EP1644105B1 - Single-use closed system for mixing, storing and homogenising liquids in clean and sterile conditions - Google Patents

Abstract

A rigid tank (1), containing a generally-rectangular, disposable pocket (2), is new. Its (2) upper and lower surfaces are permanently connected by a mixing line (3) passing through a dedicated, non-intrusive pump (4) (an external peristaltic pump is shown). This circulates liquid from low in the pocket, to its top. The pump can be opened and closed, allowing the mixing line to be inserted into it, or removed from it. An independent claim is included for the corresponding method of mixing.

Description

The present invention relates to a closed system for single use of mixing, storage and homogenization of liquids under clean or sterile conditions preferably applicable to bio-pharmaceutical, pharmaceutical and medical industries.

In the medical, bio-pharmaceutical, pharmaceutical or paramedical fields, but also in other fields such as the food industry in particular, there is the problem of mixing large volumes of fluids under clean or sterile conditions.

• le maintien d'une bio-charge initiale dans les constituants du mélange et dans le mélange lui-même au niveau le plus bas possible ;
• une teneur en endotoxines dans les constituants du mélange et dans le mélange la plus limitée possible (et souvent la combinaison des deux critères ci-dessus) ;
• dans des conditions plus critiques, en outre le maintien de la stérilité des constituants du mélange et du mélange résultant ;
• dans des conditions encore plus particulières, en plus des critères ci-dessus, la protection des opérateurs vis à vis de la toxicité potentielle des constituants du mélange et du mélange lui-même.

Mixing liquids under clean or sterile conditions is a common operation that often has to meet the following criteria:

• maintaining an initial bio-charge in the constituents of the mixture and in the mixture itself at the lowest possible level;
• an endotoxin content in the constituents of the mixture and in the most limited mixture possible (and often the combination of the two criteria above);
• under more critical conditions, further maintaining the sterility of the constituents of the mixture and the resulting mixture;
• under even more particular conditions, in addition to the above criteria, the protection of the operators with respect to the potential toxicity of the constituents of the mixture and of the mixture itself.

Currently, this type of mixing operation is generally carried out by means of stainless steel tanks provided with an agitator immersed in said tanks.

By nature, because of their cost, these tanks must be reusable. This induces a number of disadvantages and associated risks.

• la nécessité de préparer au préalable la cuve, ce qui induit des opérations de nettoyage, de désinfection, de pré-stérilisation sur place (CIP ou Clean In Place) et de stérilisation sur place, par exemple utilisation de vapeur d'eau fluente (SIP ou Steam In Place);
• l'utilisation d'une cuve à fermeture étanche avec un mélangeur, typiquement un mélangeur à hélices, qui plonge dans la cuve, rend nécessaire l'usage d'un presse-étoupe autour de l'axe du mélangeur pour étanchéifier le système. Les opérations de pré-stérilisation et de stérilisation ont un coût important, et ces opérations doivent être revalidées régulièrement, compte tenu d'exigences constamment accrues des autorités réglementaires, sanitaires ou autres ;
• un risque de contamination bactérienne, soit au travers de l'ouverture de la cuve, soit au travers du presse-étoupe, voire à cause d'une erreur de l'opérateur ;
• on peut enfin citer le risque classique de contamination croisée entre lots, risque inhérent à la réutilisation des équipements.

The most important of these risks are:

• the need to pre-prepare the tank, which leads to cleaning, disinfection, pre-sterilization on site (CIP or Clean In Place) and sterilization on site, for example use of fluent water vapor (SIP or Steam In Place);
• the use of a tight-closing tank with a mixer, typically a propeller mixer, which plunges into the tank, makes it necessary to use a stuffing box around the axis of the mixer to seal the system. Pre-sterilization and sterilization operations are costly, and these operations need to be revalidated on a regular basis, given the ever-increasing requirements of regulatory, health and other authorities;
• a risk of bacterial contamination, either through the opening of the tank, or through the stuffing box, or even because of an error of the operator;
• Finally, there is the classic risk of cross-contamination between batches, a risk inherent in the reuse of equipment.

It would therefore be desirable to have a mixing system preferably of simple design and construction, meeting all or some of the criteria set out above.

US-A-5 941 635 discloses a system comprising a pocket provided with several plunger tubes, in which the sampling of the liquid to be mixed is made in the middle of the pocket, using one of the plunger tubes, and the return of said liquid is carried by the bottom of the pocket, through an inner tube comprising a mixing head, connecting the top and the bottom of the pocket.

In addition to its complexity, this system involves intervening inside the pocket during its manufacture, in particular to insert the dip tubes and the mixing head. There is therefore a significant risk of introduction of pyrogenic particles.

Therefore, the subject of the present invention is a closed system for single use for mixing, storing and homogenizing liquids, comprising an assembly consisting of a rigid container provided with a non-invasive pump, said container enclosing a pocket for use single generally parallelepipedal shape, characterized in that the lower face of the pocket comprises a liquid outlet orifice to the outside of the pocket, the upper face comprises a liquid return port through which said liquid returns inside of the pocket, said orifices are irremovably connected by means of an external mixing pipe which is inserted into the pump which, in action, allows the circulation in a closed circuit of the liquid taken from the bottom of said pocket, the pump being open so as to be able to insert and extract the mixing duct.

The container can of course be reusable. On the other hand, the pocket and its conduit are for single use.

The collection of the liquid is carried out completely at the bottom of the bag by the liquid outlet orifice towards the outside of the bag. It then travels through the external mixing duct, moved by the pump. The return of the liquid inside the pocket is effected from above, and it opens on the upper surface of the liquid present in the pocket.

Under preferred conditions of implementation of the invention, the outer mixing pipe is fixed by each of its ends to the surface of the pocket without a dip tube or comprises a short dip tube, with a length of less than 2 cm. , especially less than 1 cm.

In other preferred conditions of implementation of the invention, the noninvasive pump is a peristaltic pump provided with a rotor that compresses the outer mixing duct with two or three pads and thus pushes the product with each rotation towards repression.

To better understand the cooperation between the container and the bag, the operating mode of the liquid mixing system is explained below. The set can work as follows:

We install a pocket above in a container, we insert the conduit into the pump, then we put the pump into action to create a circulating in closed circuit of the liquid or liquids installed in the container to proceed with the mixing. Of course the dimensions of the duct (length, diameter) and its flexibility must be compatible with the criteria of the chosen pump.

The installation of the liquids to be mixed in the bag can be carried out by aseptic connection under a laminar airflow hood to the sources of these liquids, in particular by a single-use sterile connection device of the type for example KLEENPAK® Connector sold by the company PALL. Corporation and preferably when said pocket is in place in the container.

In the present application and in the following, the term "container" designates for example a stainless steel container, generally parallelepipedal shape, preferably 304L or 316L stainless steel of parallelepipedal shape whose capacity is particularly adapted to that of the bag installed therein, and particularly a container of the type for example described in EP-A-1 012 073. The container is advantageously provided with a metal carcass, especially particularly stainless steel.

The pump may be installed above or preferably below the pocket location.

Under preferred conditions of implementation of the invention, the bottom of the container is provided with an elongate slot for insertion and passage of the mixing duct.

A particularly movable device parallel to the bottom of the container such as a flattened drawer is advantageously provided to partially close the slot, which allows to pass through the mixing duct while minimizing the free surface of the slot, and thus effectively support the bottom of the slot. poached.

In other preferred conditions of implementation of the invention, the above container comprises one or two side doors to allow the installation of the pocket.

In still other preferred conditions of implementation of the invention, the above container is provided with a bottom wall movable horizontally, preferably removable in the manner of a drawer, provided with one or more, in particular two elongated slots.

In still other preferred conditions of implementation of the invention, the swinging door edges comprise a U-shaped vertical section, the openings facing each other, in which a profiled plate is slid and adjusted to hold the door leaves in closed position. The central portion of this plate is preferably coplanar with the inner surface of the two doors.

In still other preferred conditions of implementation of the invention, the swinging edge of a side door comprises a door provided with closures cooperating with systems provided on the other side door to hold the door leaves in closed position . The central portion of this door is preferably coplanar with the inner surface of the two doors of the container.

In still other preferred conditions of implementation of the invention, the swinging edges of two side doors comprise a U-shaped section the openings turning the back, in which is slipped a profiled and adjusted plate comprising two U-shaped returns. openings facing each other, to hold the door leaves in the closed position. The central part of this plate is preferably coplanar with the two doors and advantageously forms a channel in which the mixing duct can be installed to protect it, preferably with the aid of a gate flap.

In still other preferred conditions of implementation of the invention, the protection of the mixing duct is integrated into a door of the container and preferably comprises a gate flap.

A cover such as that described in EP-A-1 012 073 may advantageously be provided above the bag.

In the present application and in what follows, the term "pocket" designates for example a container of flexible plastic material of generally parallelepipedal shape, preferably transparent in order to be able to visually observe the turbidity of the contents and particularly one of those described in EP-A-1 012 227.

Its capacity may range, for example, from 25 to 3000 liters, preferably from 50 to 1500 liters and particularly from 50 to 500 liters.

It may be made for example of flexible plastic film based on polyethylene (PE), ethylene, vinyl acetate (EVA), polypropylene (PP) or advantageously a combination of these materials, preferably in film multilayer multi-material flexible co-extruded or laminated and particularly multilayer laminated single film as described in EP-A-1 012 227.

It may comprise for example from 1 to 8, in particular from 1 to 4 welded or glued tubes on chimneys provided on the top of the pocket, one of the tubes being the above conduit and one or more, in particular 1 or 2 bungs of bottom, one of the bungs communicating with the conduit above.

The usable pump is of the non-invasive type. A non-invasive pump is a pump acting on the circulation of a fluid without the pump being in contact with the fluid. The usable pump is preferably a pump with several pump heads and particularly of the peristaltic type. Mention may be made, for example, of those sold by WATSON MARLOW, a 700 series company.

The conduit may be made for example of thermoplastic elastomer, preferably MARPRENE® and particularly platinum catalyzed silicone. Its internal diameter may advantageously be between 6 and 40 mm, preferably between 9 and 31 mm, especially between 12.70 and 19.10 mm.

It may advantageously comprise upstream and / or downstream of the pump taps for example to add preferably liquid compounds subsequently to the initial filling or on the contrary to withdraw a portion of the mixture, for example for sampling or emptying.

• le nombre de connexions en condition d'asepsie est limité au maximum, ce qui réduit le risque de contamination des produits par toucher par les mains de l'opérateur ;
• le système étant clos, il est à l'abri de l'air ambiant, ce qui de ce fait réduit les risques de contamination bactérienne et limite les risques d'oxydation ;
• toujours compte tenu du caractère clos du système, l'opérateur n'est pas exposé à la toxicité éventuelle d'un des composants du mélange ou du mélange lui-même.

The liquid mixing systems of the present invention possess outstanding qualities:

• the number of connections in aseptic condition is limited to the maximum, which reduces the risk of contamination of the products by touching by the hands of the operator;
• the system being closed, it is protected from the ambient air, which thus reduces the risks of bacterial contamination and limits the risks of oxidation;
• always taking into account the closed nature of the system, the operator is not exposed to the possible toxicity of one of the components of the mixture or of the mixture itself.

The system according to the invention allows the mixing of liquids in a closed circuit.

Single use, the system of the invention eliminates any risk of cross-contamination between different batches.

These qualities justify the use of the systems described above in many applications by providing them with the advantages set out above.

For example in the field of biotechnology, the systems of the invention allow the preparation of cell culture media for transfer into a bio-reactor, by dissolving a mixture of powders in water for injections. There may also be mentioned the addition to culture media of fetal calf serum, for example to produce a medium containing 10% fetal calf serum and obtaining a homogenized mixture.

The adjustment of the pH or of the conductivity of a culture medium can also be mentioned by means of acidic, basic or saline solutions and homogenization of the mixture.

There may also be mentioned the preparation of buffer solutions for chromatography columns or tangential filtration systems, in separation and or purification of compounds, and their homogenization.

In all these cases the mixtures, thanks to the systems according to the invention, are carried out under sterile conditions, whatever the stage of the process. biotechnological process, according to the requirements or recommendations of the regulatory authorities.

In the pharmaceutical field, a traditional application is for example, in traditional pharmacy, the bulk pharmaceutical formulation of solutions of injectable products, in particular cytotoxic as anticancer, and their bulk storage before pharmaceutical distribution in their final unit packaging, for example in injectable ampoules. Such an operation can be carried out thanks to the system according to the invention in a single step, or be split into two steps, first of all for the preparation of a concentrated solution, and then of dilution.

Indeed, the toxic nature of these solutions implies that such a mixture is done in a closed system, or even in a confined environment.

In the medical field, an application is for example, in parenteral nutrition, the preparation of mother batches of nutrient mixtures to be subsequently distributed in multiple administration pockets, from solutes or base suspensions such as amino acid solutions, glucose solutions, and / or lipid emulsions.

All these qualities justify the use of the mixing systems described above, in a process for compound mixing.

The closed systems for single use according to the invention are intended for mixing liquids.

This is why the present application also relates to a compound mixing process, characterized in that a single-use disposable pouch is installed in a rigid container equipped with a non-invasive pump, the lower surface of which is the upper face are irremovably connected by means of a mixing pipe, the pipe is inserted into the pump, and the pump is actuated to create a closed circuit circulation of the liquid or liquids installed in the container for mix.

Under preferential conditions of implementation of the process described above, the pump gives the mixture a circulation rate of 6 to 1500. liters per minute, preferably 10 to 1000 liters per minute, especially 10 to 750 liters per minute.

In other preferred conditions of implementation of the invention, the system of generally parallelepiped shape is arranged to create turbulence during recirculation through the conduit, which facilitates the mixing of the content.

The preferred conditions of implementation of the single-use closed systems described above also apply to the other objects of the invention referred to above, especially to the processes for preparing mixtures.

• la figure 1 représente un schéma d'ensemble d'une poche à usage unique installée dans son dispositif de stockage, de transport et de mélange.
• la figure 2 représente un schéma d'ensemble d'une poche à usage unique installée dans son dispositif de stockage, de transport et de mélange.
• la figure 3 représente une poche de stockage et de mélange vue en perspective ainsi qu'une pompe servant au mélange.
• la figure 4 est une vue en perspective d'un dispositif de stockage et de transport de poches servant à la mise en oeuvre du procédé de mélange selon l'invention.
• la figure 5 est une vue en perspective d'un dispositif de stockage et de transport de poches servant à la mise en oeuvre du procédé de mélange selon l'invention.
• la figure 6 représente un détail de fermeture de porte avant d'un dispositif de transport et de mélange selon l'invention.
• la figure 7 représente un détail de fermeture de porte avant d'un dispositif de stockage, de transport et de mélange selon l'invention.
• la figure 8 représente un détail de porte avant d'un dispositif de stockage, de transport et de mélange selon l'invention.
• la figure 9 représente un détail de porte avant d'un dispositif de stockage, de transport et de mélange selon l'invention.
• les figures 10 et 11 représentent vu de dessus un détail de la paroi de fond d'un dispositif de stockage, de transport et de mélange selon l'invention.
• la figure 12 représente une variante de réalisation du dispositif illustré à la figure 11.
• la figure 13 représente vu de dessus un détail de la paroi de fond d'un dispositif de stockage, de transport et de mélange selon l'invention.

The invention will be better understood with reference to the accompanying drawings in which

• Figure 1 shows an overall diagram of a disposable bag installed in its storage device, transport and mixing.
• Figure 2 shows an overall diagram of a disposable bag installed in its storage device, transport and mixing.
• Figure 3 shows a storage and mixing pocket perspective view and a pump for mixing.
• Figure 4 is a perspective view of a bag storage and transport device for carrying out the mixing method according to the invention.
• Figure 5 is a perspective view of a bag storage and transport device for carrying out the mixing method according to the invention.
• FIG. 6 represents a front door closing detail of a conveying and mixing device according to the invention.
• Figure 7 shows a front door closure detail of a storage device, transport and mixing according to the invention.
• Figure 8 shows a front door detail of a storage device, transport and mixing according to the invention.
• Figure 9 shows a front door detail of a storage device, transport and mixing according to the invention.
• Figures 10 and 11 show seen from above a detail of the bottom wall of a storage device, transport and mixing according to the invention.
• FIG. 12 represents an alternative embodiment of the device illustrated in FIG. 11.
• 13 shows a top view of a bottom wall of a storage device, transport and mixing according to the invention.

In Figure 1, there is a container 1 containing a single-use bag 2 of generally parallelepiped shape. The lower face of the bag 2 comprises a liquid outlet orifice towards the outside of the bag, and the upper face comprises a liquid return orifice through which said liquid opens into the inside of the bag 2. The two orifices of the pocket 2 are irremovably connected via a pipe 3 of mixing.

This irremovable conduit 3 mixture is functionally inserted in a pump 4 located above the pocket, and which, by its rotation, allows the flow of liquid, for example the bottom of the pocket to its top, according to the arrows shown.

A lateral opening of the container 1 is possible thanks to two doors 5, 6 allowing the lateral opening of the container 1. It is thus easy to insert the bag 2 with its irremovable conduit 3 into the container 1, and to insert the conduit 3 mixing in operational position in the pump 4.

Figure 2 is a variant of Figure 1, wherein the pump is installed below the bag instead of being installed above the bag as in Figure 1. In this diagram, the doors 5, 6 of the container. have been represented in semi open position. We can also observe the bottom 7 of the container 1, bottom 7 which is intended to support the pocket 2. The bottom 7 is provided with an elongated slot 8 for insertion and passage of the immovable conduit 3 mixture.

In Figure 3, there is a pocket 2 for carrying out the method according to the invention. This pocket 2 for single use, of the type for example described in EP-A-1 012 227 comprises in particular a bottom wall 10 which comprises a liquid outlet orifice to the outside of the pocket, and a top wall 11 which comprises a liquid return port in the pocket. An irremovable conduit 3 mixture connects in fluid communication the outlet orifice and the return orifice formed on the top wall 11. This conduit is of sufficient length to be inserted into a pump 4 forcing a liquid contained in the pocket 2 to circulate being drawn by the bottom 10 of the bag 2 to be returned to the pocket back by its top wall 11.

The external mixture duct 3 is fixed by each of its ends directly to the surface of the pocket without a dip tube.

The pocket 2 shown here further comprises in addition to the access door inside the pocket 12 on which is installed the immovable conduit 3 mixing, three other access doors inside the pocket, 13 , 14, 15 can be used in particular for the addition of various liquids to achieve a mixture. In the top magnifying glass is shown a variant in which a bypass 16 has been installed on the irremovable conduit 3 mixing. Similarly, the bottom magnifying glass illustrates a variant in which a bypass 17 has been installed at the bottom of the mixing duct 3.

In Figure 4 which shows a container 1 according to the invention (without the pump) can be better distinguished an elongated slot 8 for the passage of an immovable conduit 3 mixture. A drawer 20, allows to close the slot partially, to allow passage to the conduit 3 mixing and thus support the bottom of the pocket.

FIG. 5 shows a container 1 according to the invention provided with a removable bottom wall 10 in the manner of a drawer provided with two elongated slots 8.

FIG. 6 shows a closing detail of doors 5, 6 of a container 1 according to the invention. The sleeping song of the doors 5,6 is conventional but the swinging songs comprise a U-shaped section, the openings facing each other, in which one slips a profiled plate and adjusted 21 to hold the door leaves 5.6 in the closed position. The central portion 22 of this plate is coplanar with the two doors 5,6.

FIG. 7 shows a detail of another type of door closure 5, 6 of a container 1 according to the invention. The side edge of the side door 5 is conventional and the swinging song comprises a gate 23 provided with closures cooperating with systems provided on the other door 6 to hold the doors of doors 5,6 of the container in the closed position. The central portion 22 of this door 23 is coplanar with the two doors 5,6 of the container.

In Figure 8 can be observed a detail of closing doors 5.6 of a container 1 according to the invention. The sill of the doors 5.6 of the container is conventional but the swinging songs include a U-profile openings to the back, in which one slips a profiled plate and adjusted 24 to hold the door leaves 5.6 in the closed position . The central portion 22 of this plate is coplanar with the two doors 5,6 and forms a channel in which the mixing duct 3 can be installed to protect it, with the aid of a gate flap.

In FIG. 9, the protection of the mixing duct 3 is integrated with the door 6 of the container and also comprises a door leaf.

Figures 10 and 11 illustrate how to close the bottom wall of the container on the pipe 3 mixing after installation of a pocket.

FIG. 12 illustrates a top view of a variant of FIG. 10, provided with particular door leaves 5, 6, shown in the closed position in FIG. 13.

FIG. 13 illustrates, in a view from above, in particular the closing of the bottom slot 8 of the container, after passage and installation of the irremovable duct 3 (not shown), by means of a rotary guillotine closure system 27, as well as the closing the front face of the container, after passage of the immovable duct 3, by means of a U-shaped section 24 slid between the door leaves, according to the embodiment of Figure 8. The non-removable conduit 3 crosses the plane of this figure in two places, namely the bottom plate 7 (conduit not shown) and the central space of the closure profile 24 (conduit 3 shown).

Claims (14)

1. A closed single-use system for mixing, storing and homogenizing liquids, comprising an assembly constituted by a rigid container (1) fitted with a non-invasive pump (4), said container (1) enclosing a generally parallelepipedic single-use bag (2), characterized in that the lower face of the bag includes an orifice for the liquid to discharge to the outside of the bag, the upper face includes an orifice for the liquid to return through which said liquid returns to the inside of the bag, said orifices are connected in fixed manner by means of an external mixing duct (3) which is inserted into the pump (4) which, during operation, allows the closed-circuit circulation of the liquid taken from the bottom of said bag (2), the pump (4) being open so that the mixing duct (3) can be inserted into it and extracted from it.
2. A system according to claim 1, characterized in that the bottom (7) of the container (1) is fitted with an elongated slit (8) allowing the insertion and the passage of the mixing duct (3).
3. A system according to claim 1 or 2, characterized in that it includes a device (20, 27) which can be shifted parallel to the bottom of the container in order to partially close the slit (8).
4. A system according to one of claims 1 to 3, characterized in that the container (1) includes one or two side doors (5, 6) in order to allow the installation of the bag (2).
5. A system according to one of claims 1 to 4, characterized in that the container (1) is fitted with a bottom wall (7) which can be shifted horizontally, fitted with one or more elongated slits.
6. A system according to one of claims 4 and 5, characterized in that the flaps of the side doors (5, 6) comprise a vertical U-section, the openings facing each other, into which a profiled plate (21) is slid and adjusted in order to keep the flaps of the side doors (5, 6) held in the closed position.
7. A system according to claim 6, characterized in that the central part of the profiled and adjusted plate (24) is preferably coplanar with the internal surface of the two side doors (5, 6).
8. A system according to one of claims 4 to 7, characterized in that the flap of a side door (5, 6) includes a gate (23) fitted with fastenings cooperating with systems provided on the other side door (5, 6) in order to keep said flaps in the closed position.
9. A system according to claim 8, characterized in that the central part (22) of this gate (23) is coplanar with the internal surface of the two side doors (5, 6) of the container (1).
10. A system according to one of claims 4 to 9, characterized in that the flaps of two side doors (5, 6) comprise a U-section, the openings being turned away from each other, into which a profiled plate is slid and adjusted (24) comprising two U-bends, the openings facing each other, in order to keep the flaps of the side doors (5, 6) in the closed position.
11. A system according to claim 10, characterized in that the central part (22) of the profiled and adjusted plate (24) is coplanar with the two side doors (5, 6) and forms a channel in which the mixing duct (3) can be installed in order to protect it.
12. A system according to one of claims 4 to 11, characterized in that a protection of the mixing duct (3) is integrated in a door (6) of the container and includes a gate flap (25).
13. A method for mixing compounds, characterized in that a closed single-use system, as described in any one of claims 1 to 12 is installed, comprising a rigid container (1) fitted with a non-invasive pump (4), a single-use bag (2) is installed, the lower face and the upper face of which are connected in fixed manner by means of a mixing duct (3), the duct (3) is inserted into the non-invasive pump (4), and said pump is actuated in order to produce a closed-circuit circulation of the liquid or liquids introduced into the container (1) in order to carry out the mixing.
14. A method according to claim 13, characterized in that the pump (4) causes the mixture to circulate with a flow rate of 6 to 1500 litres per minute

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