Apparatus and method for the mixing or agitating of components, comprising a flexible deformable container

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DESCRIPTION

Apparatus and method for mixing or stirring components, comprising a flexible deformable container.

The present invention relates to a device for creating movement in a fluid according to the preamble part of claim 1, for example in the form of a disposable mixing system or a system useful for mixing components or for providing agitation in the biopharmaceutical industry.

Background

The biopharmaceutical industry has traditionally used stainless steel pipes and systems in their manufacturing procedures because they can be steam sterilized and reused.

Often the cost of these systems is prohibitive. Furthermore, such systems are static, are often welded together, and are not easily reconfigured.

The industry has begun to explore an alternative solution, namely to use individual disposable plastic bags and pipes to replace traditional stainless steel. This allows the flexibility to rearrange these systems at minimal cost. Additionally, the initial capital investment is several times less than that of stainless steel systems, allowing biopharmaceutical products to be manufactured in smaller quantities, making available new therapeutic agents that before this advance were not justified from an economic point of view and enabling the expansion of contract manufacturing of such products or when demand quickly requires additional capacity.

One aspect of the disposable biopharmaceutical installation has been the bioreactor, which requires a permanent supply of gas and nutrients and the extraction of waste products and expelled gases. Additionally, a constant movement of the cells in the reactor helps to provide a constant mixing of the contents.

One system for a bioreactor has been to use a large table, equipped with motors or hydraulic equipment, on which a bioreactor bag is placed. Hydraulic motors / equipment balance the bag communicating a constant movement to the cells. Additionally, the bag has a tube for the supply of gas and nutritional principles and a tube for the products and residual gases that allow the supply of nutrients and gases such as air for aerobic organisms and the extraction of residues such as breathed gases, dioxide. carbon and similar products. The tubes are intended to work with the movement of the bag in order to allow a uniform movement of gases and fluids / solids. See US Patent Number 6,190,913.

Said system requires the use of equipment with a large capital investment, with components that are susceptible to wear. Additionally, the size of the bag that can be used with the table is limited by the size of the table itself and by the lifting capacity of the table. motors / hydraulics.

An alternative system uses a long, flexible tubular bag that has both ends attached to movable arms in such a way that the bag, after filling, is suspended below the movable arms in the shape of a U. Then, the arms they alternately move up and down with respect to each other, in order to produce a rocking motion and movement of the fluid contained in the bag. If desired, the center section could contain a restrictor, to cause a more intimate mixing action.

This system requires the use of a specially shaped bag and hydraulic or other lifting equipment to cause movement of the liquid. Additionally, due to weight considerations, the size and volume of the bag are restricted by the lifting capacity of the equipment and by the mechanical strength of the bag.

Document WO 01 / 83004A describes a device for dispensing an anticoagulant from a flexible container or CPD bag. The purpose of the dispensing device is the continuous dosing of the anticoagulant in precise proportions to an aspirated quantity of blood. The device comprises a bag with pressurized air to dispense the anticoagulant when the device is aspirating blood but not when it is aspirating air. The pressurized air bag 31 is either evacuated to be completely away from the CPD bag or inflated to provide pressure on the CPD bag. The purpose of inflating the air bag is to activate or deactivate the dispensing of the liquid from the CPD bag, but not to mix the fluid within the bag.

What is needed is a cheaper device that is not limited by size to perform the same function as current devices and that eliminates or minimizes the capital investment involved in such devices. More preferably, this device is disposable.

The present invention provides a device for creating movement in a first fluid as defined in claim 1, and a system and method for mixing two or more components using said device. Preferred embodiments of the device are defined in the dependent claims.

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Summary of the invention

The present invention uses one or more bags that are selectively pressurized and deflated in conjunction with a disposable bio-bag such as a fermenter, a mixing bag, a storage bag, or the like. The pressurized bag (or pressurized bags) could surround a selected outer part of the biobag, or it could be contained within an inner part of said biobag. By selective pressurization and deflation of the pressurized bag (or bags), the movement of the fluid contained in the bio-bag can be achieved thereby ensuring the suspension of cells, and the mixing and / or transfer of gases and / or or nutrients and / or excrement inside the bio-bag without damaging the shear stresses or the generation of foam.

Preferably, two or more pressure bags are used at or near opposite ends of the bio-bag. Each pressure bag has an intake and discharge that can be selectively opened or closed. An air supply is provided at the pressure bag inlet. Optionally, a vacuum feed is provided at the discharge. While one pressure bag is inflated by closing the discharge and opening the intake, the other is deflated by closing the intake and opening the discharge. This inflation / deflation process applies pressure to one end of the bag, compressing the fluid present at that end and moving it toward the end where the pressure is lower. By alternating the inflation / deflation process in the opposing pressure bags, an undulating or rocking motion of the fluid is achieved throughout the bio-bag. Description of the drawings

Figure 1 shows a first embodiment of the present invention in cross-sectional view.

Figure 2 shows a second embodiment of the present invention in cross-sectional view.

Figure 3 shows the embodiment of Figure 2 in use.

Figure 4 shows a third embodiment of the present invention in cross-sectional view.

Figure 5 shows another embodiment of the present invention in cross-sectional view.

Figure 6 shows another embodiment of the present invention in cross-sectional view.

Figure 7 shows another embodiment of the present invention in cross-sectional view.

Figure 8 shows another embodiment of the present invention in cross-sectional view.

Figure 9 shows another embodiment of the present invention in cross-sectional view.

Figure 10 shows another embodiment of the present invention in cross-sectional view.

Figure 11 shows another embodiment of the present invention in cross-sectional view.

Figure 12 shows a control unit for an embodiment of the present invention.

Detailed description

Figure 1 presents a first embodiment of the present invention, consisting of a bag 2 containing a fluid 4. The fluid can be a cell suspension, a fermentation broth or some other liquid. Around a part 6 of the bag 2 there is a pressure bag 8. As shown in the figure, the pressure bag is located towards one end of the bag 2. It could also be located near or in the center or at the other end of bag 2, if desired. Alternatively, and as described below, the pressure bag (or bags) S could be contained within the interior of the bag 2.

The pressure bag 8 has an intake 10 and a discharge 12. Preferably, at least the intake 10 has a valve 14 to selectively isolate the intake 10 from a supply 16 of pressurized fluid. Preferably, the pressurized fluid feed 16 is air or some other gas, although, in some applications, it could be a liquid such as water or other hydraulic fluid.

Bag 2 also contains an inlet 18 and discharge 20 which are preferably connected to either a sterile filter or a sterile closed system (not shown).

To use the system, the bag inlet 18 is opened and a liquid 4 and / or gases are introduced, such as a liquid containing microbes and a nutrient feed in the case of a bioreactor. Such fluids are well known and may comprise an aqueous medium and one or more cell lines for fermentation and growth. One such fluid is a fluid containing the E.coli bacteria made from cell tissue culture medium, vitamins, or other nutrient supplements. Other applications may include wine making, beer making, mixing large volumes of components such as a powder into a liquid or two miscible liquids

ES 2 289 388 T3 or similar products. The amount of liquid introduced is typically less than the volume of the bag itself 2. Typically from about 10% to about 90%, preferably from about 20% to about 80% of the volume of the bag, is aspirated by the liquid 4- A gas can be introduced into some or all of the remaining volume if desired. In most embodiments, the volume of liquid / gas within bag 2 should be less than the total volume of bag 2. In some cases, it could be equal to the remaining volume of bag 2 to create a relatively rigid container. .

The inlet 18 and outlet 20 of the bag could either be closed or left open, provided they are in a closed system or provided with a sterilizing filter (not shown) to prevent the displacement of contaminants, such as bacteria or viruses, into the bag 2 or the displacement of the constituent elements in the bag 2 out of the bag 2, such as an aerosol or similar product.

The pressure bag 2 is initially deflated. The discharge 12 is closed and the intake 10 is open to the supply 16 of pressurized fluid through the valve 14. The pressure bag 8 is inflated by compressing the area 6 of the bag 2 that it surrounds. This causes the fluid 4 contained in bag 2 to move towards the opposite end 22 of bag 2. When a sufficient pressure has been reached, the intake valve 14 is closed and the discharge 12 is opened to release the pressure, causing the fluid 4 to return to the area 6 containing the pressure bag 8.

Figure 2 presents an embodiment in which two pressure bags 8A and 8B are used, operating in sequence such that when the 8A is inflated, the 8B is deflated, and vice versa.

Figure 3 presents the embodiment of Figure 2 in use. Pressure bag 8A is inflated and pressure bag 8B is deflated. The liquid 4 appears to travel to the end of the bag containing the pressure bag 8B. Also shown in this figure are sterilizing filters 24 or bag inlet 18 and bag discharge 20.

Figure 4 presents another embodiment of the present invention. The pressure bag 30 is located under a part of the bag 2. In this case, it is shown at or near the left end of the bag 2, but could be at or near the right end or in the center. Additional pressure bags 30 could also be used, for example by placing one at or near each end of bag 2.

The intake 32 and the discharge 34 of the pressure bag 30 function in the same way as in Figures 1 to 3 to alternately inflate and deflate the pressure bag 30 resulting in the displacement of the fluid 4 contained in the bag 2.

If necessary, some means (not shown) could be provided to fasten pressure bag 30 to bag 2 in order to prevent displacement of bag 2. Loop fixing tapes could be used as fixing means. , hook or strip, adhesives, heat bonding or similar devices.

Figure 5 presents an embodiment of Figure 4 using two pressure bags 30A and 30B. Bag 30A is shown inflated and 30B deflated. By alternately inflating and deflating the two bags 30A and 30B, an undulating movement is created inside the bag 2 and in the fluid 4 contained therein.

Figure 6 presents another embodiment in which the pressure bag 40 is located above or to one side of the bag 2 instead of around or below it. In this case, the pressure bag 40 is fastened to an immobile plate 42 in such a way that all the force applied to the pressure bag 40 is directed against the bag 2. Said plate 42 can be a metal beam or plate, of plastic or wood fixed to a wall, frame or similar element. As in the other previously described embodiments, more than one pressure bag 40 could be used in such a system, preferably at different locations along the length of bag 2.

Figure 7 presents a variant of the embodiment of Figure 6, in which the pressure bags 40A and 40B are mounted on plates 42A and 42B respectively at the end of the bag 2. As shown in the figure, the inflation of a bag, in this case 40A, causes the fluid to move to the other end where bag 40B is deflated. By alternately inflating and deflating the bags 40A and 40B, the movement of the fluid 4 within the bag 2 occurs.

Figure 8 shows another embodiment of the present invention. In this embodiment, the pressure bag 50 is contained within the bag 2. The intake 10 and the discharge 12 to the pressure bag 50 are directed through openings made in the wall of the bag 2 forming a tight seal. of liquids around inlet 10 and discharge 12.

Figure 9 presents an embodiment that is similar to the embodiment of Figure 8, but has two pressure pockets 50A and 50B.

Figure 10 presents another embodiment in which the pressure bag 60 forms a central part of the bag 2. Through the bag 60 a conduit 62 is formed to provide fluid communication between the first section 64 of the bag 2 and The Second Part 66. Preferably, the outer surface of pressure bag 60 is permanently attached to the inner wall of bag 2 such that inflation and / or deflation tends to concentrate movement toward the center of bag 2. Fluid moves between parts 64 and 66 by infla4

In addition, by using a constriction restriction in the form of conduit 62, mixing of the fluid as it passes through the conduit can be achieved. This effect can be expanded through the use of paddles (not shown) in conduit 62 to create a static mixer. Optionally, one or more additional pressure pockets (not shown) similar to those in Figures 1-9 could be added to amplify fluid movement.

Figure 11 presents a further embodiment of the present invention. In this case, the pressure bag 70 surrounds a central part of the bag 2 and when inflated, it forces the fluid 4 towards the ends. After deflation, the fluid 4 is displaced again towards the center and towards the opposite end. The embodiment creates a high degree of mixing and turbulence, and is particularly useful in mixing applications.

A further use for the system of the present invention is as a pressure regulated feed vessel or pump for the liquid within. If it is desired to pump the fluid contained in the bag to another location, such as for storage or further treatment, the pressure bags and a valve installed at the outlet of the bag can be used to selectively drive some, most or all the fluid out of the bag discharge. Similarly, when the fluid contained in the bag is to be filtered, pressure bags can be used to create a constant pressure on the fluid contained in the bag and then supply that pressurized fluid from the bag through its discharge to an intake. of a filter. This eliminates the need for a pump in this disposable procedure. The pressure inside the pressure bags as well as the fluid can be monitored and adjusted as necessary to provide the correct pressure feed to the fluid when it is being filtered.

The bags used in the present invention can be those typically used in the biopharmaceutical industry for bioreactors, fermenters, storage bags, and the like. These bags are manufactured by a variety of suppliers such as Stedim SA of France and Hyclone of Loga, UTA. The capacity of these bags ranges from a few liters to 2,000 liters or more. They are typically manufactured from a multi-layer plastic film (extruded or laminated) such as polyethylene, polypropylene, EVA copolymers, VEO, PET, PETG, special or exclusive polymers such as HyQ CX5-14 film manufactured by Hyclone which is a multilayer film coextruded with an outer layer of an elastomer with a protective layer of VEO and a contact layer of an ultra-low density polyethylene product, polymer blends and similar products. The selected polymer (s) are chosen with the intended combination of cleanliness, strength, and workability in mind.

The pressure bag (or bags) could be made of the same materials as the bags 2 and can be made in the same way such as blow molding, heat sealing the flat film seams together to form a bag, and by similar techniques. When pressure bags are used outside of bag 2, the issue of cleanliness might be less important. The fundamental attributes of outer pressure bags are mechanical strength, strength (to withstand repeated inflation and deflation operations) and cost. If these bags are to be reused, consider using elastomeric materials such as rubbers (natural or synthetic such as nitrile, neoprene and similar materials), elastomers such as styrene-butadiene-styrene copolymers (hereinafter SBS copolymers), elastomers thermoplastics such as SANTOPRENE resin^®manufactured by Advanced Elastomer Systems of Akron, Ohio and similar suppliers. When used indoors and therefore in contact with the product, the pressure bags should be made of the same materials as the bags themselves 2 in order to maintain cleanliness.

As described above, the pressure bags could be inflated with air, other gases, or fluids. The chosen medium depends on the user and the most common font available. Most factories have air and vacuum lines installed indoors and it is these that would most typically be used in this application.

In some installations, pressure regulators may be required to maintain the pressure of the air entering the bags within a desired regulated range in order to prevent the bag from deteriorating from over-inflation or to prevent under-inflation of the bag. The pressure used in a given bag will vary depending on the mechanical strength of the bag, the amount of compression or movement of the bag desired, and the available source of pressure. Typically, the pressure will be from about 34.47 kPa to about 689.47 kPa (5 to 100 pounds per square inch), more typically from about 68.94 kPa to about 551.58 kPa (10 to 80 pounds per square inch). square).

If desired, the use of a vacuum in the discharge of the pressure bag could aid in rapid deflation of the bag when desired. Although useful, it is nevertheless not necessary to the present invention. All that is needed is a simple pressure release valve, because moving the fluid in the bag from the inflated end to the deflated end will add weight (that of the fluid moving inside the bag). against the pressure bag that deflates to aid deflation.

When using a liquid such as water or hydraulic fluid, pumps could be used to supply the desired pressure and draw the intended amount of pressurized liquid from the pressure bags as needed. Any pump commonly used in the pharmaceutical or food industry could be used including piston pumps, rotary pumps, peristaltic pumps, and the like.

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The number of swells / deflates per hour or per minute depends on the application involved. Some applications such as mixing will require almost continuous movement of the liquid in the bag, thus requiring one or more inflation / deflation cycles per minute. Often the inflation / deflation cycle can range from one (1) to about thirty (30) inflation / deflation cycles per minute. in those applications. At the other extreme, when only slight fluid movement is required or desired, the inflation / deflation cycle could be on the order of about one (1) to about sixty (60) cycles per hour. In other applications, such as for mixing components that can withstand shear and foaming, the cycles could be even faster than those mentioned above, if desired.

Additionally, the inflation / deflation cycle could be coupled with other functions of the bag such as the supply of nutrients or the supply of gases and the extraction of exhaust gases, excrement and bio-product. The timing of the introduction of gases, nutrients and similar products can be done with the movement of the bag through the pressure bag in such a way that the movement of the liquid creates a suction or pressure difference in the admission of the gas / nutrient to the bag to aid aspiration of the desired amount into the bag as required. Similarly, the pressure difference can work on the discharge to the exhaust spent respiratory gases or to allow the taking of samples of an aliquot of liquid for testing or the extraction of a part of the liquid to remove excrement and the like.

Inflation / deflation could be done manually or automatically. The system is preferred to be automatic to reduce labor costs and ensure repeatability of accuracy. One such system is shown in Figure 12. In this case, a control unit 100 monitors a parameter of the pressure bags 102A and B such as the inflation or deflation time, the pressure or the like. When the parameter in a bag, for example the pressure in the 102B reaches a regulated lower level or a zero level, the control unit stops inflating the bag 102A, begins to fill the bag 102B through the pressure feed 104 and begins deflating bag 102A through discharge line 106 shown with preferred release valve 108. Also shown is a pressure monitor 110 for the bags and a measuring apparatus to display the number of cycles for a given time (either minutes or hours). If desired, the control unit could be a proportional integral and derivative controller (hereinafter PID controller) or a computer. Software could also be incorporated into the system as desired to allow greater flexibility and control.

The use of controllable valves, such as pneumatically controlled valves or solenoid valves installed in the inlets and outlets to the bags 102A and B, allows the control unit 100 to operate more efficiently. However, other means of controlling inflation / deflation of bags 102A and B are also contemplated. For example, a simple slow release flow restrictor could be used in the discharge of bags 102A and B that deflates at a slower rate than the air supplied to the bag to allow it to inflate when desired. The air pressure is simply switched from one bag intake to the other based on the deflation rate of the restrictor, thus controlling the inflation / deflation cycle in that way.

The present invention provides a simple system for moving liquid, even in large volumes, in a disposable system. It allows you to achieve the right movement for mixing components as desired without the need for capital investments or maintenance intensive equipment such as dump trucks or hydraulic forklifts or cranes. It also takes advantage of common air / vacuum feeds in factories. Although it has been contemplated for use in the biopharmaceutical industry, it is apparent that the device of the present invention has applications in other fields such as beer making, wine making, blending of hazardous ingredients, paints, epoxy resins and the like in disposable bags.