CZ304107B6 - Method of packaging albumin protein and process of packaging albumin protein in a flexible polymeric container - Google Patents

Abstract

In the present invention, there is disclosed a flexible polymeric container (12) for holding albumin. The container (12) is made of a sheet of flexible polymeric film (34) formed into a bag having a cavity enclosed by a first wall, an opposing second wall, and seals about a periphery of the first and second walls. The seals join an interior portion of the opposing first and second walls and create a fluid-tight chamber within the cavity of the container for storing a concentration of the albumin. A method of packaging the albumin protein into a flexible polymeric container is also provided. Therein a flexible polymeric material is converted into bags, the bags are filled with a quantity of albumin by a filler (44), and a seal area of the bags is sealed to enclose the albumin within the bag.

Description

Technical field

The present invention relates generally to the packaging of proteins in a flexible polymeric packaging and more particularly to the packaging of albumin in a flexible polymeric packaging material, wherein the packaging is performed in an aseptic environment of the packaging machine for forming, filling and subsequently sealing the packaging.

BACKGROUND OF THE INVENTION

A number of uses of many peptides and proteins for pharmaceutical or other purposes are known, including glycoproteins, lipoproteins, immunoglobulin, monoclonal antibodies, enzymes, blood proteins, protein binding receptors, and hormones.

One type of such mixture is albumin. Albumin is a water-soluble sulfur-containing protein that solidifies on heating and occurs in egg white, milk, blood and other animal and plant tissues and secretions. Albumin is often used as a blood-enhancing agent, thereby contributing to maintaining the patient's blood pressure, or sometimes contributing to increasing the patient's blood pressure during bleeding.

Proteins, such as albumin, are adsorbed by most of the artificial materials, including coatings for liquids made of different polymers. The adsorption of proteins on artificial polymer surfaces causes the protein content of such a solution to be reduced. Some protein solutions may be adversely affected by protein adsorption on artificial surfaces in a process called denaturation. Denaturation is a process in which the protein is not adsorbed permanently into the polymeric envelope, but the protein molecules are adsorbed on the envelope and then released. Adsorption and release can alter the shape of the molecule (ie, deprive it of its original properties). Often, when protein molecules in solution undergo denaturation, they can lose their efficacy and utility. Therefore, to date, proteins such as albumin have been stored for individual use in glass ampoules to eliminate the risk of denaturation. Because of the cost of manufacturing, packaging, shipping, transporting and storing glass ampoules, as well as the cost of glass ampoule weight and the high risk of glass ampoule breakage, it is desirable to overcome these disadvantages and to use a more efficient, inexpensive and user-friendly means. packaging proteins such as albumin.

One type of packaging used for packaging non-proteinaceous drugs is a polymer bag formed in a packaging machine to form, fill and then seal the packaging. Packaging machines for forming, filling and subsequently sealing the packaging are devices for packaging certain medicaments and many other products in a cheap and efficient manner.

In accordance with FDA requirements, certain drugs packaged in a packaging machine for forming, filling and sealing the package are typically sterilized after packaging in an autoclave. This step of packaging the drug involves placing the sealed package containing the drug in an autoclave and sterilizing with steam or heating the package and its contents to a desired temperature, which is often about 120 ° C (250 ° F) for a predetermined period of time. This stabilization step causes destruction of the bacteria and other contaminants present within the package, whether on the inner layer of the coating or in the drug itself.

However, certain types of packaged drugs, including proteins such as albumin, cannot generally be sterilized in this manner. This is because the heat needed to kill the bacteria used in the autoclave destroys or destroys certain drugs. In addition, in the case of albumin protein, heat can cause protein coagulation.

- 1 GB 304107 B6

A package in which the package is formed, filled and subsequently sealed may also present other problems beyond the sterilization of certain proteins such as albumin.

Particularly conventional packaging devices, where the mold is filled and the packaging sealed, bring heat to certain regions of the polymeric packaging material to form a tight seal there. If heat comes into contact with the protein, during this sealing step the protein may coagulate or otherwise lose its properties during high temperature sterilization. Moreover, since certain proteins, such as albumin, act as insulators, all surfaces to be sealed must be protein-free in order for the polymeric materials to heat-seal together. If any protein, such as albumin, is present on the sealing surface prior to sealing, the integrity of the tight joint may be compromised.

Therefore, there is a need to provide suitable, economically advantageous compositions for packaging certain proteins, including compositions such as albumin.

SUMMARY OF THE INVENTION

The present invention provides a flexible polymeric coating for preserving the concentration of peptides and / or proteins. Such peptides and proteins include: glycoproteins, lipoproteins, immunoglobulin, monoclonal antibodies, enzymes, blood proteins, protein binding receptors, and hormones. Further, the present invention provides a method of packaging such a composition in a flexible polymeric wrapper. Generally, the flexible polymeric wrapper comprises a flexible film sheet formed into a bag. The bag has a cavity bounded by a first wall and an opposite second wall. The bag further has a seal around the periphery of the first and second walls, which connects the inner portion of the opposing first and second walls and thus forms a waterproof chamber within the cavity of the package. A compound of unchanged concentration is then stored within the waterproof chamber. In one embodiment, the compound is albumin.

The essence of the method for packaging an albumin protein consists in the steps of: providing a flexible polymeric shell having an opening from the cavity of the polymeric shell; providing an amount of concentrated albumin in a sterile solution; providing a filler neck with an outer casing concentric with the filler neck, and an air passageway extending between the interior of the housing and the exterior of the filler neck, the outer casing defining contact between the polymeric opening and the filler neck, wherein sterile air passes through the airflow passageway; omitted adjacent the end portion of the filler neck and against the albumin outlet; introducing albumin under positive pressure in the solution delivery line, from about 28 to about 138 kPa, into the cavity of the polymeric shell through an opening formed therein; and sealing the opening for securing the liquid albumin within the liquid-tight chamber of the polymer container cavity.

The principle of packaging an albumin in a flexible polymeric package is to comprise a layer of flexible polymeric film formed into a bag having a cavity, closed by a first wall and an opposed second wall and a first longitudinal seal, a second longitudinal seal and an end seal around the perimeter of the first and second walls The seals connect the inner portion of the opposed first and second walls to form a liquid tight chamber within the container cavity, wherein the concentrated albumin at least about 20% mixed with sterile water and stabilizer solution is stored within the liquid tight chamber and wherein the seals are free of concentrated albumin.

According to one aspect of the present invention, the flexible polymeric coating for preserving the concentration of water-soluble albumin comprises a layer of flexible polymeric material which is first formed into a tube by a forming apparatus and subsequently transformed into a row of adjacent bags. The bags have a first side member and a second side member closely coupled to the first side member and a cavity between the interior of the first and second side members. A dose of concentrated water-soluble albumin is then stored within the bag cavity. The bag openings are then sealed to form a waterproof chamber.

-2GB 304107 B6

According to another aspect of the present invention, the package has a plurality of peripheral edges. Three of the peripheral edges are sealed by heating and one of the peripheral edges comprises a fold that separates the first wall or first side member from the opposite second wall or second side member.

According to another aspect of the present invention, another accessory adjacent the fold is attached to the package. This accessory extends from the outside of the package at the fold and is provided with a channel connected to the waterproof chamber of the package. The sealed channel opens into the container cavity to allow passage of albumin from the waterproof chamber. On the opposite sides of the accessory and along the fold, an arrow-shaped sample may be placed at some distance to assist in the removal of albumin from the container.

According to another aspect of the present invention, the peripheral edge of the wrapper opposite to the fold comprises a first seal and a second seal. The first and second seals connect the opposing first and second walls. Between the first and second seals there is an opening that extends between the first and second and opposite walls.

According to yet another aspect of the present invention, the flexible polymeric material comprises a laminated film having an outer layer of linear low density polyethylene, a gas tight layer, a central layer of polyamide, and an inner layer of linear low density polyethylene. These layers are glued together using polyurethane adhesive.

According to another aspect of the present invention, the albumin at 20 and 25% concentration is packaged in a flexible polymeric wrapper. The flexible polymer packaging may have a volume of 50 or 100 ml.

Another, further aspect of the present method of packaging albumin proteins comprises forming a flexible polymeric coating having an opening opening into the polymeric packaging cavity, preparing a dose of sterile concentrated albumin solution, injecting albumin using pressure into the polymeric packaging cavity through the opening, and sealing the opening to the liquid-tight chamber, in the cavity of the container, sealed tightly.

Another, further aspect of the present invention is a filling device used to incorporate albumin into a flexible container. The filling device is provided with a distal end with adjacent first and second inner channels. The first inner channel has a cross-sectional area larger than the second inner channel. The second inner channel abuts the first inner channel and extends to the end surface, wherein the albumin is dispersed from the feed device through the second inner channel.

Yet another aspect of the present invention is that the transition between the first inner channel and the second inner channel is within the outer end portion, wherein the second inner channel opens at the outer end portion. The albumin is maintained in the transition portion between the first and second inner channels during the interruption of the bag filling.

Another aspect of the present invention is to locate the housing from outside the portion of the filler neck adjacent the end. The housing prevents contact between the polymeric coating and the filling device.

An aspect of the present invention is also that the housing is positioned concentrically with the filler neck. An air duct extends between the inside of the housing and the outside of the filler neck. Sterilized air passes through the air duct and is deflated at the tip of the filling device prior to the albumin outlet.

An aspect of the present invention is that the albumin is packaged in a series of flexible polymeric packages in a packaging machine that performs package shaping, filling, and subsequent sealing. A certain amount of filtered albumin and a flexible polymeric material is used, wherein the packaging machine, which shapes, fills and seals the packages, converts the flexible polymeric material into a variety of bags. The bags are filled with doses of albumin in a packaging machine for forming, filling, and filling

Subsequent sealing of the package, the sealing surface of the bags being sealed by the packaging machine, thereby closing the dose of albumin in the bag.

Another aspect of the present invention is that the adjacent bags are initially joined, then sequentially filled with doses of albumin, and then separated from each other following filling.

Another further aspect of the present invention is that the packaging forming machine, the filling and sealing packages, is provided with an aseptic zone. The sterilized, flexible polymeric material is located in the aseptic zone and is also formed into sachets in the aseptic zone. Also, filtered albumin is introduced into sachets in this aseptic region, as well as the sachets in this aseptic zone are sealed to form a liquid-tight coating.

Another aspect of the present invention is that the albumin is packaged in a plurality of polymer packages in a packaging machine for forming, filling and sealing the packages by the following process: the resilient polymeric material is transformed into a tube shape in the packaging machine; the tube is transformed into a series of bags in a packaging machine to form, fill and subsequently seal the wrapper, which is gradually filled with albumin doses, then sealing the sealing area in the packaging machine, thereby sealing the albumin doses inside the bag. The bags may be filled with a filling device that dispenses albumin into the bag without coming into contact with the sealing region of the bag opening.

According to yet another aspect of the present invention, the albumin is packaged in a flexible polymeric wrapper using the following procedure: concentrating albumin; utilizing a packaging machine having a forming portion, a filling portion, and a sealing portion each located in the inner aseptic environment of the packaging machine to form, fill and then seal the package, and utilize a flexible polymeric film that forms into an elongate tube in the forming parts. Thereafter, a portion of the elongated polymer foil tube is sealed in the sealing portion of the device, whereupon the sealed polymer foil is metered into a bag having a sealing area around its periphery, a cavity situated within the bag between the sealed regions and an opening connecting the cavity with the bag. The bag is filled with albumin under pressure in the filling section. The filling section is provided with a filling tube passing through an opening in the bag into the bag cavity and a cover that is concentric to the outer surface of the filling tube. Through the feed tube, albumin is directed into the interior of the bag, without touching the perimeter of the opening in the bag, with the cover preventing contact between the feed tube and the bag. The bag opening is then sealed to seal the albumin inside the bag cavity.

The flexible polymeric albumin storage container formed in accordance with the present invention provides an inexpensive, easy-to-manufacture and efficient container, and the invention also provides a method of manufacture. The effective container and method of the invention overcome the disadvantages associated with previously known containers and production methods for packaging albumin.

Other features and advantages of the invention will be apparent from the following description taken in conjunction with the accompanying drawings.

Overview of the drawings

BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be explained in more detail with reference to the drawings, in which: Figure 1 is a cross-sectional side view of a packaging machine forming, filling and sealing the containers according to the invention for the manufacture of polymeric containers holding concentrated albumin;

Fig. 2 is a schematic view of a method of making a flexible polymeric wrapper according to the present invention capable of storing concentrated albumin;

Fig. 3 shows a side view of a flexible polymeric coating according to the present invention, for preserving concentrated albumin;

Fig. 4 is a partial side view of the flexible polymeric envelope of Fig. 3 according to the present invention capable of storing concentrated albumin;

Figure 5 is a side view of a portion of the filling device of the present invention;

Figure 6 is an enlarged side view of a portion of the filling device of Figure 5;

Fig. 7 is a side cross-sectional view of a housing for a filling device according to the present invention; Figure 8 is a view of the ends of the housing of Figure 7;

Fig. 9 shows schematically a cross-section of one embodiment of a laminated film structure according to the present invention; and Fig. 10 is a cross-sectional view of an end of a feed tube and a cover according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

While the present invention may be practiced in many different embodiments, it is shown in the drawings and described in detail in the preferred embodiments of the invention, and it is understood that the present description is intended to be exemplary of the principles of the invention. design.

As noted above, the breadth of the present disclosure encompasses packaging for any type of certain pharmaceutical compound, such as peptides and proteins for pharmaceutical or other uses. Such compounds are known and include: glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, protein binding receptors, and hormones.

For purposes of example, however, the detailed description of the present invention is directed to providing albumin with a flexible polymeric coating.

FIG. 3 shows in detail the flexible polymeric wrapper 12 of the present invention storing concentrated albumin.

Preferably, the flexible polymeric wrapper 12 is manufactured on a packaging machine 10 that forms, packs, and seals the wrapper as shown in Figure 1, using the method shown schematically in Figure 2.

The aseptic packaging machine forms a wrapper for filling and sealing, generally comprising an unwinding section 14, a sterilizing section 16 for sterilizing the foil, a drying section 18 for drying the foil, a support roller, a cylindrical section 20 of support rolls / tensioning rolls, a section (not shown) assembled of the nip drive rollers, the forming section assembly 22, the seam sealing section assembly 24, the attachment section 26 for attaching additional accessories, the filling section assembly 30, the end sealing / cutting section assembly 32, and the conveyor section not shown here. Each of these assemblies, located away from the winding section 14, is located in the inner aseptic environment of the packaging machine 10 forming, filling and sealing the packages.

One function of one possible assembly of the packaging machine 10 is as follows: the unwinding section 14 comprises a roll with a wound flexible polymeric film 34 which is ultimately formed into a package. A peroxide bath is used to sterilize the resilient polymeric film, which in the sterilization section 16. The drying section 18 for drying the resilient polymeric film 34 is equipped with means for drying and removing peroxide from the resilient polymeric film 34. The forming section 22 is provided with a forming darkness36.

304107 B6 for converting the film into a tube 38 that eventually turns into a flexible wrap 12 or bag.

The seam sealing section 24 provides a longitudinal seal 40 on the tube 38, which eventually becomes a longitudinal seal 40 on the flexible package 12. The connecting section 26 connects the element 42 to the tube

38. The fill section 30 comprises a filler neck 44 which fills the flexible polymeric wrappers 12 with a substance that is concentrated water-soluble albumin in this preferred embodiment of the present invention. The end sealing / cutting section 32 comprises shearing and sealing jaws 46 that form end seals 76, 78 of the resilient polymeric wrapper 12 to seal the albumin within the resilient polymeric wrapper 12.

In a preferred embodiment, the albumin used for packaging is either 20% human albumin or 25% human albumin. Albumin is usually mixed with sterilized water and stabilizers to achieve the desired concentration level. Prior to packaging, albumin is pasteurized at a given concentration and stored in large stainless steel storage tanks (not shown) having a volume capacity of 500 to 600 liters, maintaining the temperature at 2 to 8 ° C. Just prior to packaging, albumin containers are removed from the refrigerators and allowed to equilibrate with the packaging room temperature (approximately 20 ° C (ie 68 ° F)). It is important that the albumin is processed at a temperature that does not lead to protein denaturation, at about below 60 ° C. However, a temperature between 0 and 60 ° C is acceptable, but a temperature between 20 and 45 ° C is more preferred. In one embodiment of the invention, the treatment temperature is 20 to 25 ° C (ie, 68 to 77 ° F). Albumin is filtered through a 0.2 µm filter when it enters the packaging machine 10.

The flexible polymeric film 34 used in the preferred embodiment of the present invention is a linear low density polyethylene laminate. It has been found that such a flexible, gas-tight polymeric film 34 is particularly suitable for encapsulating oxidation-prone solutions, such as said proteins, including albumin. In particular, it has been found that this film 34 reduces or eliminates the denaturation process previously associated with the placement of proteins such as albumin in a plastic container. As shown in Fig. 9 of the preferred embodiment, the laminated flexible polymeric film 34 has an outer layer 52 of linear low density polyethylene (LLDPE), a gas tight layer 54, a core layer 56 of polyamide and an inner layer 58 of linear low density polyethylene. 60. In view of the material requirements of the laminated structure, it is most preferred that the structure has the following characteristics: an outer layer 52 of linear low density polyethylene (LLDPE) (about 61 pm ± 10 pm) 2; a layer of polyurethane adhesive 60, a polyvinylidene chloride (PVDC) gas tight layer 54 (about 19 µm ± 5 µm); a layer of polyurethane adhesive 60; a nylon core layer 56 (about 15 pm ± 5 pm), a polyurethane adhesive layer 60, and an outer layer 52 of linear low density polyethylene LLDPE (about 6 pm ± 10 pm). The total thickness of the flexible polymeric film 34 is approximately 160 µm ± 25 µm.

It is preferred to use a polyvinylidene chloride (PVDC) gas-tight layer 54, manufactured by Dow Chemical and sold under the trademark SARAN. This film is described in U.S. Pat. No. 4,692,361. The owner of U.S. Pat. No. 4,692,361 is the applicant for the present invention. This document is incorporated into and constitutes a part of this invention. This flexible polymeric film 34 is manufactured by Fujimori under the trade name FTR-13F.

The inner aseptic zone of the packaging machine 10 must be sterilized daily before use. This sterilization is carried out with hydrogen peroxide vapors that pass through the aseptic zone of the packaging machine.

As can be seen from FIG. 1, a roll of flexible polymeric film 34 is placed in the unwinding section 14 of the packaging machine 10. While the wrapping machine 11 is in operation, the flexible polymeric film 34 is conveyed through the hydrogen peroxide bath of the sterilization section 16 to be sterilized before entering the aseptic In this sterilization step, the flexible polymer film 34 is cleaned so that it can be

Used to create a sterile product. Sterilization and cleaning of the film is critical in the medical field when parenteral or enteral products are packaged in the flexible polymer film 34. In particular, this sterilization step is critical if the end product is not sterilized at the end of production, i.e., if a packaging machine 10 equipped with an aseptic zone is used. After the flexible polymeric film 34 is washed, cleaned or sterilized, liquid or other residues, such as a sterilizing chemical agent or wetting agent, such as hydrogen peroxide, usually remain on the film. It is therefore necessary to remove this liquid and / or residues from the flexible polymer film 34. To remove liquid and other residues from the flexible polymeric film 34, an air curtain is used (an air stream driven across the surface of the flexible polymeric film 34 to blow off the liquid adhered therein) located in the drying section 18 through which the elastic polymeric film is removed. 34 removes liquid and other debris prior to entering the aseptic zone of the packaging machine.

In the aseptic zone of the wrapping machine 10, the flexible polymer film 34 passes before it enters the forming section assembly 22 through the cylindrical section 20 and through the drive cylindrical section. Before it enters the forming section assembly 22, the flexible polymer film web 34 is substantially planar and has a first surface 62 and a second surface 64. The first surface 62 faces downward as the flexible polymer film 34 enters the forming section assembly 22, finally becomes the interior of the wrapper 12, while the second surface 64 of the resilient polymeric film 34 faces upward as the film enters the forming section assembly 22 and eventually becomes the outside of the wrapper 12.

3 and 4, the resilient polymer film 34 has a theoretical line around which the web of film 34 is bent about the longitudinal centerline of the web of the resilient polymer film 34. The area around the theoretical line around which the bending occurs, becomes the fold region 67 which separates the first wall 66 and the second wall 66, respectively. a first side member from the second wall 68, respectively. a second side member of the package 12.

The forming darkness 36 is located in the forming section 22. The forming darkness 36 converts the original, substantially planar web of flexible polymeric film 34 into an elongated and substantially cylindrical tube 38. Of course, the elongated cylindrical tube 38 or member is not generally shaped 4, but having a somewhat flattened shape as shown in FIG. 4. In connection with the marking of the web surfaces of the flexible polymer film 34, as described above, after passing the flexible polymer film 34 through the forming section assembly 22, the first surface 62 of the first wall 66 it aligns against the first surface 62 of the second wall 68.

After the cylindrical tube 38 has been formed, the cylindrical tube is provided with a longitudinal seal 40 in the seam sealing section assembly 24, the element 42 engaging with the pipe 38 in the connecting section assembly 26. The device is pressed against the outside of the shell shell 12 in the fold region 67 of the shell 12 around which it is guided using a heated device to seal the contact between the member 42 and the fold region 67. Typically, the sealing member 42 operates at a temperature of from about 212.77 to about 232.22 ° C (415 to about 450 ° F), at a pressure of about 379 to about 483 kPa (55 to about 70 psig), although any range is applicable. at the specified intervals. As shown in FIG. 4, the member 42 is provided with a sealed channel that cooperates with the interior of the tube 38. The channel opens into the cavity 82 of the container 12 and allows the albumin to be released from the liquid-tight chamber. It should be understood that in some embodiments, albumin may be injected into the cavity 82 of the container 12 by the element 42.

The seam sealing section 24 applies a temperature to exert pressure on the resilient polymeric film 34 to form a longitudinal seal 40 at the peripheral edge of the tube 38 which is opposite the fold region 67. Typically, the seam sealing section 24 operates at a temperature of about 176.66 to about 193 33 ° C (350 to about 380 ° F) and at a pressure of about 276 to about 552 kPa (40 to about 80 psig), however, any range within these ranges is possible. In a preferred embodiment of the package 12 shown in Fig. 3, the longitudinal seal 40, the first longitudinal seal 70 and the second longitudinal seal 72. The first longitudinal seal 70 and the second longitudinal seal 72 connect the first surface 62 of the first wall 66 to the opposite first surface 62 an opening 74, typically used for hanging

304107 B6 of the formed container 12 is formed between the first longitudinal seal 70 and the second longitudinal seal 72. The aperture 74 extends through the first wall 66 and the opposite second wall 68.

The sealed cylindrical tube 38 proceeds from the seam sealing section 24 to the filling section 30 and to the end sealing section 32. At the end sealing section 32, the packaging machine 10), for forming, filling and sealing the wrapper, utilizes heat and pressure to convert the sealed pipe 38 Typically, the end seal section 32 operates at a temperature of from about 190.55 to about 207.22 ° C (375 to about 405 ° F) and a pressure of about 3447 to about 5861 kPa (500 to about 300 ° F). 850 psig), although any range within these intervals may be utilized. The sealed tube 38 is first provided with a lower end seal 76 to form a shell 12 having a cavity 82 disposed between the first wall 66 and the second wall 68 of the shell 12 and a lower bag end seal 76 and an opening 80 connecting the cavity 82 of the shell 12 to the outside. Obviously, during the manufacturing process when the container 12 is formed, filled and sealed, the opening 80 from the cavity 82 of the container 12 extends to the center of the tube 38. After forming the bottom end seal 76, the container 12 is filled through the opening 80 with albumin. an upper seal 78 is formed, thereby sealing or sealing the top seal 78; it closes the opening 80 to form a liquid-tight cavity 82 in which the albumin is placed. After the lower end seal 76 has been formed, the resilient polymer film 34 can be sized for an open package 12 having sealing areas around its periphery (a longitudinal seal opposite the fold region 67 and a bottom end seal 76 connecting the fold region 67 and the longitudinal seal 40) and having a cavity 82 disposed within the container 12 and between the seals 40, 76 and the fold region 67. By the method in which the container 12 is shaped, filled and sealed, a final container 12 is formed having sealed areas on three sides thereof: an upper seal 78, a lower end seal 76 and a longitudinal seal 40. The longitudinal seal 40 connects the upper seal 78 and the lower end seal 76. In a preferred embodiment of the method, the upper seal 78 of the first package 12 is formed simultaneously as the lower end seal 76 of the adjacent subsequent package 12. end sealing section 32. Neighbor The wrappers 12 lying in the row of bags are initially joined both by being part of the cylindrical tube 38 from which the bags are formed and by having end seals formed in the same end sealing section 32.

In a preferred embodiment of the method for forming and filling the containers 12 according to the present invention with albumin, the containers 12, as shown in Figures 1 and 2, are filled with albumin by a filling section 30 which extends down the tube 38. This filling section 30 fills the container cavity 82 12 through the opening 80 after forming an open package 12 having three sides.

The filling section 30 is shown in Figures 5 to 8 and 10 in accordance with a preferred embodiment. The filling section 30 comprises a pressure filler neck 44 formed by a filling tube 84 and a housing 86 disposed concentrically around the periphery of the filling tube 84.

The pressure filler neck 44 typically operates under pressure in the solution supply line, which ranges from about 28 to about 138 kPa (from about 4 to about 20 psig), but any ranges that are within that range are possible. In a preferred embodiment, the pressure filler nozzle 44 operates with a solution supply line pressure of from about 10 to about 16 psig, with the most preferred mode where the solution line pressure is from about 83 to about 100 psig (10 to about 16 psig). to about 110 kPa (12 to about 16 psig). Said ranges are used to reduce turbulence and spattering of albumin and other proteins when the container 12 is filled. As noted above, after forming the lower end seal 76 of the subsequent container 12, the upper seal 78 is formed. is part of the tube 38 and so on. Adjacent packages 12 in the array of packages 12 are initially joined and separated after subsequent filling and sealing of each respective package 12.

As shown in Fig. 5, in a preferred embodiment, the filler neck 44 of the filler section 30 is configured as a sleeve tube 86 extending over the tube 84. The sleeve tube 86 is arranged concentrically around the filler tube 84 with an air passageway 88 extending between the inner diameter of the sleeve tube and the outside diameter of the feed tube 84. Sterilized air passes through the air passage 88 and is discharged at the end of the feed tube 84 before exit 92 from the feed tube 84.

-8EN 304107 B6

In a preferred embodiment of the feed tube 84 shown in FIG. 5, the feed tube 84 is provided with a diffuser 85 in which the feed tube 84 conically extends in the direction of its length from the first diameter to the second, larger diameter. As shown further in FIG. 6, the end 90 of the feed tube 84 has a first inner channel 94 concentric and adjacent to the second inner channel 96. In a preferred embodiment of the present invention, the first inner channel 94 typically has a circular cross-section with a first inner diameter and the second inner channel 96 typically has a circular cross-section having a second inner diameter.

The inner diameter of the first inner duct 94 is dimensionally larger than the inner diameter of the second inner duct 96 and hence the cross-sectional area of the first inner duct 94 is larger than the cross-sectional area of the second inner duct 96. The transition 98 between the first inner duct 94 and the second inner duct 96 an inner channel 94 and a second inner channel 96 at a location that is within the outer outlet 92 of the end 90 of the filler tube 84 of the filler neck 44.

In a preferred embodiment, the transition 98 comprises a tapered step between the first inner channel 94 and the second inner channel 96 to thereby sharply reduce the diameter of the first inner channel 94 to the diameter of the second inner channel 96. The transition 98 between the first inner channel 94 and the second inner channel 96 fulfills an important function during operation of the filler neck 44.

Since the albumin is dispensed from the outlet of the second inner channel 96 of the filler neck 44, the capillary forces in the fill tube act such that the albumin, based on the transition 98 between the first inner channel 94 and the second inner channel 96, forms a cup shape here. instead of producing this at the outlet 92 of the second inner channel 96. Although albumin is scattered from the filler neck 44 through the second inner channel 96, during each interruption of filling between successive packings 12, the albumin remains within the filler neck 44 at some distance from the outlet the filler neck 44 at the transition 98 between the first inner channel 94 and the second inner channel 96. Such an arrangement greatly contributes to preventing unwanted removal of albumin from the outlet of the filler neck 44. Any albumin migration may cause the transfer of albumin to the exterior of the filler neck 1a 44 and its transfer to a flexible polymeric film 34 · As explained above, albumin acts as an insulator. If albumin were transferred to the resilient polymeric film 34, this would likely compromise the integrity of the top seal region. The arrangement of the solution according to the present invention thus provides a means to overcome this disadvantage. In the leak test of the container 12 of the present invention, 99.90% of the formed containers 12 had a minimum breaking strength value of 138 kPa (20 psi).

As explained above, the sleeve 86 is disposed concentrically around the periphery of the fill tube 84, wherein an air channel 88 is guided in the space between the inner diameter of the sleeve tube 86 and the outer diameter of the fill tube 84.

In a preferred embodiment, a remote end portion 100 is mounted to the housing 86 as an adapter, which end portion 100 may be formed as part of the housing 86 without interfering with the intended function of the housing 86. As shown in Figures 7 and 8, the end portion 100 a plurality of vent holes 102 are formed near the end of the end portion 100 of the capsule 86. These vent holes 102 disperse sterilized air from the air duct 88. Since the vent holes 102 are located at the beveled edge 104 of the cartridge 86, the sterilized air flow profile corresponds outside of the circumference of the albumin flow profile that is supplied from the feed end, so that there is no mixing of the albumin flow with the sterilized air flow. This reduces the possibility of swirling in the introduced albumin. In addition, since the airflow profile is situated externally and away from the liquid albumin flow profile, there is minimized the possibility of foaming that could arise when the air contacts the albumin. As well as the advantages associated with the dual internal diameters of the feed tube 84, the advantages associated with the use of sterilized air flow are extremely useful. Such an arrangement greatly contributes to preventing splashing and foaming of albumin as it exits from the filling throat 44. This prevents contact of albumin

304107 B6 with a portion of the resilient polymeric film 34 which is then converted into an upper seal region, thereby also aiding in the continuous formation of a stronger upper seal.

The first inner diameter 106 of the end portion 100 of the housing 86 is sized to engage the housing 86 and is secured thereto by an adjusting screw 110. The second inner diameter 108 of the end portion 100 of the housing 86 is sized to allow air channel 88 between As shown in FIG. 7, at the end of the end portion 100 with the second inner diameter 108, a bevel 112 is provided to further reduce the inner diameter of the sleeve 86. An inverted bevel 114 is formed on the outer portion of the sleeve end 86.

The sleeve 86 and the feed tube 84 are shown in the assembly of Figure 10. As is apparent from Figure 10, the outer diameter of the tube is sized to be equal to or slightly less than the reduced inner diameter of the sleeve 86 at the chamfer 112. In a preferred embodiment the second inner diameter of the housing 86 is approximately 0.014 m (0.584 inches) and is reduced at a chamfer 112 to approximately 0.0127 m (0.500 inches). The outer diameter of the feed tube 84 in a preferred embodiment of the present invention is about 0.0127 m (0.500 inches). In this arrangement, the transition between the bevel 112 and the feed tube 84 acts to close the air passage 88, expelling sterilized air out of the air vents 102 located upstream of the exit 92 of the second internal passage of the feed tube 84 for the albumin.

As shown in FIG. 10, the outer diameter of the sleeve 86 is larger than the diameter of the filling tube 84 extending outside the sleeve 86. During the filling of the foil tube 38, the tube 38 often comes into contact with the filling section 30. the arrangement of the fill tube 84 and the sleeve 86, the fill tube 84 of the fill section 30 extends through the opening 80 of the container 12 into the cavity 82 of the container 12, the sleeve 86 is outside the portion of the fill tube 84 and hence only the sleeve 86 can touch the tube 38 thereby preventing contact between The outlet 92 of the filler tube 84 is located at a distance from the inner wall of the flexible polymeric wrapper 12. The position and size of the housing 86 in conjunction with the inner surface 98 of the first and second inner ducts and the inverted bevel 114 prevents albumin from reaching the outside of the filling section 30 and coming into contact with the sealing surface which eventually becomes the top seal 78 of the finished package. Since albumin acts as an insulator, it is necessary to keep all sealing surfaces clean, protein-free, so that the polymeric materials can be sealed together when heated.

If any amount of albumin was present on the sealing surface prior to sealing, this could compromise the integrity and thus the tightness of the joint. In said embodiment, the albumin is supplied from the feed tube 84 to the bottom of the bag 12 without contacting the seal sealing area of the package 12, which eventually becomes the top seal 78.

Typical embodiments of the invention have been illustrated and described above. It will be appreciated, however, that numerous modifications can be made without departing from the spirit of the invention. The scope of protection is only limited by the scope of the appended claims.

Claims (36)

PATENT CLAIMS What is claimed is: 1. A method of packaging an albumin protein comprising the steps of: providing a flexible polymeric wrapper (12) having an opening (80) from a cavity (82) of the polymeric wrapper (12); providing an amount of concentrated albumin in a sterile solution; securing the filler neck (44) with an outer sleeve (86) with a concentric soiling sleeve (44), and an air passageway (88) extending between the inside of the sleeve (86) and the outside of the filler neck (44); 86) defining contact between the aperture (80) of the polymeric package (12) and the filler neck (44), and wherein sterile air passes through the air passageway (88) and is discharged adjacent the end portion of the filler neck (44) and against the albumin outlet; introducing albumin under positive pressure in the solution delivery line, from about 28 to about 138 kPa, into the cavity (82) of the polymeric shell (12) through the opening (80) formed therein; and sealing the opening (80) for securing the liquid albumin within the liquid-tight chamber of the cavity (82) of the polymeric shell (12). The method of claim 1, wherein the albumin is maintained at a temperature of about 20 ° C prior to introduction into the cavity (82) of the polymeric shell (12). The method of claim 1, wherein the albumin is introduced into the cavity (82) of the flexible polymeric shell (12) under a positive pressure of about 83 to about 110 kPa in the solution delivery line. Method according to claim 1, characterized in that the flexible polymeric coating (12) is provided internally with the aseptic environment of the packaging machine (10) forming, filling and sealing the package, wherein the albumin is introduced into the cavity (82) of the flexible polymeric coating (12). ) in the aseptic environment of the packaging machine (10) forming, filling and sealing the package, and wherein the packaging opening (80) is sealed in the aseptic environment of the packaging machine (10) forming, filling and sealing the package. The method of claim 1, wherein the end portion (90) of the filler neck (44) comprises a first and a second, adjacent, internal passageway (94, 96), the first internal passageway (94) having a greater cross section than a second inner passageway (96), the second inner passageway (96) extending adjacent the first inner passageway (94) to the outside of the end portion (90), and wherein the albumin is supplied from the filler neck (44) through the second inner passageway ( 96). The method of claim 5, wherein the first and second inner passageways (94, 96) are concentric, the first inner passageway (94) having an inner diameter dimensionally larger than the inner diameter of the second passageway (96). Method according to claim 1, characterized by centering. Method according to claim 1, characterized by centering. The method of claim 1, wherein (12) has a volume of 50 ml. The method of claim 1, wherein (12) has a volume of 100 ml. in that the albumin is supplied in 20% accounts, that the albumin is delivered in 25% accounts, that the resilient plastic polymeric coating by the resilient plastic polymeric coating The method of claim 1, further comprising providing a flexible polymeric coating (12) comprising a laminated flexible polymeric film (34) having an outer layer (52) of linear low density polyethylene, a gas tight layer (54), a central layer (56) of polyamide and an inner layer (58) of linear low density polyethylene, wherein the layers are bonded together with a polyurethane adhesive (60). The method of claim 1, wherein the filtered albumin protein is packaged in a series of resilient polymeric sheaths (12), and wherein the step of providing the resilient polymeric sheath (12) comprises: providing a flexible polymeric material; Providing a packaging machine (10) forming, filling and sealing the package, and processing the resilient polymeric material into a series of bags in the packaging machine (10) forming, filling and sealing the package; and wherein the step of administering the albumin comprises: - filling the bags with batches of albumin in a packaging machine (10) forming, filling and sealing the packaging; and wherein the step of sealing the opening (80) comprises: - sealing the sealing area of the bags with the packaging machine (10) to seal the dose of albumin inside the bags. Method according to claim 12, characterized in that adjacent bags adjacent to each other in a series of bags are initially joined together and separated after each bag has been filled. The method of claim 13, further comprising providing a forming mandrel (36) in the packaging machine forming, filling and sealing the package. The method of claim 14, further comprising reshaping the resilient polymeric material into the tube by means of forming darkness (36) and further reshaping the tube into a series of adjacent bags. The method of claim 12, wherein the bags are sequentially filled with doses of albumin. 17. The method of claim 12, further comprising heat sealing the periphery of the bags to close the albumin dose within the bags. The method of claim 12, wherein the flexible polymeric wrapper (12) comprises a laminated film (34) having an outer layer (52) of linear low density polyethylene, a gas tight layer (54), a central layer (56) of polyamide, and an inner layer (58) of linear low density polyethylene, wherein the layers are bonded together with a polyurethane adhesive (60). The method of claim 12, wherein the packaging machine forming, filling and sealing the packaging has an aseptic region, wherein the resilient polymeric material is secured in the aseptic region and is formed into a series of adjacent bags within the aseptic region, wherein albumin is subsequently introduced into the aseptic region. of the bags in the aseptic region, and wherein the bags are subsequently sealed within the aseptic region to form a liquid-tight package. The method of claim 12, wherein the end portion (90) of the filler neck (44) comprises a concentric first and a second inner passageway (94, 96), the first inner passageway (94) having a cross-sectional area greater than the area a cross-section of the second inner passageway (96), wherein the interface between the first and second inner passageway (94, 96) is inside the outer end portion (90), the second inner passageway (96) extending to the outer end portion, wherein albumin exits a filler neck (44) through the second inner passageway (96), and wherein the albumin is maintained at the interface between the first and second inner passageways (94, 96) during the interruption of filling. The method of claim 12, further comprising the step of filtering the albumin through a 0.2 µm filter. The method of claim 1, wherein the albumin is packaged in a sterile flexible polymeric container (12), comprising the step of: - providing a packaging machine (10) having a filling assembly (30) and a sealing assembly (32), the filling and sealing assembly (30, 32) being located within the aseptic environment of the packaging machine (10); and wherein the step of administering the albumin comprises: - 12GB 304107 B6 - filling the container with albumin under pressure by means of a filling assembly (30) within the aseptic region of the packaging machine (10), the filling assembly (30) having a filler neck outlet (44) spaced from the wall of the flexible polymeric sleeve (12); directing the albumin into the package cavity (82) towards the periphery of the package opening, and the filler neck (44) retains the albumin in the filler neck (44) spaced from the outlet of the filler neck (44) during the filling interruption; and wherein the step of sealing the opening comprises: - sealing the opening of the package in the aseptic area of the packaging machine (10) to retain the albumin within the package cavity (82). The method of claim 1, wherein the step of providing a flexible polymeric wrapper (12) comprises: - providing a packaging machine (10) having a forming section (22), a filling section (30), and a sealing section (32), each of which is located within the aseptic environment of the packaging machine (10); - providing a flexible polymeric film (34); - shaping the flexible polymer film (34) into the elongate tube by a shaping section (22); - sealing a portion of the elongate polymer foil tube (34) with a sealing section (32), the sealed polymer foil (34) being sized to form a bag having a sealing region around its periphery, a cavity (82) located within the bag and between the sealing regions; an opening from the cavity (82) to the outside of the bag; and wherein the albumin loading step comprises: - filling the bag with albumin under pressure in the solution line by means of a filling section (30), the filling section (30) having a filling throat (44) passing through the opening of the bag and into the bag cavity (82), and a sleeve (86) concentric with the outside (44), the filler neck (44) directs albumin into the interior of the bag at a distance from the periphery of the bag opening, and the housing (86) defines contact between the filler neck (44) and the bag; and wherein the opening sealing step comprises: - sealing the opening of the bag to hold the albumin in the bag cavity (82). 24. The method of claim 23, wherein the sealing regions are provided around the entire circumference of the bag except the opening. A method according to claim 23, characterized in that said plurality of adjacent bags. characterized in that it further comprises converting the tube 26. The method of claim 25, further comprising sealing at least three sides of the bags. 27. The method of claim 25, further comprising sequentially filling the sachets with a dose of albumin. 28. The method of claim 27, further comprising sequential sealing of the bag opening. 29. The method of claim 23, wherein the end portion (90) of the filler neck (44) comprises a concentric first and second inner passageway (94, 96), a first inner passageway (94). ) has a cross-sectional area larger than a cross-sectional area of the second inner passageway (96), the interface between the first and second inner passageways (94, 96) being inside the outer end portion (90), the second inner passageway (96) extending to the exterior of the end portion (90), wherein the albumin exits the filler neck (44) through the second inner passageway (96), and wherein the albumin is maintained at the interface between the first and second inner passageways (94, 96) during the filling interruption. An albumin package in a flexible polymeric package obtainable by a method according to any one of claims 1 to 29, comprising: a layer of flexible polymeric film (34) formed into a bag having a cavity (82) closed by the first wall (66) and the opposite one A wall (68) and a first longitudinal seal (70), a second longitudinal seal (72) and an end seal (76) around the periphery of the first and second walls (66, 68), connect the seal (70,72, 76) an inner portion of the opposed first and second walls (66, 68), forming a liquid-tight chamber within the cavity (82) of the container, wherein concentrated albumin at least about 20% mixed with sterile water and stabilizers is stored within the liquid-tight chamber; 76) are free of concentrated albumin. Albumin package according to claim 30, characterized in that the flexible polymeric film comprises a laminated polymeric film (34) having an outer layer (52) of linear low density polyethylene adhesively bonded together by a polyurethane adhesive (60) to the first side of the polyvinylidene chloride layer. the polyvinylidene chloride layer is adhesively bonded to the first side of the polyamide layer, the second side of the polyamide layer is adhesively bonded with the polyurethane adhesive (60) to the inner layer (58) of the linear low density polyethylene. The albumin package of claim 30, wherein the bag has a plurality of peripheral edges, the three peripheral edges are heat sealed, and one of the peripheral edges comprises a fold (67) that separates the first wall (66) from the opposite second wall (68). ). Albumin package according to claim 32, characterized in that the cobal is connected to an element (42) adjacent to the fold (67), the element (42) is provided with a sealed passageway which cooperates with the liquid-tight chamber of the package, the sealed passageway extending into a container cavity (82) to allow release of albumin from the liquid-tight chamber. Albumin package according to claim 32, characterized in that the peripheral edge opposite to the fold (67) comprises a first longitudinal seal (70) and a second longitudinal seal (72), the first longitudinal seal (70) and the second longitudinal seal (70). 72) connect the first and second opposing walls (66, 68), and wherein an opening (74) extending through the first and second opposing walls (66, 68) is located between the first longitudinal seal (70) and the second longitudinal seal (72). The albumin package of claim 33, further comprising at least one cuff seal in the fold (67). The albumin package of claim 33, further comprising a cuff seal at the fold (67) on opposite sides of the element (42).