are matched with corresponding hooks or projections arranged on the contact surface of the second mating part. In this way, a framework equipped with a flexible container, a static mixing device, a conduit and any other components as described above can be attached to the second mating part, and then the first mating part can be placed against the second mating part to close the framework. This will make the sealable area in the framework seal contact with the first mating part, and the back side of the framework will seal contact with the second mating part.

[0094] On the other hand, the present invention relates to a kit, which includes a frame as described herein. The kit also includes any one or a combination of the following components: (a) a first and / or second flexible matrix container; (b) a flexible waste container; (c) a flexible product container; (d) a static mixing device; and / or (e) one or more conduits for connecting the outlet port of the first matrix container to the first inlet port of the static mixing device, the outlet port of the second matrix container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet port of the flexible waste container and the flexible product container. According to one of the preferred embodiments, the kit includes all components (a) to (e) (including the first and second flexible matrix containers and all conduits for specific fluid connections). In a related embodiment, the kit also includes a component that can be used in combination with a conduit (such as a conduit for connecting the outlet port of the static mixing device to the inlet port of the flexible waste container and the flexible product container, respectively) or can be arranged in a conduit. For example, the kit may include any one or a combination of T-shaped and Y-shaped pieces, any one or a combination of valves, or any other component described herein that can be used to assemble the kit, operate the assembled frame or the assembled kit, or perform any method and process described herein.

[0095] In some preferred embodiments, the flexible substrate container, the flexible waste container and the flexible product container are containers as described above. In particular, the flexible product container may include at least one inlet port and / or at least one outlet port, to which the flexible tube fluid comprising a sterile disconnector is connected. In addition, the flexible tube fluidly connected to at least one outlet port of the product container may have a downstream end fluidly connected to a sampling tube, and the sampling tube may have a downstream end fluidly connected to a sterile filter.

[0096] In some embodiments, this kit is provided with vacant substrate container so that the user can fill the substrate container with interested fluid material.In some other embodiments, this kit is provided with the first and second containers filled (preferably filled with liquid substrate).If so, the liquid substrate (also referred to as the first substrate) contained in the first flexible substrate container is preferably different from the liquid substrate (also referred to as the second substrate) contained in the second flexible substrate container.Usually the selection of the first and second substrates forms a liquid product (such as a liquid pharmaceutical composition for injection purposes) when mixing in a static mixing device.As mentioned above, framework and the kit comprising framework are particularly useful for preparing aseptic liquid products in small batches using a simple standardized process of error proofing basically; This process depends on disposable components, and these disposable components do not need to be cleaned after preparing a batch of products.Therefore, based on the present invention, the preparation of aseptic injection products in small batches can be very efficient.

[0097] An example of a sterile product that can be prepared by mixing two liquid matrices is a pharmaceutical composition comprising a colloidal carrier of a lipid nanoparticle (LNP), liposome or similar active ingredient. For example, some modern mRNA-based vaccines are based on LNP, which can be prepared by mixing an organic solution of lipids and an aqueous solution of mRNA. Therefore, in some embodiments, a first flexible container is filled with a first matrix consisting of a preferably sterile organic solution of one or more lipids capable of forming LNP, and a second flexible container is filled with a second matrix consisting of a preferably sterile aqueous solution of mRNA (such as mRNA capable of expressing an antigen).

[0098] As mentioned above, the kit according to one aspect of the present invention may include some or all of the components required for assembling the frame so that it is ready for use. Kits representing a subset of any components configured to be used with the frame are also within the scope of the present invention. For example, the kit may consist only of empty or pre-filled first and second flexible substrate containers configured for the preparation of a specific product.

[0099] In some embodiments, the flexible product container is partially prefilled with a third matrix. This third matrix can be used as another component of the final product; for this component, it is desirable to add the component only after the mixing process (i.e., mixing the first matrix with the second matrix in a static mixing device). For example, the third matrix can be a diluent (such as a sterile aqueous diluent or a sterile aqueous buffer solution). For example, at a first pH, it is better and more efficient to form LNPs loaded with mRNA by mixing an organic lipid solution and an mRNA aqueous solution, and the long-term stability of the final product is higher at a second pH. In this case, it may be beneficial to partially prefill the flexible product container with a sterile aqueous buffer to buffer the final product at a second pH.

[0100] Likewise, the flexible product container may be provided in an empty form or partially pre-filled, and the flexible product container may be provided together with the frame and / or any other components required to assemble the frame so as to be ready for use.

[0101] The static mixing device (e.g., as part of a kit) configured to be used with the frame or the frame is suitable for holding can be selected from any static mixing device capable of aseptically mixing two liquids. In some embodiments, the static mixing device comprises or consists of a T-piece mixer, a Y-piece mixer, a vortex mixer, a baffle-based static mixer, a microfluidic mixing device, a multi-inlet vortex mixer, or a jet impact reactor. In some preferred embodiments, the static mixing device is a jet impact reactor.

[0102] Jet impact reactor is a fluid reactor for mixing fluids or producing particle fluids by collision. For example, jet impact reactor can be used to produce nanoparticle fluids of mixed water-poor active ingredients. The function of these reactors is based on the use of two fluid streams, at least one of which usually contains active ingredients, which are injected into the reactor chamber and collide in the turbulent mixing area to produce nanoparticles. One of the main principles associated with jet impact reactors used is solvent / non-solvent precipitation, in which the first fluid containing the active ingredient dissolved in a suitable solvent contacts with a non-solvent or anti-solvent under defined conditions, thereby causing the nanoparticles containing the active ingredient to precipitate. In the case where one of the solvents contains lipids, lipid nanoparticles can be produced by means of a jet impact reactor, which can, for example, be subsequently loaded with bioactive compounds (e.g., by pH changes).

[0103] The jet impact reactor comprises a reaction chamber with two fluid inlets having nozzles that allow two fluids to be injected into the reaction chamber at a pressure generally above ambient pressure. Through the first and second fluid inlets, two fluid streams are injected to meet in the reaction chamber and form a collision or mixing zone. An outlet is also provided for obtaining the resulting product.

[0104] An example of a jet impact reactor is the microfluidic reactor disclosed in EP 1165224 B1. This microfluidic reactor has at least two nozzles or pinholes positioned relative to each other, each nozzle or pinhole having an associated pump and feed line for directing liquid to a common collision point in a reaction chamber enclosed by a reactor shell. The reaction chamber includes two bores that intersect each other and produce a small cavity in which two fluids collide without possibly contacting the wall of the cavity. One of the bores accommodates two fluid inlets, while the second bore accommodates another opening in the reactor shell through which gas, evaporating liquid, cooling liquid or cooling gas can be introduced to maintain the gas atmosphere in the reaction chamber or for cooling. Another opening is provided at the other end of the second bore for discharging the resulting product and excess gas from the reactor. If solvent / non-solvent precipitation is performed in this microfluidic reactor, a dispersion of precipitated particles is obtained. The reactor is also suitable for using a third fluid that is an external gas or cooling liquid source.

[0105] WO 2018 / 234217 A1 discloses another jet impact reactor having a shell enclosing a reaction chamber and a first fluid nozzle and a second fluid nozzle oriented in a colinear manner. The second nozzle is positioned directly opposite the first fluid nozzle in the injection direction of the nozzle. The nozzles extend into the reaction chamber and form a collision area in the form of a disc between each other. This type of reactor has at least one flushing fluid inlet arranged on one side of the first fluid nozzle and at least one product outlet arranged on one side of the second fluid nozzle, and can be used for continuous preparation of particle fluid. In addition, the flushing fluid guiding structure is designed as parallel channels located on one side of the first fluid nozzle, which produce a flushing fluid flow guided along the injection direction of the first fluid nozzle, and guide the flushing fluid in the direction of the collision disc, thereby slightly deforming the collision disc. This allows the particles produced in the reactor to be transported out of the collision zone. Therefore, when a production process is performed in the reactor disclosed in WO 2018 / 234217 A1, the production process depends on the presence of the flushing fluid guiding structure and the flushing fluid.

[0106] In some preferred embodiments, the jet impact reactor used in the context of the present invention is a device described in WO 2023 / 025736A1, the entire disclosure of which is incorporated herein by reference. The jet impact reactor includes a reaction chamber defined by the inner surface of the reaction chamber wall, wherein the reaction chamber has a substantially spherical overall shape. The reaction chamber also includes a first and a second fluid inlet, wherein the first and second fluid inlets are arranged at relative positions of the first central axis of the reaction chamber so as to point to each other, and wherein each of the first and second fluid inlets includes a nozzle; and a fluid outlet, the fluid outlet is arranged at a third position, the third position is located on the second central axis of the chamber, and the second central axis is perpendicular to the first central axis. In addition, the distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or less than the diameter of the reaction chamber along the first central axis.

[0107] In some preferred embodiments, each nozzle has a downstream end substantially aligned with the inner surface of the chamber wall. In addition, the reaction chamber preferably has no other inlet or outlet openings. According to further preference, each of the first and second fluid inlets is provided by a fluid inlet connector having an upstream end, a downstream end of the nozzle holding the first or second fluid inlet, and a fluid conduit for guiding the fluid from the upstream end to the downstream end, wherein the downstream end of each fluid inlet connector is detachably inserted into the chamber wall to provide the first and second fluid inlets.

[0108] The reactor is used to mix two fluids by a method comprising the following steps: providing a jet impact reactor according to the present invention; guiding a first fluid flow into a reaction chamber through a first fluid inlet; and guiding a second fluid flow into the reaction chamber through a second fluid inlet so as to collide with the first fluid flow at an angle of approximately 180°.

[0109] Furthermore, in some preferred embodiments, the orifice of the first nozzle is larger than the orifice of the second nozzle, and / or the flow rate of the first fluid is larger than the flow rate of the second fluid, and wherein the pressures of the first fluid and the second fluid can be adjusted so that the first fluid flow and the second fluid flow have substantially the same kinetic energy when entering the reaction chamber.

[0110] The jet impact reactor described in patent application WO 2023 / 025736 A1 can be made by injection molding. For example, the jet impact reactor or at least the reactor wall can be made of a thermoplastic polymer by injection molding, wherein a prefabricated inlet nozzle consisting of a hard non-thermoplastic material (such as metal, glass or ceramic) is inserted into the mold during the injection molding process, or wherein mechanical or laser drilling is used to produce the nozzles on both sides of the reactor.

[0111] Another jet impact reactor that is particularly useful for practicing the present invention is the device described in co-pending patent application EP22195145.2, the entire disclosure of which is incorporated herein by reference. The jet impact reactor comprises a shell made of a polymer material, which encloses a reaction chamber, the reaction chamber having a substantially spherical shape, wherein the spherical shape is interrupted only by: at least a first and a second fluid inlet, wherein the first and second fluid inlets are arranged at relative positions on a first central axis of the reaction chamber so as to point to each other, and wherein each of the first and second fluid inlets is provided by a nozzle; and a fluid outlet arranged at a position located on a second central axis of the reaction chamber, the second central axis being perpendicular to the first central axis; the reactor also comprises first, second and third fluid conduits, wherein the first and second fluid conduits are arranged to guide a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and wherein the third fluid conduit is arranged to guide a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first and second fluids in the reaction chamber; wherein the shell consists of at least two mutually fixed parts, wherein the first part comprises at least the main part of the first or second fluid conduit, and the second part comprises at least one of the nozzles.

[0112] The jet impact reactor may also be prepared by a method comprising the steps of injection molding the first part and / or the second part of the housing.The jet impact reactor is described as being particularly useful in the aseptic manufacture of sterile liquid pharmaceutical compositions.

[0113] According to a further preferred embodiment, the kit comprises a jet impact reactor having a reaction chamber of substantially spherical shape; the spherical shape is interrupted by first and second fluid inlets and a fluid outlet, wherein the first and second fluid inlets are arranged at relative positions on a first central axis of the reaction chamber so as to point to each other, and wherein each of the first and second fluid inlets is provided by a nozzle; and the fluid outlet is arranged at a position located on a second central axis of the reaction chamber, the second central axis being perpendicular to the first central axis. The reactor further comprises first, second and third fluid conduits, wherein the first and second fluid conduits are arranged for guiding a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and wherein the third fluid conduit is arranged for guiding a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first and second fluids in the reaction chamber. Furthermore, the reactor comprises at least two parts fixed to each other, wherein the first part is made of a polymer material and comprises at least a part of the first or second fluid conduit and at least a hemispherical part of the reaction chamber; and the second part can be at least partially inserted into the first part and comprises a fluid outlet. Such a reactor is described in co-pending patent applications EP23163257.1 or PCT / EP2023 / 075054, the entire disclosure of which is incorporated herein by reference.

[0114] According to some further preferred embodiments, each kit component or part is sterile, or can be sterilized by heating, radiation or ethylene oxide. For example, the flexible container (i.e., the matrix container, the waste container and / or the product container) can be made of a material similar to an infusion bag or a mixing bag for injection, such as ethylene-vinyl acetate copolymer (EVA), which can be autoclaved or steam sterilized (e.g., sterilized in 121° C. steam for 15 minutes), gamma sterilized (e.g., at 25-40 kGy) or sterilized with ethylene oxide. Preferably, the static mixing device (even if made of a substantially polymerized material) and the conduit are also arranged in a sterilized form, or are sterilizable.

[0115] It should be noted that the present invention is particularly useful for performing an aseptic mixing process using only sterile raw materials and pre-sterilized containers and product contact equipment components. In this case, the final product does not have to be sterilized.

[0116] The kit may include any other features that have been described in the context of the frame. In particular, as the skilled person will appreciate, any preferences that have been disclosed in the context of the frame should also apply to the kit.

[0117] On the other hand, the present invention relates to a flexible container, which is suitable for use as a flexible substrate container, a flexible waste container or a flexible product container as described above. The container has an inner space for accommodating fluid materials, which is surrounded by a flexible front wall and a flexible rear wall, and each wall portion is made of a polymer material. In addition, the container also includes at least one inlet port or outlet port for realizing fluid communication with the inner space. The flexible front wall and the flexible rear wall are connected to each other, thereby forming a sealing edge that basically surrounds the inner space. The edge includes four corner areas so that the inner space has a square or rectangular overall shape when vacant. The container is also characterized in that at least two through holes are provided in the sealing edge, wherein the first through hole is arranged in or near the first corner area of ​​the edge, the second through hole is arranged in or near the second corner area of ​​the edge, and the second corner area is adjacent to the first corner area.

[0118] The flexible front wall and the flexible rear wall can be formed by two pieces of flexible polymer material of similar size and shape, which are fixed (e.g., welded) to each other to form a sealed (e.g., welded) edge that substantially surrounds the interior space. The two pieces of flexible polymer material can have a generally square or rectangular overall shape (i.e., having four corners), and when the interior space is empty, it also transforms into a generally square or rectangular overall shape of the interior space. In this case, the corner should be understood to include rounded corners. In some embodiments, the corners of the container and / or the interior space are rounded. In addition, in this case, the terms "substantially", "substantially" and "generally" should be understood as modifiers that allow small deviations. For example, the sealing edge can surround the entire interior space except where the inlet port or outlet port is located; and the overall shape of a square or rectangle may not represent a perfect square or rectangular shape. In addition, the expression "close to the first corner area" or "close to the second corner area" should be understood to refer to any one of the three dimensions of the container, compared to the distance from any central axis of the container, closer to the corresponding corner.

[0119] At least two through holes allow the container to be held or fixed thereto by a matching retaining member (such as a pin). As discussed above in the case of a sealable area (such as a cavity in a frame or a tray portion of a frame), these members for holding a flexible container can be arranged in the cavity. In addition to the fixing function, these members can also help prevent assembly errors because a specific spatial arrangement can be used for through holes and matching retaining members (e.g., pins) to match only the correct or specified container and only in its desired direction. In other words, the position of the first through hole and the second through hole matches the position of the corresponding retaining member (which is arranged to hold the flexible container) arranged in the sealable area or cavity of the frame or tray portion. In some preferred embodiments, each flexible container has at least three through holes. It is also preferred to have a container with four through holes.

[0120] In some embodiments, the flexible container comprises at least one inlet port and / or at least one outlet port.Preferably, the flexible pipe fluid is connected to the inlet port and / or the outlet port.The flexible pipe may include an aseptic disconnector.Alternatively, each inlet port and the outlet port of the flexible container include an aseptic disconnector.In this case, the aseptic disconnector refers to a transmission conduit or conduit segment (e.g., described in WO2010 / 008396) that is easily disconnected or another conduit with identical or similar functions.These embodiments are particularly advantageous as flexible product containers because they are convenient to discharge the product quickly after the mixing process while minimizing the risk of product microbial contamination.

[0121] In some further embodiments of the flexible container, the flexible tube fluidly connected to the at least one outlet port has a downstream end fluidly connected to a sampling tube, wherein the sampling tube has a downstream end fluidly connected to a sterile filter. Again, these embodiments are particularly advantageous as flexible product containers because they allow easy removal of samples from the product container without any risk of product contamination.

[0122] In addition, in some further embodiments, the flexible container includes an identification tag (such as an RFID tag). As described above, the identification tag (such as an RFID tag) can also be on the frame itself, on the static mixing device or on any other component of the kit as described above.

[0123] On the other hand, the present invention relates to the equipment for operating the framework in its assembled state.In some embodiments, this equipment is the equipment used as a filling station.More specifically, this equipment can be suitable for receiving the framework as above in its operating position, wherein the first and second flexible matrix containers are empty, and remain in the first and second sealable areas.This equipment also includes the member for aseptically filling the first and / or second matrix into the first and / or second flexible matrix container respectively.In these embodiments, framework is fully assembled, i.e. this framework keeps the first and second matrix containers, flexible waste container, flexible product container, static mixing device and the conduit for the outlet port of the first matrix container and the first inlet port of static mixing device, the outlet port of the second matrix container and the second inlet port of static mixing device and the outlet port of static mixing device and the inlet port fluid connection of waste container and product container.In addition, conduit is assembled to actually provide corresponding fluid connection.In some embodiments, as further described above, this equipment also includes the member for partially filling the flexible product container with the third matrix (such as diluent or aqueous buffer solution).

[0124] In some further preferred embodiments, this equipment is a device configured to be used as a mixing station. Specifically, this equipment can be suitable for receiving a frame in its operating position, wherein the frame is assembled and keeps the first and second substrate containers, a flexible waste container, a flexible product container, a static mixing device, and a conduit that the outlet port of the first substrate container is connected to the first inlet port of the static mixing device, the outlet port of the second substrate container is connected to the second inlet port of the static mixing device, and the outlet port of the static mixing device is connected to the inlet port fluid of the waste container and the product container. In these embodiments, the first and second flexible substrate containers are prefilled, that is, they are equipped with the first and second substrates respectively. In addition, the equipment also includes a member for driving the first and second substrates to flow into the static mixing device from the first and second flexible substrate containers to mix and form a liquid product. As those skilled in the art will understand based on the above disclosure, the liquid product can flow from the static mixing device to the flexible waste container and / or the flexible product container by a conduit, which, for example, depends on the setting of one or more valves in one or more conduits that can be arranged to connect the outlet port of the static mixing device to the waste container and the product container. In addition, in these embodiments, optionally, as described above, the product container can be partially filled with the third substrate.

[0125] The member for driving the first and second substrates to flow from the first and second flexible substrate containers into the static mixing device may include one or more pumps. In some preferred embodiments, the member is suitable for applying pressure to the first and second flexible substrate containers to extrude the substrate. According to a particularly preferred embodiment, the member for driving the substrate to flow from the first and second flexible substrate containers into the static mixing device includes a pressurized gas. An example of a pressurized gas is pressurized air. In other words, this preferred embodiment provides a kind of equipment, wherein pressure is applied by the pressurized gas of the outer surface of the contact first and second flexible substrate containers, and wherein the pressurized gas is provided to the surface by a first through hole arranged in the first sealable region and a second through hole arranged in the second sealable region.

[0126] In addition, this equipment can comprise the mating piece of framework, and this mating piece seals and covers the first and second sealable areas separately, and sealable areas keep the first and second substrate containers thus.Each sealable area and the corresponding lid provided by the first mating piece form a pressurized chamber together.As mentioned above, can be pressurized by pressurized gas chamber, and this pressurized gas can enter the chamber by the through hole that is arranged in the sealable area.Preferably, these chambers are sealed separately, promptly also seal relative to each other.

[0127] In some further preferred embodiments, as described above, the device further comprises a second mating piece. In addition, the first mating piece and the second mating piece can be hinged to each other.

[0128] In some preferred embodiments, pressurized gas is provided by pressure storage chamber.These pressure storage chambers are suitable for keeping the pressurized gas of specific volume, and if being communicated with the sealed chamber fluid that holds flexible substrate container, these pressure storage chambers can pressurize these sealed chambers immediately.As mentioned above, the chamber (also referred to as substrate chamber) that keeps substrate container should preferably be sealed separately.Therefore, it is also preferred that pressure storage chamber is separately set for each substrate chamber.Preferably, any pipeline leading to substrate chamber from pressure storage chamber should be as short as possible, and has sufficiently large diameter to realize rapid pressure balance.Also described in detail in patent application EP21206216.0 or WO 2023 / 079039 A1 in simultaneous application, utilize gas pressure to drive liquid substrate by static mixing device and utilize pressure storage chamber to provide this gas pressure, the full disclosure of this patent application is incorporated herein by reference.

[0129] In yet another aspect, the present invention relates to a method (especially for mixing two fluid matrices or reacting two fluid matrices), the method comprising using a frame, kit, flexible container or device as described above. In some preferred embodiments, the method is carried out under aseptic conditions (i.e., using a sterile matrix and pre-sterilized containers and product contact device components).

[0130] In a related aspect, the present invention also relates to a process for preparing an assembly frame or a process for preparing an assembly kit (as described herein in any one or a combination of their respective embodiments) for use in a method of mixing or reacting two fluid matrices, the process comprising at least the following steps:

[0131] a) filling the first and second flexible matrix containers with a first and a second liquid matrix, the first and second liquid matrix preferably being different;

[0132] b) optionally, filling the flexible product container with a third liquid (such as a buffer); and

[0133] c) removing residual gas or air from the first and second flexible substrate containers;

[0134] Optionally, any one or all of steps a) to c) are performed aseptically or under aseptic or clean room conditions.

[0135] In one embodiment, at least the step a) and optional step b) of filling the container are carried out under aseptic conditions. In some embodiments, the filling of the substrate container defined in step a) or the product container of optional step b) can be carried out by being connected to the inlet port of the container of the aseptic disconnector described herein.

[0136] Steps a) to c) are preferably performed on a fully assembled frame comprising all the component parts required to perform the mixing method (e.g., component parts of a kit or component parts provided by a kit). However, in an alternative embodiment, the process may include a first step of assembling the following onto the frame, preferably before step a) and optional step b) of filling the container, comprising at least:

[0137] - first and second flexible substrate containers;

[0138] - Flexible product containers;

[0139] - Flexible waste containers;

[0140] - static mixing device; and

[0141] one or more conduits, and optionally components disposed within the conduits (such as Y-pieces and / or T-pieces), for fluidly connecting, for example but not limited to, an outlet port of a first substrate container with a first inlet port of a static mixing device, an outlet port of a second substrate container with a second inlet port of the static mixing device, and an outlet port of the static mixing device with an inlet port of a flexible waste container and an inlet port of a flexible product container; or

[0142] Any component part of the kit provided herein.

[0143] In a related optional embodiment, a step of sterilizing the assembled kit may also be performed.

[0144] In one embodiment, the frame is prepared in its operating orientation according to the above process, ready for use. For example, any one or a combination of steps a) to c) may be performed when the frame is in its operating orientation, wherein the operating orientation is preferably a vertical operating orientation. In some embodiments, step c) is performed when the frame is arranged in an apparatus adapted to receive the assembled frame in its operating orientation. In one embodiment, the apparatus may be an apparatus configured to be used as a mixing station and for operating the frame in its assembled state.

[0145] In an alternative embodiment, the frame is prepared for steps a) to c) not in its vertical operating orientation but when the frame is at an inclined angle relative to a vertical axis. In some embodiments, any one or a combination of steps a), b) or c) (but preferably at least step c)) is performed when the frame is in an inclined position (where, for example, the top edge of the frame is positioned at an angle of at least 25°, 30°, 35°, 40° or 45° or at least between 25° and 45° to the vertical axis of its operating orientation).

[0146] As described above, the present invention also provides an apparatus for use as a filling station. In one embodiment, the apparatus may be adapted to receive a fully assembled frame and, instead of or in addition to maintaining the frame in, for example, its vertical operating orientation, may be adapted to maintain the frame in an angled position different from its operating orientation, for example, at an angle of between 25° and 45° from the vertical axis, as described above.

[0147] Step c) can be for example performed in the following manner: apply positive pressure or negative pressure (for example, vacuum) to remove any residual gas (for example, inert gas or air) in the flexible container. For example, once the framework has been oriented in its operating orientation or for performing step c) another preferred orientation (such as with angle as described above), residual gas can be removed by applying a certain amount and / or external pressure for a period of time that is enough to remove residual gas from the container on the outer surface of the flexible container. In one embodiment, removing residual gas from the first and second substrate containers is sequentially performed (that is, not performed simultaneously). In some embodiments, when flexible substrate bag is performed step d), clamping members (for example, pipe clamp) can be utilized to prevent liquid substrate from flowing to static mixer prematurely from another flexible substrate bag. Clamping members can also be used between the steps of the above-mentioned process or during any one step, to prevent fluid flow as required, such as during the transport of the assembled framework or during the assembly framework and / or during the removal of residual gas or air from the flexible substrate container.

[0148] In some embodiments, the residual gas is removed and collected in a flexible waste container. In other embodiments, depending on the configuration of the assembled frame, the residual gas is not removed to a flexible waste or product container, but is removed from the assembled frame to the exterior, for example, through a port configured within or as part of a conduit that is in fluid communication with an inlet port of the product container or waste container.

[0149] In some preferred embodiments, the method includes the use of a matrix that produces an aqueous pharmaceutical composition comprising colloidal particles (such as nanoparticles comprising an active ingredient) when mixed. For example, the nanoparticles may represent lipid nanoparticles (LNPs as described above) that carry an active ingredient, such as a nucleic acid (e.g., mRNA) that can express an antigen. In other words, the product obtained by mixing the first and second matrices may be a pharmaceutical composition representing a vaccine.

[0150] Other liquid compositions which can be prepared by mixing two liquid bases, preferably under sterile conditions, are generally known to those skilled in the art.

[0151] Furthermore, various optional or preferred features have been described above in the context of frames, kits, and components of kits; as will be appreciated by those skilled in the art, these features should also apply to the methods and processes provided by the present invention.

[0152] Detailed description with drawings

[0153] Figure 1A perspective view (not drawn to scale) of a frame (10) according to the present invention is shown in its operative orientation vertically and parallel to a vertical axis (100). The frame comprises a tray portion (15) which, in the embodiment shown, also forms an integral part of the frame. The frame simultaneously holds: (a) a first flexible substrate container (11) and a second flexible substrate container (12), each of which comprises an outlet port (91) and a sealed inlet port (92); (b) a flexible waste container (13) comprising an inlet port (93); (c) a flexible product container (14) comprising an inlet port (94) and a resealable outlet port (95); (d) a static mixing device (16) comprising a first inlet port (96), a second inlet port (97) and an outlet port (98); and (e) a plurality of flexible substrate containers (11) and a plurality of flexible substrate containers (12) each comprising an outlet port (91) and a sealed inlet port (92). ) a conduit (17a) for fluidly connecting the outlet port (91) of the first substrate container to the first inlet port (96) of the static mixing device, a conduit (17b) for fluidly connecting the outlet port (91) of the second substrate container (12) to the second inlet port (97) of the static mixing device (16), and conduits (17c, 17d) for fluidly connecting the outlet port (98) of the static mixing device (16) to the inlet ports (93, 94) of the product container (14) and the waste container (13), respectively. The frame (10) also includes a member (18) for retaining valves disposed in the conduits (17c, 17d).

[0154] The illustrated frame (10) includes cavities (211, 212, 224, 225) shaped to receive each container. The containers (11, 12, 13, 14) are each secured to their respective cavities by a plurality of container securing members (26). As illustrated in the present figure, the securing members (26) are disposed in up to four different locations (not all are shown, see also FIG. Figure 2 , Figure 3 and Figure 4 ), wherein the fixing points are located at the peripheral area or sealing edge of the container and are located at or near the four corners of the corresponding container. It should be understood by those skilled in the art that the number of fixing points or fixing members is not limited, but can vary depending on, for example, the type of member selected for fixing the container, the size of the container, and in some cases the operating orientation of the frame.

[0155] In the embodiment shown, the first cavity (211) is shaped to hold the first flexible substrate container (11), the sealed inlet port (92), the outlet port (91), the conduit (17a) connecting the outlet port (91) of the container with the first inlet port (96) of the static mixing device (16), and the inlet port (96) of the static mixing device. The second cavity (212) is shaped to hold the second flexible substrate container (12), the sealed inlet port (92), the outlet port (91), and the conduit (17b) connecting the outlet port (91) of the second substrate container (12) with the second inlet port (97) of the static mixing device (16), and at least partially holds the second inlet port (96) of the static mixing device (16) itself. The first cavity (211) and the second cavity (212) also each include a circumferential gasket (19) adapted and shaped to the respective cavity and used to form a seal to these cavities when a suitable counterpart or housing device is applied thereto. The cavity (224) for holding the flexible product container (14) is also shaped to accommodate at least a portion of the inlet port (94) of the container and at least a portion of the resealable outlet port (95). The cavity (225) for holding the flexible waste container (13) is also shaped to accommodate at least a portion of the inlet port (93) of the container (13).

[0156] As shown, the first and second flexible substrate containers (11, 12) and the static mixing device (16) held in the cavities (211, 212, 224, 225) in the tray portion (15) of the frame (10) are arranged in such a manner that fluid flows at least partially in a direction counter to gravity from the first and second flexible substrate containers (11, 12) to the static mixing device (16), and also flows at least partially in a direction counter to gravity from the static mixing device (16) to the waste container (13) or the product container (14). In addition, the first cavity (211), the second cavity (212) and the member for holding the static mixing device are arranged so that in the operating orientation of the frame (10), the positions of the outlet ports (91) of the two flexible substrate containers (11, 12) are lower relative to the positions of the corresponding inlet ports (96, 97) of the static mixing device (16).

[0157] Figure 2 Shows Figure 1 A front view of the frame (10) in its vertical operating orientation parallel to the vertical axis (100) (also not drawn to scale), including the frame (10) held as shown Figure 1 The assembled tray portion (15) of the components described. As shown, each cavity holding the first and second flexible substrate containers (11, 12) respectively includes a gasket (19) circumferentially surrounding the cavity.

[0158] Figure 3 Shows Figure 2 The same front view (not drawn to scale) of the frame (10) in its operating position parallel to the vertical axis (100), but without showing any of the first and second flexible substrate containers, the flexible waste container, the flexible product container, the static mixing device and the conduit.

[0159] Figure 4 Shows Figure 3 A perspective view of the frame (10) in its operative orientation (again not drawn to scale), but without showing any of the assembled first and second flexible substrate containers, flexible waste container, flexible product container, static mixing device and associated conduits.

[0160] Figure 3 and Figure 4 A frame (10) is shown including a tray portion (15), the tray portion comprising: a) a first cavity (211) shaped to hold a first flexible matrix container and its outlet port and inlet port, a conduit for fluidly connecting the outlet port of the container to the first inlet port of a static mixer, and a first inlet port of the static mixing device; b) a second cavity (212) for holding a second flexible matrix container and its outlet port and inlet port, a conduit for fluidly connecting the outlet port of the container to the second inlet port of the static mixer, and a second inlet port of the static mixing device; and c) a member (223) for holding the static mixing device, wherein the member (223) is in the form of a groove in the tray portion (15) which is suitable for accommodating at least a portion or a partial profile of the static mixing device.

[0161] like Figure 3 As shown in the embodiment of the present invention, each of the first and second cavities (211, 212) includes a gasket (19) surrounding the corresponding cavity, wherein a portion of the gasket of each corresponding cavity is configured to seal against a portion of the static mixing device and the corresponding inlet port.

[0162] In the illustrated embodiment, the cavities (211, 212, 224, 225) for holding the first and second flexible substrate containers, for holding the flexible product container, and for holding the flexible waste container each include a through hole (27) (i.e., an opening in the cavity) shaped to accommodate the respective container and its associated features. The through hole (27) of the first cavity (211) is shaped to accommodate the first flexible substrate container and at least a portion of its outlet port and inlet port, a conduit for fluidly connecting the outlet port of the container to the first inlet port of the static mixer, and the first inlet port of the static mixer. The through hole (27) of the second cavity (212) is shaped to accommodate at least a portion of the second flexible substrate container and its outlet port and inlet port, and a conduit for fluidly connecting the outlet port of the container to the second inlet port of the static mixer. The through holes (27) of the first and second cavities (211, 212) allow for separate pressurization of the gas in each of these cavities when the respective cavities are closed after the frame (10) and tray portion (15) are inserted into the respective housings of the apparatus described herein.

[0163] The cavity (224) for holding a flexible product container includes a through hole (27) shaped to accommodate at least a portion of the flexible container, at least a portion or all of the inlet port of the container, and a resealable outlet port. The cavity (225) for holding a flexible waste container includes a through hole (27) shaped to accommodate at least a portion of the flexible waste container and at least a portion or all of the inlet port of the container. When the tray and its assembly components are operated in a method (e.g., in a method of preparing nanoparticles described herein), the through holes (27) provided in these cavities can be used to accommodate the fill volume of the flexible product container and / or the flexible waste container.

[0164] like Figure 3 and Figure 4 As shown, a member (28) for holding a conduit is also provided; in the example shown, the member is a through hole formed in the tray portion (15) of the frame (10) to hold or accommodate a conduit downstream of the outlet port of the static mixing device. For example, the member (28) is suitable for holding a conduit directly upstream of the corresponding inlet ports of the flexible waste container and the flexible product container and for holding one or more conduits or conduit segments directly upstream of the outlet port of the static mixing device. As shown, the member (28) is adjacent to the cavity (224, 225) for holding the container (especially the corresponding through hole (27) of the cavity) and is also adjacent to the member (223) for holding the static mixing device (i.e., the groove (223)), wherein a portion of the member (28) is also adjacent to or passes through the member (18) for holding the valve.

[0165] Figure 3 and Figure 4 Also shown are fixing members (26) for holding the container. These fixing members may be, for example, but not limited to, protrusions or pins in the cavities (211, 212, 224, 225) and may be Figure 1 and Figure 2 The assembled frame shown has identical, matching or complementary components to those shown on the flexible container. As shown, each cavity (211, 212, 224, 225) includes at least four components (26) or points for securing the container to the cavity.

[0166] Figure 5 A perspective view (not drawn to scale) of another embodiment of a frame (50) according to the present invention is shown, having a horizontal operating orientation. In its horizontal operating orientation, the plane formed by the two longer dimensions of the frame is perpendicular to the vertical axis (100). The exemplary frame (50) includes a tray portion (55) which, in the illustration, forms substantially the entirety of the frame, the frame (50) simultaneously holding: (a) a first flexible substrate container (51) and a second flexible substrate container (52), each of which includes an outlet port (91) and a sealed inlet port (92); (b) a flexible waste container (53) including an inlet port (93); (c) a flexible product container (54) including an inlet port (94) and a resealable outlet port (95); (d) a static mixing device (16) including a first inlet port, a second inlet port, and an outlet port (98); (e) a conduit for fluidly connecting the outlet port (91) of the first substrate container (51) to the first inlet port of the static mixing device (16) and the outlet port (91) of the second substrate container (52) to the second inlet port of the static mixing device (16) (see further details). Figure 6 and (f) conduits (17c, 17d) for fluidly connecting the outlet port of the static mixing device (16) to the inlet ports (94, 93) of the product container (54) and the waste container (53), respectively.

[0167] The frame (50) shown includes cavities (551, 552, 524, 525, not all reference numerals are shown, see Figure 6 and Figure 7), these cavities are shaped to hold each container. In the illustrated embodiment, the first cavity (511) is shaped to hold the first flexible matrix container (51), at least a portion of the sealed inlet port (92), the outlet port (91), a conduit connecting the outlet port (91) of the container (51) with the first inlet port of the static mixing device (16), and the inlet port of the static mixing device (16) itself. The second cavity (552) is shaped to hold the second flexible matrix container (52), at least a portion of the sealed inlet port (92), the outlet port, a conduit connecting the outlet port of the second flexible container (52) with the second inlet port of the static mixing device (16), and the second inlet port of the static mixing device. The cavity (524) for holding the flexible product container (54) is also shaped to accommodate at least a portion of the inlet port (94) of the container and at least a portion of the resealable outlet port (95). The cavity (525) for holding the flexible waste container (53) is also shaped to accommodate at least a portion of the inlet port (93) of the container.

[0168] In this embodiment of the frame (50) according to the invention, the first and second flexible substrate containers (51, 52) and the static mixing device (16) are held in cavities (551, 552) in a tray portion (55) of the frame (50) in such a manner that in its horizontal operating orientation, fluid flows from the static mixing device (16) through its outlet port to the waste container or product container (54, 53) at least partially in a counter-gravity direction. Furthermore, the first cavity (551) and the second cavity (552) and the means for holding the static mixing device (16) are arranged on the tray portion (55) so that the outlet ports (91) of both flexible substrate containers have a lower position (with respect to the vertical axis (100)) relative to the position of the corresponding inlet ports (93, 94) of the flexible waste container (53) and the flexible product container (54).

[0169] Figure 6 yes Figure 5 A top view (ie, on a vertical axis (100)) of the same frame (50) as described in FIG. 1 . This view (also not drawn to scale) shows the circumferential gasket (19) in the first and second cavities (also see FIG. Figure 7 ). Each of these gaskets (19) is adapted and formed to fit within a corresponding cavity and serves to form a seal thereto when a suitable counterpart device is applied thereto.

[0170] As shown and indicated in the figure, the containers (51, 52, 53, 54) are each secured to their respective cavities by a plurality of means (26) for securing the containers. As exemplified in the present description, up to four means (26) for securing are provided, wherein the securing points are located in the peripheral region of the containers, on or near at least two corners of the sealed edge of the containers.

[0171] As further shown in the figure, the first flexible matrix container (51) and the second flexible matrix container (52) are respectively held by the arrangement of the first cavity and the second cavity on the tray portion (55) of the frame (50), so that the outlet port (91) of the first flexible matrix container (51) and the outlet port (91) of the second flexible matrix container (52) are coaxially opposed (see also Figure 7 In particular, the outlet port (91) of the first flexible substrate container (51) and the outlet port (91) of the second flexible substrate container (52) are coaxially opposed at an angle of approximately 45° relative to the longitudinal center axis (not shown) of the frame (50). The conduits 17a, 17b for fluidly connecting the outlet port (91) of the first substrate container (51) to the first inlet port (96) of the static mixing device (16) and for fluidly connecting the outlet port (91) of the second substrate container (52) to the second inlet port (97) of the static mixing device (16) are also substantially coaxially opposed.

[0172] Similarly, the flexible waste container (53) and the flexible product container (54) are each held by their respective cavities arranged on the tray portion (55) of the frame (50) such that the respective inlet ports (93, 94) of these containers are also coaxially opposed (see also Figure 7 According to the arrangement provided by the frame (50), at least a portion or a major portion (i.e., at least more than 50% of the longitudinal length) of the conduits (17c, 17d) for fluidly connecting the outlet port (98) of the static mixing device (16) to the flexible product container (54) and the flexible waste container (53), respectively, are also coaxially opposed.

[0173] Figure 7 Shows Figure 650 and its tray portion (55) as described in the above, but without showing any assembly components of the first and second flexible substrate containers, the flexible waste container, the flexible product container, the static mixing device and their associated conduits. A cavity (551) for holding the first flexible substrate container, a cavity (552) for holding the second flexible substrate container, a cavity (525) for holding the flexible waste container, and a cavity (524) for holding the flexible product container are shown. A member (523) for holding the static mixing device is also shown, wherein the member (523) is a groove in the tray portion (55) of the frame (50). The groove is adjacent to the first cavity (551) and the second cavity (552) and is suitable for holding the static mixing device so that the fluid can immediately flow out of the outlet port of the static mixing device in the direction against gravity. Each of the first and second cavities (551, 552) includes a gasket (19) surrounding the respective cavity, wherein a portion of the gasket of each respective cavity is arranged to seal against a portion of the static mixing device and its respective inlet port. Also shown is a member (28) for holding conduits, in particular conduits for fluidly connecting the outlet ports of the static mixing device to the flexible product container (54) and the flexible waste container (53), respectively, which member is also arranged in the form of a groove in the tray portion (55) of the frame (50).

[0174] Figure 8A perspective view (not drawn to scale) of another embodiment of a frame (80) according to the present invention is shown, having a horizontal operating orientation. In its horizontal operating orientation, the plane formed by the two longer dimensions of the frame (80) is perpendicular to the vertical axis (100). The exemplary frame (80) includes a tray portion (85) which, in the illustration, substantially forms the entirety of the frame (80), the frame simultaneously holding: (a) a first flexible substrate container (81) and a second flexible substrate container (82), each of which includes an outlet port (91) and a sealed inlet port (92); (b) a flexible waste container (83) including an inlet port (93); (c) a flexible product container (84) including an inlet port (94) and a resealable outlet port (95); (d) a first inlet port (96), a second inlet port (97), and an outlet port (98); (e) conduits (17a, 17b) for fluidly connecting the outlet port (91) of the first substrate container (81) to the first inlet port (96) of the static mixing device (16) and the outlet port (91) of the second substrate container (82) to the second inlet port (97) of the static mixing device (16), and conduits (17c, 17d) for fluidly connecting the outlet port (98) of the static mixing device (16) to the inlet ports (94, 93) of the flexible product container (84) and the flexible waste container (83), respectively. The frame also includes a member (18) for holding a valve.

[0175] The frame shown includes cavities (881, 882, 824, 825) shaped to accommodate each container. In the embodiment shown, the first cavity (881) is shaped to hold the first flexible matrix container (81), its sealed inlet port (92), the outlet port (91), the conduit (17a) connecting the outlet port of the first container to the first inlet port (96) of the static mixing device (16), and the inlet port (96) of the static mixing device (16). The second cavity (882) is shaped to hold the second flexible matrix container (82), its sealed inlet port (92), the outlet port (91), the conduit (17b) connecting the outlet port of the second flexible container (82) to the second inlet port (97) of the static mixing device (16), and the second inlet port (97) of the static mixing device (16). The first cavity (881) and the second cavity (882) also each include a circumferential gasket (19) adapted and shaped to the respective cavity and used to form a seal to the cavities when a suitable counterpart is applied thereto. The cavity (824) for holding the flexible product container (84) is also shaped to accommodate the container (84), at least a portion of the inlet port (94) of the container, and at least a portion of the resealable outlet port (95). The cavity (825) for holding the flexible waste container (83) is also shaped to accommodate at least a portion of the inlet port (93) of the container (83).

[0176] The containers (81, 82, 83, 84) are each fixed to their respective cavities by a plurality of members (26) for fixing the containers. As exemplified in the present figure, the members (26) for fixing are arranged at two locations on the peripheral area of ​​the container or the sealing edge of the container (not all are marked, see also Fig. 9 , Fig.10 and Fig.11 ).

[0177] In this illustrated embodiment of the frame (80) according to the invention, the first and second flexible substrate containers (81, 82) and the static mixing device (16) are held in the cavity of the tray portion (85) of the frame (80) in an arrangement such that in its horizontal operating orientation fluid flows at least partially in a counter-gravity direction from the static mixing device (16) through its outlet port (98) to the waste container or product container (83, 84).

[0178] Fig. 9 Shows Figure 81 . This view (also not drawn to scale) shows circumferential gaskets 19, which are each included in a first cavity (881) and a second cavity (882). Each of these gaskets (19) fits into a corresponding cavity and is used to form a seal on these cavities when a suitable counterpart is applied thereto.

[0179] As shown and indicated in the figure, the containers (81, 82, 83, 84) are each secured to their respective cavities by a plurality of means (26) for securing the containers. As exemplified in the present figure, each cavity is provided with two means (26) for securing, wherein the securing points are located in the peripheral region of the container and near the substrate container outlet (91) or the product container or waste container inlet (94, 93).

[0180] As further shown in the figure, the first flexible substrate container (81) and the second flexible substrate container (82) are respectively held by the arrangement of the first cavity (881) and the second cavity (882) on the tray portion (85) of the frame (80) so that the outlet port (91) of the first flexible substrate container (81) and the outlet port (91) of the second flexible substrate container (82) are coaxially opposed. The conduits for fluidly connecting the outlet port of the first substrate container (81) to the first inlet port (96) of the static mixing device (16) and for fluidly connecting the outlet port of the second substrate container (82) to the second inlet port (97) of the static mixing device (16) are also substantially coaxially opposed.

[0181] Fig.10 Shows Figure 8 The same perspective view (not drawn to scale) of the frame (80) in its horizontal operating position, wherein the plane formed by the two longest dimensions of the frame is perpendicular to the vertical axis (100), but without showing any of the first and second flexible substrate containers, the flexible waste container, the flexible product container, the static mixing device and the associated conduits.

[0182] Fig.11 Shows Fig. 9 80 (also not drawn to scale), but without showing any of the assembled first and second flexible substrate containers, flexible waste container, flexible product container, static mixing device and associated conduits.

[0183] exist Fig.10 and Fig.11An exemplary frame (80) is shown in the figure including a tray portion (85), the tray portion comprising: a) a first cavity (881) shaped to accommodate a first flexible matrix container and at least a portion of its outlet port and sealed inlet port, a conduit for fluidly connecting the outlet port of the container to the first inlet port of the static mixer, and the first inlet port of the static mixing device; b) a second cavity (882) for accommodating a second flexible matrix container, at least a portion of its outlet port and sealed inlet port, a conduit for fluidly connecting the outlet port of the container to the second inlet port of the static mixing device, and the second inlet port of the static mixing device; and c) a member (823) for retaining the static mixing device, wherein the member is a groove in the tray portion (85) which is suitable for accommodating at least a portion or a partial profile of the static mixing device and for retaining the device in an arrangement such that, in combination with the operating orientation of the frame (80), the fluid can immediately flow out of the outlet port of the mixing device, at least partially in a direction counter to gravity. In the unassembled state of the frame (80) (ie in the absence of the matrix container and the mixing device), the recess (823) is also in fluid communication with the first cavity (881) and with the second cavity (882).

[0184] like Fig.10 and Fig.11 As shown, the first and second cavities each include a gasket (19) surrounding the respective cavity, wherein a portion of the gasket of each respective cavity is arranged to seal against a portion of the static mixing device and against its respective inlet port.

[0185] like Fig.10 and Fig.11 As shown, a member (28) for holding or partially holding a conduit is also provided. The member (28) for holding a conduit for fluidly connecting the first and second containers to the inlet port of the static mixing device is provided as a recess in the tray portion (85). The member (28) adapted to at least partially hold a conduit located directly upstream of the inlet ports of the flexible waste container and the flexible product container, respectively, is also provided in the tray portion (85) in the form of a recess. The member (18) for holding a valve may further include a member for holding a conduit located downstream of the outlet port of the static mixing device.

[0186] Fig.10 and Fig.11 Also shown is a fixing member (26) for holding the container. Fig.10 As shown, the cavities (881, 882, 824, 825) include arrowhead or mushroom head shaped protrusions, barbed pins or plugs adapted to receive flexible containers having through holes positioned to mate with the protrusions (for reference, see Figure 8 and Fig. 9 (The frame is shown and the corresponding positions of the fixing members in the assembly with the flexible container).

[0187] The cavity (881) for holding the first flexible matrix container and the cavity (882) for holding the second flexible matrix container also include a gas pressure distribution member (29). When the cavity is closed by the counterpart device and the member for driving the liquid matrix from the first and second flexible matrix containers into the static mixing device is arranged in the form of a pressurized gas (e.g., pressurized air), the member can be used to evenly distribute the airflow through the cavity to the flexible container. The gas pressure distribution member (29) can be arranged as a series of vents, which are suitable for the shape of the cavity in which the flexible matrix container can be placed. In an alternative embodiment, the cavity (881, 882) includes a plurality of laterally arranged through holes (e.g., through holes in the form of slits or vents), which allow pressurized air to enter the cavity in a diffused manner.

[0188] Fig.12 A front view (not drawn to scale) of another example of a frame (120) according to the present invention is shown. The frame (120) is shown in its operational orientation, which is vertical and parallel to the vertical axis (100). The frame (120) includes a tray portion (125) that simultaneously holds a first flexible substrate container (121), a second flexible substrate container (122), and a static mixing device (16), each substrate container including an outlet port (91), and the static mixing device including a first inlet port (96), a second inlet port (97), and an outlet port (98). The frame (120) also simultaneously holds a flexible waste container (123) including an inlet port (93), a flexible product container (124) including an inlet port (94), conduits (17, 17c, 17d) for fluidly connecting the outlet port (98) of the static mixing device (16) to the inlet ports (94, 93) of the product container (124) and the waste container (123), and valves (20) arranged with the conduits (17, 17c, 17d) for directing fluid flow from the outlet port (98) of the static mixing device (16) to the inlet port (93) of the waste container (123) or to the inlet port (94) of the product container (124). Circumferential gaskets (19) are provided for each of the first and second cavities; these circumferential gaskets can be used to form a seal to these chambers when suitable counterparts are applied thereto.

[0189] As shown, the first and second flexible substrate containers (121, 122) and the static mixing device (16) are held in the cavity of the tray portion (125) of the frame (120) in an arrangement such that in its illustrated operational orientation, fluid flows at least partially in an anti-gravity direction from the outlet (98) of the static mixing device (16) to the waste container or product container (123, 124). In some embodiments, the frame (120) can be configured to be detachably secured to an apparatus such as defined herein (e.g., an apparatus for filling substrate containers). For its operational orientation, the frame (120) is also configured such that the outlet ports (91) of both flexible substrate containers have a lower position relative to the vertical axis (100) relative to the position of the corresponding inlet ports (93, 94) of the flexible waste container (53) and the flexible product container (54).

[0190] Fig.13 An example of a flexible container (1) according to any one of the embodiments or combinations of embodiments described herein is shown, the flexible container being used with a frame or a tray portion of a frame or a device, or being provided as part of a kit. The flexible container (1) can be used as a flexible substrate container, a flexible waste container or a flexible product container, and is adapted to be detachably retained in a corresponding cavity of the frame. The flexible container comprises at least one inlet port or outlet port (2), and in this embodiment comprises a sealable port (3), which can be sealed depending on the function of the container or its state of use (such as in the method of using the frame or device described herein).

[0191] In the embodiment shown, the flexible container comprises an interior space (4) for holding a fluid material, the interior space being surrounded by a flexible wall portion formed by a front wall and a rear wall made of a polymer material, wherein the flexible front wall and the flexible rear wall are connected to each other so as to form a sealing edge (7) substantially surrounding the interior space (4), wherein the edge (7) comprises four corner regions, wherein through holes (27) are arranged in or near a first corner region of the sealing edge (7) and in or near a second corner region of the sealing edge (7), and wherein the second corner region is adjacent to the first corner region. In the example currently shown, the flexible container comprises a through hole (27) in each corner region, which through holes are positioned to match the position of a corresponding fixing or retaining member arranged in a corresponding cavity in a frame or a tray portion of the frame according to the invention.

[0192] Fig.14 yes Fig.13 A perspective side view of a flexible container (1) in the drawings, showing an end of the container including ports (2, 3) which are fluidly connected to an interior space (4) for containing a fluid material, the space being formed by a flexible front wall (5) and a flexible rear wall (6), each wall portion being connected to form a continuous sealing edge (7).

[0193] Fig.15 A front view (not drawn to scale) of the front or user-facing side of another example of a frame (150) according to the present invention is shown. The frame (150) is shown in its operating orientation, which is vertical and parallel to the vertical axis (100). The figure also shows an example of a kit according to the present invention when the frame (150) is assembled and holds the flexible containers (11, 12, 14), the conduit (17) and the static mixing device (16). The frame (150) includes a first sealable area (231) and a second sealable area (232) for holding the first and second flexible matrix containers (11, 12). The sealable areas (231, 232) are defined by a circumferential gasket (19). The sealable areas (231, 232) are positioned adjacent to each other. Although not drawn to scale, it can be seen that the first sealable area (231) is larger than the second sealable area (232), and the size difference is reflected in the sealable areas (231, 232) having the same height, but the width of the first sealable area (231) is greater than the width of the second sealable area (232). Within the sealable areas (231, 232) of the frame (150), the first and second flexible substrate containers (11, 12) are held by a member (226) for fixing them in their designated positions. The member (226) can be connected to the corresponding through holes (see 228) in the peripheral area or sealing edge (227) of the corresponding flexible container. Each substrate container (11, 12) has three ports, including an outlet port (91) and a sealed inlet port (92). The outlet port (91) is fluidly connected to a static mixing device (16) through a conduit (17), and the static mixing device is held in place by a member (223) for holding the static mixing device. Furthermore, an outlet port (91) is provided at the top of the substrate container (11, 12) so that the fluid substrate or liquid (not shown) held therein will flow out of the substrate container (11, 12) in a direction counter to gravity in order to flow towards the static mixing device (16). Also shown is a flexible product container (14), which is provided at the front side and towards the top of the frame (150) and is held by three fixing members (226) whose positions correspond to the three through holes (228) provided in the peripheral area of ​​the product container (14). It should be noted that the flexible waste container is not visible because it is fixed to the rear side of the frame (see Fig.16). The product container (14) has three ports arranged on its bottom side (in its operating orientation), including an inlet port (94) for receiving a third fluid from a static mixing device (16) through a conduit (17) and two outlet ports (95). One of the outlet ports (95) is fluidically connected to a sampling tube (241) via a flexible tube, the downstream end of which is fluidically connected to a sterile filter (242); a pinch valve (246) and a sterile disconnector (247) are provided upstream of the sampling tube (241) to facilitate the removal of product samples. Another outlet port (95) is fluidically connected to a sterile connector (245) via a flexible tube. Another sterile filter (249) is also shown, which is fluidically connected to the inlet port of the product container via a Y-piece (248). This arrangement can be used to add a diluent to the product container (14) before, during or after the mixing process to dilute or change the composition of the third fluid received from the static mixing device (16). Another advantageous use is to inject just enough diluent or sterile air as needed to push any remaining (third) fluid present in the conduit (17) between the Y-piece (248) and the inlet port (94) into the product container (14) in order to maximize the yield of the mixing process. The frame (150) also includes four through holes (251) located in the central area, which enable it to be fixed to equipment used to operate the frame (150) or the kit.

[0194] Fig.16 Shows Fig.15 A front view of the rear side of the same frame (150) or kit shown (also shown in its vertical operative orientation parallel to the vertical axis (100)). Here, the flexible waste container (13) fixed to the rear side of the frame can be seen. In the operative orientation, the bottom side of the waste container (13) has three ports, including an inlet port (93) which is fluidly connected to a valve (20) via a conduit (17), which is a one-way stopcock. The valve (20) is arranged downstream of a T-piece (21) through which a third fluid is received from a static mixing device. The T-piece (21), whose inlet is fluidly connected to the static mixing device, has a second outlet, downstream of which is another valve (20), which is also a one-way stopcock, which is arranged to be fluidly connected to a Y-piece (248), which is fluidly connected to a sterile filter (249) and is fluidly connected to a flexible product container fixed to the front side of the frame (150) (see Fig.15 In addition, a circumferential gasket (19) surrounding the through hole (27) is also provided on the rear side of the frame (150), similar to the front side (such as Fig.15 shown).

[0195] Fig.17 Shows Fig.15A front elevational view of the front side of the frame (150) shown in its vertical (parallel to the vertical axis (100)) operative orientation is shown, except that a flexible container, conduit, static mixing device, or any other component (such as a T- or Y-piece, valve, or filter) that defines a flow path for any of the first, second, or third liquids is absent. In other words, it is an illustration of an exemplary frame (150) prior to assembly into a kit according to some embodiments disclosed herein. Highlighted are the through holes (27) in the first and second sealable regions (231, 232); in an operative state, pressurized gas can be supplied through these through holes to apply pressure to the outer surfaces of the first and second flexible matrix bags. Also shown are recesses (243, 244) for holding a sampling tube and its associated sterile filter and sterile connector, respectively. The frame (150) also includes a member (233) for fixing the frame to an external retaining member (such as a hook) to, for example, assist a user in correctly positioning the frame (150) to any corresponding retaining member, which may be provided, for example, by a device for filling a flexible matrix container when the flexible matrix container is fixed to the frame (150) or by a device for operating a fully assembled frame (150) or kit. A grip or handle (234) is provided so that a user can easily hold and position the frame (150). Various small openings or through holes (235) are shown, which retain conduits or allow conduits to connect to the front and rear sides of the frame (150). In the sealable region (231, 232), a member (253) is provided for fixing or retaining at least one conduit to the frame or more specifically for retaining the conduit within the sealable region. The one or more conduits may be, for example, associated with a container inlet port (e.g., a curled tube end), and in some embodiments the member (253) may be a hook.

[0196] Fig.18 Shows Fig.17 100) is a front view of the rear side of the frame (150) shown in its operative orientation parallel to the vertical axis (100). As shown, a fixing or fastening member (26) for a flexible waste container is provided on the rear side of the frame (150). In addition, as shown in FIG. Fig.16 As depicted, two members (252) are provided for securing or holding the valve (20). Members for securing the conduit (253) to the frame are also shown.

[0197] Fig.19 Shows Fig.15 A perspective view of the front side of the frame (150) is shown. Here it can be seen how the circumferential gasket (19) surrounding the first and second sealable areas (231, 232) of the frame (150) in this embodiment is arranged on a circumferential border (22) extending from the frame (150).

[0198] Fig. 20 Shows Fig.19 A perspective view of the rear side of the frame (150) is shown. As shown, in this embodiment, the rear side of the frame (150) also has a circumferential gasket (19) disposed on the circumferential border (22).

[0199] Fig.21 Shows Fig.16 A detailed front view of a portion of the rear side of the frame (150) is shown. The two outlets of the T-piece (21) arranged downstream of the static mixing device (16) and in a higher position relative to the static mixing device (16) are connected to valves (20) (such as non-return stopcocks) capable of opening and closing the flow paths leading to the product container and the waste container (13). The valve (20) has a member (23) for mechanically operating the valve (20), which is oriented in a direction corresponding to the rear side of the frame (150) and is suitable for operation from this direction. This configuration allows the valve (20) to be operated by an automatic operating device arranged at the rear of the frame (150), that is, when viewed from the front side, for example when the frame (150) or the kit is inserted into a device suitable for operating the frame (150) or the kit.

[0200] Fig. 22 is a perspective view of an exemplary static mixing device (162) that can be used with, for example, Fig.15 and Fig.16 The frame (150) or kit shown is used in combination. According to some preferred embodiments, the static mixing device (162) can represent a jet impact reactor. The mixing device (162) shown includes a main housing (30) having an outlet port (31) and first and second inlet ports (32, 33). In this case, the static mixing device (162) is shown in its operating orientation, wherein the outlet port (31) points upward so that the third fluid flowing out of the outlet port (31) will flow in the anti-gravity direction. The first and second inlet connectors (34, 35) are respectively assembled in the first and second inlet ports (32, 33). The barb connector (36) is arranged at the upstream end of the inlet port (32, 33) and the downstream end of the outlet port (31).

[0201] Fig.23 yes Fig. 22 A perspective view of an exemplary static mixing device (162) is shown. Here, the main housing (30) having an outlet port (31) and first and second inlet ports (32, 33) is shown without the first and second inlet connections.

[0202] Fig.241 is a perspective view (not drawn to scale) of the front or user-facing side of another example of a frame (240) according to the present invention. Any other components (such as T-shaped or Y-shaped pieces, valves or filters) that define the flow path of any of the first, second or third liquids described herein are not shown in this illustration. In other words, it is an illustration of an exemplary frame (240) before being assembled into a kit according to some embodiments disclosed herein. The frame (240) is shown in its operating orientation, which is vertical and parallel to the vertical axis (100). The frame (240) includes a first sealable area (231) and a second sealable area (232) for holding the first and second flexible matrix containers (not shown). The sealable areas (231, 232) are defined by circumferential gaskets (19), which are provided by circumferential frames (22) extending from the frame. The sealable areas (231, 232) are positioned adjacent to each other. Although not drawn to scale, it can be seen that the first sealable area (231) is larger than the second sealable area (232), and the difference in size is reflected in the sealable areas (231, 232) having the same height, but the width of the first sealable area (231) is greater than the width of the second sealable area (232). In this embodiment, the shape of the first sealable area (231) is symmetrical about the vertical axis, as is the second sealable area (232). Also shown are through holes (27) in the first and second sealable areas (231, 232); in an operating state, pressurized gas can be supplied through these through holes to apply pressure to the outer surfaces of the first and second flexible matrix bags. Also shown in the first and second sealable areas are means (226) for fixing the flexible matrix container.

[0203] Also shown are recesses (243, 244) for holding the sampling tube and the sterile filter and sterile connector associated therewith, respectively. The frame (240) also includes a member (233) for fixing the frame to an external retaining member (such as a hook or recess) to, for example, assist a user in correctly positioning the frame (240) to any corresponding retaining member, which retaining member can be provided, for example, by a device for filling a flexible matrix container when the flexible matrix container is fixed to the frame (240) or a device for operating a fully assembled frame (240) or kit. A grip or handle (234) is also provided so that a user can easily hold and position the frame (240). For example, in the embodiment currently described, a member (226) for fixing a product container to the frame (240) is also provided in the upper region of the frame. Various small openings or through holes (235) are also shown for holding a conduit or allowing a conduit to connect to the front and rear sides of the frame (240). Within the sealable regions (231, 232) of the frame, there are provided means (253) for fixing or retaining conduits within the sealable regions on the frame. Specifically, one or more conduits associated with a container inlet (e.g., a curled tube end) can be retained and accommodated within the sealable regions of the frame by such means (e.g., a hook). The frame (240) also includes four through holes (251) in the central region, which enable it to be fixed to equipment used to operate the frame (240) or the kit.

[0204] Fig.25 Shows Fig.24 A perspective view of the rear side of the frame (240) shown (in its vertical operating orientation parallel to the vertical axis (100)). As shown, a fixing or fastening member (26) for a flexible waste container is provided on the rear side of the frame (240). The sealable areas (231, 232) with respect to the rear side of the frame (240) are also defined by circumferential gaskets (19) provided by a circumferential border (22) extending from the frame. The circumferential gaskets (19) provided for the rear side of the frame (240) can advantageously have gaskets (19) that are aligned with the borders of the corresponding sealable areas on the front side of the frame (see Fig.24 ) of the same shape and size. Also shown are two valves (such as Fig.16 and Fig.21 A member (252) is shown for securing the catheter to the frame (240). A member (253) is also shown for securing the catheter to the frame (240).

[0205] Reference numerals list

[0206] 1 Flexible container

[0207] 2 inlet ports / outlet ports

[0208] 3 sealable ports

[0209] 4Internal volume

[0210] 5 Flexible front wall

[0211] 6 Flexible back wall

[0212] 7. Seal the edges

[0213] 10, 50, 80, 120, 150, 240 frame

[0214] 11, 51, 81, 121 first flexible matrix container

[0215] 12, 52, 82, 122 second flexible matrix container

[0216] 13, 53, 83, 123 Flexible waste containers

[0217] 14, 54, 84, 124 Flexible product containers

[0218] 15, 55, 85, 125 pallet parts

[0219] 16.162 Static mixing device

[0220] 17, 17a, 17b, 17c, 17d catheter

[0221] 18Components for holding valves

[0222] 19 Circumferential washer

[0223] 20 Valves

[0224] 21T-shaped piece

[0225] 22 Circumferential border

[0226] 23Components for operating valves

[0227] 26Fixing or fastening components

[0228] 27 Through hole (e.g., located in a sealable area or cavity)

[0229] 28Members for holding pipes

[0230] 29 Gas pressure distribution component

[0231] 30 Main housing of static mixer

[0232] 31 Outlet port of static mixer

[0233] 32 First inlet port of static mixing device

[0234] 33 Second inlet port of static mixing device

[0235] 34 First inlet connection piece

[0236] 35 Second inlet connection

[0237] 36 Barb Connector

[0238] 91 first or second flexible matrix container outlet port

[0239] 92 First or second flexible matrix container sealed inlet port

[0240] 93 Flexible Waste Container Inlet Port

[0241] 94 Flexible Product Container Inlet Port

[0242] 95 Flexible product container with resealable outlet port

[0243] 96 static mixer first inlet port

[0244] 97 Second inlet port of static mixer

[0245] 98 static mixer outlet port

[0246] 100 vertical axis

[0247] 211, 551, 881 a first cavity for holding a first flexible substrate container

[0248] 212, 552, 882 a second cavity for holding a second flexible substrate container

[0249] 223, 523, 823 for maintaining a static mixing device

[0250] 224, 524, 824 Cavity for flexible product containers

[0251] 225, 525, 825 Cavity for flexible waste containers

[0252] 226 Members for fixing flexible substrate containers, flexible product containers or flexible waste containers

[0253] 227 Sealing edges of flexible substrate containers, flexible product containers or flexible waste containers

[0254] 228 Through hole in the peripheral area of ​​the flexible container

[0255] 231 A first sealable region for holding a first flexible substrate container

[0256] 232 A second sealable region for holding a second flexible substrate container

[0257] 233Member for securing the frame to the external retaining member

[0258] 234 handles

[0259] 235 through hole

[0260] 241 Sampling Tube

[0261] 242 Sterile Filter

[0262] 243 Recess for holding sampling tube and sterile filter

[0263] 244 Recess for holding sterile connector

[0264] 245 Sterile Connector

[0265] 246 Pinch Valve

[0266] 247 Aseptic Disconnector

[0267] 248Y-shaped parts

[0268] 249 Sterile Filter

[0269] 251Through holes for matching hooks to hold the frame in place

[0270] 252Components for fixing valves

[0271] 253Members for holding or fixing a conduit to a frame

[0272] The following numbered list of items are further embodiments included in the present invention:

[0273] 1. A framework for simultaneously maintaining: (a) first and second flexible substrate containers, each comprising an outlet port; (b) a flexible waste container comprising an inlet port; (c) a flexible product container comprising an inlet port: (d) a static mixing device comprising at least first and second inlet ports and an outlet port; and (e) conduits for fluidly connecting the outlet port of the first substrate container with the first inlet port of the static mixing device, the outlet port of the second substrate container with the second inlet port of the static mixing device, and the outlet port of the static mixing device with the inlet ports of the waste container and the product container; The frame includes a tray portion, the tray portion includes - a first cavity for holding a first flexible substrate container, - a second cavity for holding a second flexible substrate container, and - means for holding a static mixing device; Wherein the frame has an operational orientation, and wherein the first and second cavities and the means for holding the static mixing device are arranged such that in the operational orientation a flow of fluid from the first and second substrate containers to the static mixing device and / or from the static mixing device to the waste container or the product container occurs at least partially in a direction counter to gravity.

[0274] 2. A frame according to item 1, wherein the tray portion includes another cavity for a flexible product container and another cavity for holding a flexible waste container.

[0275] 3. A frame according to item 1 or 2, wherein each of the first and second cavities includes one or more members for securing the corresponding flexible substrate container, the members optionally being shaped as protrusions or pins for receiving the flexible substrate container having through holes, the through holes being positioned to match the pins or protrusions, and wherein the pins are optionally barbed pins or locking pins.

[0276] 4. A framework according to any of the above items, further comprising an identification tag, such as an RFID tag.

[0277] 5. A frame according to any one of the above items, wherein the component for holding the static mixing device is suitable for holding the static mixing device only when the static mixing device has a desired orientation, wherein when the static mixing device has its desired orientation and the frame is in its operating orientation, the liquid optionally flows out of the static mixing device through the outlet port of the static mixing device in the direction against gravity.

[0278] 6. A frame according to any of the preceding items, wherein the first and second cavities and the means for holding the static mixing device are arranged such that in the operational orientation of the frame the outlet port of the flexible matrix container is positioned lower relative to the position of the corresponding inlet port of the static mixing device.

[0279] 7. A frame according to any of the preceding items, wherein the tray portion comprises - a first through hole arranged in the first cavity and a second through hole arranged in the second cavity, and / or - A circumferential gasket for each of the first and second cavities.

[0280] 8. A frame according to any of the above items, wherein the first cavity is shaped to at least partially accommodate a conduit for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device; or wherein the second cavity is shaped to at least partially accommodate a conduit for fluidly connecting the outlet port of the second substrate container to the second inlet port of the static mixing device.

[0281] 9. A frame according to any of the preceding items, wherein the frame is adapted to be insertable in its operative orientation into a device for aseptically mixing two fluids, wherein the device comprises - a counterpart for sealingly covering the first and second cavities; and - means for applying pressure to the first and second flexible matrix containers when inserted into the first and second cavities; And wherein the frame optionally holds first and second substrate containers, a flexible waste container, a flexible product container, a static mixing device, and conduits for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device, the outlet port of the second substrate container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet ports of the waste container and the product container.

[0282] 10. A kit comprising a frame according to any one of items 1 to 9 and: (a) first and second flexible substrate containers; (b) Flexible waste containers; (c) Flexible product containers; (d) a static mixing device; and (e) a conduit for fluidly connecting an outlet port of the first substrate container with a first inlet port of the static mixing device, an outlet port of the second substrate container with a second inlet port of the static mixing device, and an outlet port of the static mixing device with inlet ports of the flexible waste container and the flexible product container; and wherein optionally each of the first and second flexible substrate containers is filled with a liquid substrate.

[0283] 11. The kit according to item 10, wherein the static mixing device comprises a T-piece mixer, a Y-piece mixer, a vortex mixer, a baffle-based static mixer, a microfluidic mixing device, a multi-inlet vortex mixer (MIVM), or a jet impact reactor, and wherein the jet impact reactor optionally comprises: - a reaction chamber defined by the inner surface of a reaction chamber wall, the reaction chamber having a substantially spherical overall shape, said chamber comprising: (a) first and second fluid inlets, wherein the first and second fluid inlets are disposed at opposite positions on a first central axis (x) of the reaction chamber so as to point toward each other, and wherein each of the first and second fluid inlets comprises a nozzle; and (b) a fluid outlet, disposed at a third position, wherein the third position is located on a second central axis of the reaction chamber, the second central axis being perpendicular to the first central axis; The distance (d) between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or smaller than the diameter of the reaction chamber along the first central axis.

[0284] 12. A flexible container for use as a flexible substrate container, a flexible waste container or a flexible product container according to any one of the above items, having: an interior space for holding a fluid material, the interior space being surrounded by a flexible front wall and a flexible rear wall, each wall portion being made of a polymer material; and at least one inlet port or an outlet port for enabling fluid communication with the interior space; wherein the flexible front wall and the flexible rear wall are connected to each other to form a sealed edge substantially surrounding the interior space; wherein the edge includes four corner regions so that the interior space has an overall shape of a square or rectangle when empty; and wherein a first through hole is arranged in or near a first corner region of the sealing edge, and a second through hole is arranged in or near a second corner region of the sealing edge; wherein the second corner region is adjacent to the first corner region.

[0285] 13. An apparatus comprising: a housing adapted to receive the frame according to item 9 in its operative orientation, wherein the first and second flexible matrix containers are empty; and means for aseptically filling the first and second matrices into the first and second flexible matrix containers.

[0286] 14. An apparatus comprising: a housing adapted to receive a frame according to item 9 in its operative orientation, wherein first and second flexible substrate containers contain first and second substrates; and means for driving the substrates from the first and second flexible substrate containers into a static mixing device for mixing to form a liquid product, wherein the means optionally comprises a pressurized gas.

[0287] 15. A method for mixing two fluid matrices, the method comprising using a frame according to any one of items 1 to 9, a kit according to item 10 or 11, a flexible container according to item 12, or a device according to item 13 or 14.

Claims

1. A framework suitable for simultaneously maintaining: (a) first and second flexible substrate containers, each comprising an outlet port; (b) a flexible waste container comprising an inlet port; (c) a flexible product container comprising an inlet port; (d) a static mixing device comprising at least first and second inlet ports and an outlet port; as well as (e) conduits for fluidly connecting the outlet port of the first substrate container with the first inlet port of the static mixing device, the outlet port of the second substrate container with the second inlet port of the static mixing device, and the outlet port of the static mixing device with the inlet ports of the waste container and the product container; The framework includes: - a first sealable area for retaining said first flexible substrate container; - a second sealable region for retaining said second flexible substrate container; and - means for holding the static mixing device; wherein the frame has an operational orientation; and wherein the first and second sealable regions and the means for retaining the static mixing device are arranged such that in the operational orientation a flow of fluid from the first and second flexible matrix containers to the static mixing device and / or from the static mixing device to the waste container or the product container occurs at least partially in a direction counter to gravity.

2. The frame according to claim 1, wherein the first and / or second sealable area is formed as a cavity.

3. A frame according to claim 1 or 2, wherein the first and / or second sealable area is defined by a peripheral border extending from the frame.

4. The frame of claim 3, wherein the peripheral border is configured to receive in a sealing manner a counterpart having a cavity for accommodating a corresponding flexible substrate container.

5. The frame of claim 2, wherein the frame comprises a tray portion, and wherein the tray portion comprises a first cavity for holding the first flexible substrate container, a second cavity for holding the second flexible substrate container, and optionally a member for holding the static mixing device.

6. A frame according to any one of the preceding claims, wherein the conduits are non-microfluidic conduits.

7. A frame according to any one of the preceding claims, wherein the conduits are flexible and detachably connectable with their ports adapted for fluid connection.

8. The frame of any of the above claims, wherein the static mixer is adapted to mix fluids at a total flow rate of about 10 mL / min to about 1000 mL / min.

9. The frame of any one of the preceding claims, wherein each of the first and second sealable regions is shaped and dimensioned to hold a flexible matrix container having an interior volume in the range of 50 mL to 1500 mL.

10. The frame of any one of the preceding claims, wherein the interior volume of the first flexible substrate container is 1.5 to 4 times greater than the interior volume of the second flexible substrate container.

11. A frame according to any one of the preceding claims, wherein the first and second sealable regions are substantially similar or identical in height and substantially different in width.

12. A frame according to any one of the preceding claims, wherein the frame comprises means for securing the flexible produce container and / or means for securing the flexible waste container.

13. A frame according to claim 12, wherein the frame has a front side facing the user when in its operating position and a rear side opposite the front side, wherein the means for securing the flexible product container is arranged on the front side of the frame, and the means for securing the flexible waste container is arranged on the front side or the rear side of the frame.

14. A frame as claimed in any preceding claim adapted for a vertical operating orientation.

15. A frame according to any one of the preceding claims, wherein each of the first and second sealable regions comprises one or more means for securing a respective flexible substrate container.

16. The frame of claim 15, wherein the one or more members for securing the flexible substrate container are disposed on a front side of the frame.

17. A frame according to claim 15 or 16, wherein the member is optionally shaped as one or more hooks, protrusions or pins, the hooks, protrusions or pins being arranged to receive a flexible substrate container having a through hole, the through hole being positioned to mate with the hooks, pins or protrusions.

18. The frame of claim 17, wherein the pin is optionally a barbed pin or a snap-lock pin.

19. A frame according to any of the above claims, wherein the first sealable area and the second sealable area are positioned adjacent to each other, and wherein a minimum distance between the first sealable area and the second sealable area is less than 10% of a width of the first sealable area.

20. The frame of any one of the preceding claims, wherein the interior volume of the flexible product container is in the range of 100 mL to 2000 mL.

21. A frame according to any preceding claim, further comprising an identification tag, such as an RFID tag.

22. A frame according to any one of the preceding claims, wherein the means for retaining the static mixing device is adapted to retain the static mixing device only when the static mixing device has a desired orientation.

23. A frame according to any one of the preceding claims, wherein when the static mixing device has its desired orientation and the frame is in its operational orientation, liquid flows out of the static mixing device through its outlet port in a direction counter to gravity.

24. A frame according to any one of the preceding claims, wherein the first and second sealable regions and the means for retaining the static mixing device are arranged such that in an operational orientation of the frame the outlet port of the flexible matrix container is positioned lower relative to the position of a corresponding inlet port of the static mixing device.

25. A frame according to any one of the preceding claims, wherein the frame or tray portion thereof comprises a first through hole provided in the first sealable region and a second through hole provided in the second sealable region.

26. A frame according to any preceding claim, wherein the frame or tray portion thereof comprises a circumferential gasket for each of the first and second sealable regions.

27. A frame according to any of the above claims, wherein the first sealable area is shaped to at least partially accommodate the conduit for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device, or wherein the second sealable area is shaped to at least partially accommodate the conduit for fluidly connecting the outlet port of the second substrate container to the second inlet port of the static mixing device.

28. The frame according to any one of the above claims is further suitable for holding a Y-shaped piece or a T-shaped piece, wherein the Y-shaped piece or the T-shaped piece is arranged in the conduit that fluidly connects the outlet port of the static mixing device with the inlet ports of the waste container and the product container, so that the inlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the outlet port of the static mixing device, the first outlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the inlet port of the waste container, and the second outlet of the Y-shaped piece or the T-shaped piece is fluidly connected to the inlet port of the product container.

29. A frame according to claim 28, wherein a one-way stopcock is arranged in the conduit portion fluidly connecting the first outlet of the Y-shaped or T-shaped piece with the inlet port of the waste container and / or in the conduit portion fluidly connecting the second outlet of the Y-shaped or T-shaped piece with the inlet port of the product container.

30. The frame of claim 29, wherein the one-way stopcock includes a member for mechanically operating the valve, wherein the member is toward or adapted to be operated from a rear side of the frame.

31. A frame according to any one of claims 28 to 30, wherein a check valve is provided in the conduit fluidly connecting the first outlet of the Y-piece or T-piece with the inlet port of the waste container, wherein the check valve is optionally located downstream of the one-way stopcock.

32. A frame according to any one of the preceding claims, wherein the frame is adapted to be insertable in its operative orientation into a device for aseptically mixing two fluids, wherein the device comprises - a first counterpart for sealingly covering said first and second sealable areas; and - means for applying pressure to said first and second flexible substrate containers when secured or inserted into said first and second sealable regions; and wherein the frame optionally holds the first and second substrate containers, the flexible waste container, the flexible product container, the static mixing device, and the conduits for fluidly connecting the outlet port of the first substrate container to the first inlet port of the static mixing device, the outlet port of the second substrate container to the second inlet port of the static mixing device, and the outlet port of the static mixing device to the inlet ports of the waste container and the product container.

33. The frame of claim 32, wherein the pressure is applied by a pressurized gas contacting an outer surface of the first flexible matrix container and an outer surface of the second flexible matrix container, wherein the pressurized gas is provided to the surfaces through a first through hole provided in the first sealable region and a second through hole provided in the second sealable region.

34. A frame according to claim 32 or 33, the rear side of the frame being adapted to be sealed to a second counterpart by means of circumferential gaskets surrounding the first and second through holes respectively.

35. The frame of claim 34, wherein the first and second mating members are hingedly connected to each other.

36. A flexible container suitable for use as a flexible substrate container, a flexible waste container or a flexible product container according to any of the preceding claims, having: an interior space for holding a fluid material, the interior space being enclosed by a flexible front wall and a flexible rear wall, each wall portion being made of a polymer material; and at least one inlet port or outlet port for enabling fluid communication with the interior space; wherein the flexible front wall and the flexible rear wall are connected to each other to form a sealed edge substantially surrounding the interior space; wherein the edge includes four corner regions so that the interior space has an overall shape of a square or rectangle when empty; and wherein a first through hole is provided in or near a first corner region of the sealing edge, and a second through hole is provided in or near a second corner region of the sealing edge; wherein the second corner region is adjacent to the first corner region.

37. A flexible container according to claim 36, comprising at least one inlet port and / or at least one outlet port, wherein a flexible tube is fluidly connected to the inlet port and / or outlet port, and wherein the flexible tube comprises a sterile disconnector.

38. The flexible container of claim 37, wherein the flexible tube fluidly connected to the at least one outlet port has a downstream end fluidly connected to a sampling tube, wherein the sampling tube has a downstream end fluidly connected to a sterile filter.

39. A kit comprising a frame according to any one of claims 1 to 35, and: (a) first and second flexible substrate containers; (b) Flexible waste containers; (c) Flexible product containers; (d) a static mixing device; and (e) a conduit for fluidly connecting the outlet port of the first substrate container with the first inlet port of the static mixing device, the outlet port of the second substrate container with the second inlet port of the static mixing device, and the outlet port of the static mixing device with the inlet ports of the flexible waste container and the flexible product container; and wherein optionally each of the first and second flexible substrate containers is filled with a liquid substrate.

40. The kit of claim 39, wherein the static mixing device comprises a T-piece mixer, a Y-piece mixer, a vortex mixer, a baffle-based static mixer, a microfluidic mixing device, a multi-inlet vortex mixer (MIVM), or a jet impact reactor, and wherein the jet impact reactor optionally comprises: - a reaction chamber defined by the inner surface of a reaction chamber wall, the reaction chamber having a substantially spherical overall shape, the chamber comprising: (a) first and second fluid inlets, wherein the first and second fluid inlets are disposed at opposite positions on a first central axis of the reaction chamber so as to point toward each other, and wherein each of the first and second fluid inlets comprises a nozzle; and (b) a fluid outlet, disposed at a third position, wherein the third position is located on a second central axis of the reaction chamber, wherein the second central axis is perpendicular to the first central axis; The distance between the nozzle of the first fluid inlet and the nozzle of the second fluid inlet is equal to or smaller than the diameter of the reaction chamber along the first central axis.

41. The kit of claim 39 or 40, wherein the jet impact reactor comprises a reaction chamber having a substantially spherical shape, wherein the spherical shape is interrupted by: first and second fluid inlets, wherein the first and second fluid inlets are arranged at opposite positions on a first central axis of the reaction chamber so as to point toward each other, and wherein each of the first and second fluid inlets is provided by a nozzle; and a fluid outlet disposed at a position on a second central axis of the reaction chamber, the second central axis being perpendicular to the first central axis; The reactor further comprises first, second and third fluid conduits, wherein the first and second fluid conduits are arranged to direct a first fluid to the first fluid inlet and a second fluid to the second fluid inlet, and wherein the third fluid conduit is arranged to direct a third fluid from the fluid outlet in a downstream direction, the third fluid being formed by mixing or reacting the first and second fluids in the reaction chamber; The reactor comprises at least two parts fixed to each other, wherein the first part is made of a polymer material and comprises at least a portion of the first or second fluid conduit and at least a hemispherical portion of the reaction chamber; and the second part can be at least partially inserted into the first part, and the second part comprises the fluid outlet.

42. A kit according to any one of claims 39 to 41, wherein the flexible substrate container and optionally the flexible waste container is a container according to claim 36, and wherein the flexible product container is a container according to claim 37 or 38.

43. An apparatus adapted to receive and hold the frame of any one of claims 1 to 35 in its operative orientation, wherein the first and second flexible substrate containers are empty and held in the first and second sealable regions, the apparatus further comprising means for aseptically filling the first flexible substrate container with a first substrate and / or aseptically filling the second flexible substrate container with a second substrate.

44. An apparatus adapted to receive and hold a frame according to any one of claims 1 to 35 in its operative orientation, wherein the first flexible substrate container contains a first substrate and the second flexible substrate container contains a second substrate, the apparatus further comprising means for forcing the substrates from the first and second flexible substrate containers to flow into the static mixing device for mixing to form a liquid product, wherein the means is adapted to apply pressure to the first and second flexible substrate containers.

45. The apparatus of claim 44, wherein the pressure is applied by a pressurized gas contacting outer surfaces of the first and second flexible substrate containers, and wherein the pressurized gas is provided to the surfaces through a first through hole disposed in the first sealable region and a second through hole disposed in the second sealable region.

46. ​​The apparatus of claim 34, comprising the first mating member and the second mating member.

47. The apparatus of claim 46, wherein the first and second mating members are hingedly connected to each other.

48. A method for mixing two fluid matrices, the method comprising using a frame according to any one of claims 1 to 35, a kit according to any one of claims 39 to 42, a flexible container according to any one of claims 36 to 38 and / or an apparatus according to any one of claims 43 to 47.

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