WO1997008503A1

WO1997008503A1 - Sealed packaging assembly useful for drying, particularly freeze-drying, and drying, particularly freeze-drying method using same

Info

Publication number: WO1997008503A1
Application number: PCT/FR1996/001301
Authority: WO
Inventors: Annie Bardat; Roland Schmitthaeusler; Gilles Beaudoin; Yannick Thomas
Original assignee: Laboratoire Français Du Fractionnement Et Des Biotechnologies
Priority date: 1995-08-22
Filing date: 1996-08-21
Publication date: 1997-03-06
Also published as: FR2740108A1; FR2740108B1

Abstract

A sealed, gas-permeable packaging assembly in which one or more open flasks (2) containing a product (3) to be freeze-dried are received is characterised in that the packaging has a portion (7) for stiffening said assembly, a lid with at least one portion comprising a liquid-impervious, but water vapour-permeable microporous hydrophobic membrane (10), a base (6), and a foldable region (8), such that the pressure applied to the lid folds said foldable region and locks closure means, thus sealing the openings of the flasks. A freeze-drying method using said packaging assembly is also described.

Description

Sealed packaging for drying, in particular lyophilization, and method of drying, in particular for lyophilization, using such packaging

The present invention relates to a sealed package, allowing drying operations to be carried out on a product of interest, in particular chemical or biological, while avoiding contamination of this product by the ambient atmosphere or contamination of the ambient atmosphere. by said product.

It relates in particular to a packaging containing sterile products and which makes it possible to maintain sterility during the operations of evaporation, of pervaporation or in particular of lyophilization. This is why the invention also relates to a method of drying, in particular lyophilization, of a product of interest, using said packaging.

Freeze-drying operations, especially at the final stage of packaging biological or pharmaceutical products, must be carried out under non-contaminating conditions. It is therefore necessary, on the one hand, to avoid contamination of the equipment in which the products treated are viruses or other contaminating substances (DNA, chemicals or molecules with high activity, for example) in order to minimize the risks of cross contamination. .

On the other hand, for other substances such as injectable pharmaceuticals, it is necessary to maintain the sterility resulting from the preceding conditioning process.

The invention also applies to the drying and freeze-drying of products which are dangerous or contaminating for the environment, which must be treated without being able to disseminate in ambient atmospheres. The invention is applicable to a large number of products such as pharmaceutical products, in particular biological products, preserved by lyophilization, including products intended for biological or chemical analysis, vaccines, pharmaceutical products such as anti-cancer, anti -inflammatory, antibiotics, but also food products to be dried sterile (sterile nutrition) and to be steamed in the same sachet.

The invention is also applicable to chemicals dangerous for the environment or health and infectious biological products such as strains of viruses, bacteria (or microorganisms in general). It is generally difficult to carry out such drying industrially, that is to say continuously without increasing the number of manipulations which on the one hand multiply the risks of contamination and on the other hand increase the cost of the final product packaged. A European container 343 596 has indeed been proposed for the lyophilization of a biological or pharmaceutical product under sterile conditions, comprising a hydrophobic, porous membrane, impermeable to germs and permeable to water vapor such as a membrane cellulose acetate or polytetrafluoroethylene or polypropylene.

However, this container does not have all the guarantees required in the event that the container bursts as this would not prevent contamination of the freeze dryer, then of the sterile unit and of the technicians when the device is unloaded. In addition, such a container does not eliminate additional handling for the final packaging of the product.

In the same vein, GB 995 930 has proposed a lyophilization process according to which the products to be lyophilized are subjected to this operation in an envelope permeable to water vapor. The envelope can then be pressed for subsequent shaping: in order to obtain a reduction in volume of radioactive products for example.

The object of the present invention is to provide packaging making it possible to considerably simplify the drying operations of products, while maintaining the sterility of said products or while protecting the apparatus from any contamination, then carrying out the packaging of said products.

The term drying will generally designate any elimination of a solvent, in particular water, in the form of vapor from a solution, a powder or a paste previously treated in an appropriate manner for the process considered. In the case of lyophilization, the solvent, in particular the water in the solution, powder or paste will be previously frozen in a known manner.

By the expression "pervaporation" is meant that the passage of water takes place essentially in vapor form, by simple gaseous diffusion at through the micropores of the membrane separating the product from the ambient atmosphere.

By the term "waterproof" is meant that the material is however permeable to water vapor. The invention firstly relates to a sealed package for drying operations under non-contaminating conditions of a product of interest, said package comprising a hydrophobic microporous membrane, impermeable to liquids but permeable to water vapor, characterized in that one or more open containers, in particular vials, containing a product to be lyophilized must be housed in said packaging, in that said packaging comprises a housing for said containers, covered with a cover, said cover being formed at least in part of a hydrophobic microporous membrane impermeable to liquids but permeable to water vapor, a closure means for each of said containers, so that a pressure exerted on said cover closes the opening of each container via closing means.

The closure means are advantageously lyophilization plugs. These plugs, in a well known manner, are provided at their base with lugs ensuring support on the neck of the containers while leaving a suitable space for the evacuation of the water vapor (position not locked). By pressure exerted on said plugs along the axis of the containers, they are driven in a translation movement from top to bottom and allow the containers to be plugged.

According to one embodiment, the packaging is formed of a flexible sheet such as a plastic film forming a tray, in which the containers are located, the edges of said sheet being secured for example by welding of an upper sheet formed of a hydrophobic membrane. The containers are provided with lyophilization plugs in the non-closed position during the drying operation. We therefore obtain a flexible closed packaging. This is advantageously placed on a rigid support such as a tray. After the drying operation, pressure exerted on the stoppers, manual or automatic, via the top sheet ensures the closure of the containers.

By drying operations under non-contaminating conditions, it will therefore be understood, as has been said previously, that these are conditions which avoid contamination of the products of interest by substances present in the ambient atmosphere (sterile conditions) or which avoid contamination by the product of interest of the ambient atmosphere. We can also speak of confinement. According to a preferred variant, the sealed packaging is preferably formed of a skirt ensuring a certain rigidity, a foldable zone, a cover and a bottom, preferably welded, a part at least the cover being formed of a microporous hydrophobic membrane impermeable to liquids but permeable to water vapor, a foldable zone, so that the pressure exerted on the cover folds the foldable zone and locks the closing means thus closing bottle openings.

The sealed packaging contains receptacles, in particular bottles, which may or may not be integral, removably or not, with the bottom or with a support housed in the packaging and in particular which can be integral with this support or with the bottom through appropriate imprints.

The bottom can constitute the support on which the bottles or other containers are fixed. The support can also be independent of the bottom and made integral with the sealed packaging by appropriate means (cleats for example) fixed to the walls of the packaging. In this embodiment, the bottom can be formed at least in part from a hydrophobic microporous membrane.

Advantageously, the foldable zone is located in the extension of the wall of the packaging and is in the form of a bellows.

It is preferably located at the top of the package. The packaging can be in the form of a cylinder of revolution, but also in the form of a solid with several vertical faces, of tetragonal, pentagonal, or more generally polygonal section.

According to a preferred variant, the waterproof packaging is characterized in that the skirt ensuring a certain rigidity of the packaging, the cover at least part of which is formed of a hydrophobic microporous membrane, impermeable to liquids, but vapor permeable. of water, form a cover, provided with a folding zone, covering said bottles and bearing on said bottom. Advantageously, the skirt is connected to the cover by a setback, the setback area being deformable - so that it folds back when a push towards the bottles is exerted.

The detachment zone is preferably at least partially elastic, so as to move the cover away from the bottles at the end of the push.

The skirt and the recess are advantageously made of thermoformable or thermomouldable polymeric material or of deformable metal, such as aluminum. The polymeric material is of any kind, for example polypropylene or polyethylene. By thermoformable material is meant a sheet which can be given a shape.

By heat-moldable material is meant a polymeric material which is poured into a mold to give it its shape.

The microporous membrane in addition to its impermeability to liquids has a porosity such that it can oppose any penetration of contaminating microorganisms.

It is a material made of a hydrophobic polymer which does not absorb water and does not offer a nucleation point to initiate the condensation of water. However, it must be porous enough to allow water vapor to pass without significantly slowing down the evaporation or sublimation process, while not allowing passage for microorganisms or lyophilisate particles.

The material, moreover, must be sealable by an appropriate means which ensures total tightness of the weld and does not alter the porosity of the envelope in the vicinity of the seal.

Hydrophobic membranes are generally made from polyolefin, optionally fluorinated, in particular polytetrafluoroethylenes such as those known under the trademark GORE-TEX® (registered trademark of the company WL GORE & Associates, Inc.) or from textured polypropylenes a nonwoven such as that known under the brand name Tyvek®.

Hydrophobic membranes can also be made of hydrophilic polymers specially treated in order to develop a crosslinking of fluocarbon radicals on the surface of the polymer. The passage of water through these membranes takes place at the state of vapor according to an osmotic evaporation process.

These membranes have a volume porosity greater than 40% and the average pore size is sufficiently reduced to prevent any introduction of microorganisms and is generally between 0.02 and 5 micrometers.

On the other hand, it has been found that membranes based on cellulose polymers are not suitable in the context of the present invention.

Other characteristics, objects and advantages of the invention will emerge from the following description, given by way of example, and without limitation, with reference to Figures 1 and 5 appended.

Figure 1 is a schematic sectional view of a sealed package intended to be introduced into a drying apparatus.

Figure 2 is a schematic sectional view of the same sealed package after folding the foldable area for subsequent use or storage.

Figure 3 is a schematic sectional view of another sealed package, provided with a cover intended to be introduced into a drying apparatus, that is to say a package as it appears during lyophilization .

Figure 4 is a schematic sectional view of the same sealed package during capping.

Figure 5 is a schematic sectional view of the same sealed package after sealing.

According to Figure 1, inside the package 1, are housed a series of bottles 2 containing a product to be freeze-dried 3, said bottles being terminated by an open neck 4 and being placed on a support 5. The package comprises a bottom 6, a cylindrical envelope 7 terminated by an upper folding zone 8, covered by a waterproof membrane 10 in

GORE-TEX® of suitable porosity to prevent the passage of microorganisms while not restricting the passage of water vapor, welded to the edge 9 of said foldable zone. The bottles are prefilled in the usual way for lyophilization.

After lyophilization, under the action of a pressure, the foldable zone 8 is folded so as to introduce the caps 11 into the opening delimited by the necks 4 and thus ensure the sealing of the bottles without loss of sterility (FIG. 2) . The packaging 13 according to FIG. 3 is formed by a support plate 14, a heat conductor on which a base 15 is positioned by means of an external return 16 to ensure the maintenance of the base 15 on the support 14 without slip possible. The bottom 15 is a plate of thermoformed material comprising at its periphery hollow guides 17, ensuring the positioning of the bottles 18, provided with necks 19, on which lyophilization plugs 20 are positioned in the open position. On the external surface 27 of said bottom released by the guides 17 bears a cover 21 formed by a skirt 22 connected by a recess 23 to the cover 24, the central part 25 of which is made of a hydrophobic microporous membrane.

The lower end of the cover is terminated by a flap 26 resting on the area 27. The cover is made of plastic material, obtained in particular by molding, such as polypropylene or polyethylene but can also be made of aluminum. The step is partially elastic so that according to FIG. 4, when a push is exerted by the upper shelf 28, the cover is lowered to lock the plugs 20 on the neck 19.

According to Figure 5, when the push is complete, the cover moves away from the plugs due to the elastic nature of the recess. In addition to the advantageous nature of the device described in Figures 3 to 5, due to its simplicity and efficiency, it will be noted that said device has additional advantages with regard to the handling of the various elements composing it. Indeed, the bottoms 15 can be stacked on top of each other as well as the covers 21. The invention also relates to a process for drying a product of interest, in particular a freeze-drying process, characterized in that one places the packaging according to the invention in an appropriate drying apparatus, in particular a freeze-dryer, in that it is dried, in particular a vacuum is produced, for a determined period depending on the product to be dehydrated, in that it is closed the bottles by pressing on the closing means, then in that the packaging is recovered for possible subsequent treatment of destruction or recycling.

According to a preferred method, the packaging comprises a foldable zone which is folded so as to bear on the means for closing the bottles. S

This process is advantageously suitable for continuous implementation minimizing the number of manipulations.

Advantageously, the process can also be carried out automatically. The closure by welding of the container filling orifice achieves the conservation of the product in sterile conditions whatever the subsequent manipulations and operations necessary for the lyophilization process to take place.

Furthermore, the packaging can be used for the prior freezing operation because it can be refrigerated at a temperature low enough to freeze the solution introduced.

The sealed packaging can also be loaded with frozen product obtained in the form of flakes or beads; the charge thus formed can then be lyophilized without opening the sachet since the vapors pass through the porous hydrophobic wall.

The container can also receive dry powder, directly recovered from an atomized stream of hot air from a solution of the product to be preserved. The powder enclosed in the sachet can then undergo sterilization by irradiation. The invention is not limited to the embodiments which have just been described.

According to another variant, for example, the container can be fitted with inlet and outlet pipes, as found on flexible infusion systems, allowing the reconstitution of the product with its solvent and the aseptic connection of various pipes. infusion.

According to other variants, the packaging can be reusable or disposable.

Claims

1. Sealed packaging (1) for drying operations under non-contaminating conditions of a product of interest (3), comprising a hydrophobic membrane (10) microporous, impermeable to liquids but permeable to water vapor, characterized in that that one or more open containers (2), in particular bottles, containing a product (3) to be lyophilized must be housed in said packaging, in that said packaging comprises a housing (7) for said containers covered with a lid ( 10), said cover being formed at least in part of a hydrophobic microporous membrane (10) impermeable to liquids but permeable to water vapor, a closure means (11) for each container, so that a pressure exerted on the lid closes the opening of each container by means of the closing means.

2. A sealed package according to claim 1, characterized in that the closing means (11) are lyophilization plugs positioned on the opening of the containers in the unlocked position.

3. A sealed package according to claim 1 or 2, characterized in that the housing is formed of a flexible sheet whose edges are integral with the edges of an upper sheet forming a cover in microporous hydrophobic membrane.

4. A sealed package according to claim 3, characterized in that the housing is placed on a rigid support.

5. A sealed package according to claim 3, characterized in that the flexible and upper sheets are welded.

6. Waterproof packaging according to claim 1, characterized in that said packaging comprises a part (7) ensuring a certain rigidity of the packaging, a cover at least part of which is formed of a microporous hydrophobic membrane (10) impermeable to liquids but permeable to water vapor, a bottom (6), a foldable area (8) so that the pressure exerted on the cover folds the foldable area and locks the closure means thus closing the openings of the bottles.

7. A sealed package according to claim 6, characterized in that it contains containers (2), in particular bottles, which may be removably or not integral with the bottom (6) of the package or of a support ( 5) housed in the packaging.

8. A sealed package according to claim 6, characterized in that the foldable zone consists of a bellows (8).

9. Packaging according to one of claims 6 to 8, characterized in that the packaging is a cylinder of revolution or a polygonal solid of which a part of the envelope forms the foldable area.

10. Packaging according to one of claims 6 to 9, characterized in that the bottom (6) of the packaging is formed of a microporous hydrophobic membrane and the bottles are held by a suitable support (5) integral with the packaging.

11. Packaging according to claim 1, characterized in that the hydrophobic microporous membrane has a volume porosity greater than 40% and in that the average pore size is between 0.02 and 5 microns.

12. Packaging according to claim 11, characterized in that the hydrophobic microporous membrane is formed at least in part of an optionally fluorinated polyolefin polymer.

13. Packaging according to claim 12, characterized in that the microporous membrane is in woven polypropylene or in polytetrafluoroethylene.

14. Packaging according to claim 1, characterized in that the products to be lyophilized are chosen from the group consisting of biological products, chemicals, pharmaceutical products or food products.

15. Packaging according to claim 14, characterized in that the products to be lyophilized are in frozen and aseptic form, or are dangerous for the environment.

16. Waterproof packaging according to one of claims 6 to 15, characterized in that the skirt (22) ensuring a certain rigidity of the packaging, the cover (24) at least part of which is formed of a microporous hydrophobic membrane. (25) impermeable to liquids but permeable to water vapor form a cover (21) provided with a folding zone (23), covering said bottles (18) and bearing on the bottom (15).

17. A sealed package according to claim 16, characterized in that the skirt (22) is connected to the cover (24) by a recess (23), the zone forming a recess being deformable so that it folds back when a thrust towards the bottles is exerted on the lid.

18. A sealed package according to claim 17, characterized in that the recess forming area is at least partially elastic.

19. A sealed package according to one of claims 16 to 18, characterized in that the skirt and the recess are made of thermoformable polymeric material or of deformable metal.

20. A sealed package according to claim 19, characterized in that the material is chosen from the group consisting of polypropylene, polyethylene, aluminum.

21. Sealed packaging according to one of claims 16 to 20, characterized in that the bottom is provided near the periphery of an edge (17) forming a guide ensuring the positioning of the bottles.

22. A sealed package according to claim 21, characterized in that the inner part of the guide is hollow so that the bottoms are stackable on top of each other.

23. Sealed packaging according to one of claims 16 to 22, characterized in that the bottom (15) is provided on the periphery of a return (16) ensuring the positioning of the bottom on the support (14) on which said bottom is placed.

24. Sealed packaging according to one of claims 16 to 23, characterized in that the lower end of the skirt is extended by a horizontal external flap which bears on the surface (27) of the bottom, external to the guide.

25. A method of lyophilization of a product of interest, characterized in that a packaging according to one of claims 1 to 24 is placed in an appropriate lyophilizer, in that a vacuum is produced for a determined period , depending on the product to be dehydrated, in that the bottles are closed by pressure exerted on the closure means and in that the packaging is recovered for possible subsequent treatment.

26. A method of lyophilization of a product of interest, characterized in that a packaging according to one of claims 6 to 24 is placed in a suitable lyophilizer, in that the vacuum is produced for a determined period , depending on the product to be dehydrated, in that the bottles are closed by pressure exerted on the closure means, and in that the foldable zone is folded so as to bear on the closure means bottles and in that the packaging is recovered for possible further processing.

27. The method of claim 25 or 26, characterized in that the method is carried out automatically.