BRPI0208033B1 - method of packing albumin protein - Google Patents

Abstract

"Method of packaging albumin protein, process of packaging albumin in a flexible polymeric container, flexible polymeric container, and albumin-containing container". a polymeric container for containing albumin. the container (12) is made of a flexible polymeric film sheet (34) shaped into a bag having a cavity surrounded by a first wall, an opposite second wall and seals around the periphery of the first and second walls. the seals join an inner part of the first and second opposing walls and create a fluid impermeable chamber within the container cavity to store an albumin concentration. Also provided is a method of packaging the albumin protein into the flexible polymeric container. therein a flexible polymeric material is converted into bags, the bags are filled with an amount of albumin by a filler (44) and a sealing area of the bags is sealed to include albumin within the bag.

Description

(54) Title: METHOD OF PACKING ALBUMINE PROTEIN (73) Holder: BAXALTA GMBH ,. Address: ThurgauerstraBe 130, 8152 Glattpark, Opfikon, SWITZERLAND (CH); BAXALTA INCORPORATED, Legal Person. Address: 1200 Lakeside Drive, Bannockburn, IL 60015, UNITED STATES OF AMERICA (US), North American (72) Inventor: JAMES D. LEWIS, JR .; WILLIAM BACCIA; JOSEF SCHMIDT; JOHAN VANDERSANDE; JOHN CARL CARD; THEODOR LANGER; GEORG HABISON; HELMUT EDER.

Validity Period: 10 (ten) years from 11/21/2018, subject to legal conditions

Issued on: 11/21/2018

Digitally signed by:

Alexandre Gomes Ciancio

Substitute Director of Patents, Computer Programs and Topographies of Integrated Circuits / 21 “METHOD OF PACKING ALBUMINE PROTEIN”

Technical Field [0001] The present invention relates generally to the packaging of a protein in a flexible polymeric container and, more specifically, to the bulk packaging of albumin in flexible polymeric containers, in an aseptic environment of a conformal-filling packaging machine. sealing.

Background of the Invention [0002] Many peptides and proteins for pharmaceutical or other uses are known, including glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins and hormones.

[0003] One type of such a compound is albumin. Albumin is a water-soluble protein, containing sulfur, which hardens when heated and occurs in egg white, milk, blood and other animal and vegetable tissues and secretions. Albumin is often used as a blood dilator to assist in maintaining the patient's blood pressure or, sometimes, to assist in increasing the patient's blood pressure during blood loss.

[0004] Proteins, such as albumin, are adsorbed by most man-made materials, including liquid containers made of various polymers. The adsorption of the protein on the artificial polymeric surface results in a decrease in the protein content of that solution. Some protein solutions can be adversely affected by protein adsorption on artificial surfaces, through a process called denaturation. Denaturation is a process by which the protein is not permanently adsorbed in the polymeric container, but, more precisely, the protein molecules are adsorbed in the container and then released. Adsorption and release can change the shape of the

Petition 870180058002, of 07/04/2018, p. 9/40 / 21 molecule (that is, to denature it). Often, when protein molecules in protein drug solutions are denatured, they can lose their effectiveness and utility. Therefore, until today, proteins such as albumin have been stored for individual use in glass jars, in order to avoid the risk of denaturation. Due to the cost found in the production, packaging, boxing, shipping and storage of glass bottles, as well as the cost and weight of the glass bottle and the ease with which the glass bottle can break, a more efficient, cheap and convenient way for the user to pack proteins such as albumin, to possibly eliminate the above disadvantages, it is desirable.

[0005] One type of packaging used to package non-protein pharmaceuticals is polymeric bags conformed with a forming-filling-sealing packaging machine. Forming-filling-sealing packaging machines are typically used to package a product in a flexible container. The forming-filling-sealing packaging machine provides an apparatus for packaging certain pharmaceuticals and many other products in an inexpensive and efficient manner.

[0006] In accordance with FDA requirements, certain pharmaceuticals packaged in conformation-fill-seal packages are traditionally sterilized in an autoclaving step. The post-packaging step includes placing the sealed package, containing the pharmacist, in an autoclave and steam sterilizing or heating the package and its contents to a required temperature, which is often approximately 121 ^o C, for a prescribed period of time. This sterilization step works to kill bacteria and other contaminants found inside the package, either in the inner layer of the film or inside the pharmacist himself.

[0007] Certain packaged pharmaceuticals, including certain proteins, such as albumin, however, generally cannot be sterilized in such a way.

Petition 870180058002, of 07/04/2018, p. 10/40 / 21 way. This is because the heat required to kill bacteria in the autoclaving process destroys or renders certain pharmacists useless. In addition, in the case of protein albumin, heat can operate to harden the protein. [0008] The forming-filling-sealing package can also present other problems besides sterilization concerns, when packaging certain proteins such as albumin. Specifically, conventional forming-filling-sealing packaging machinery introduces heat in certain areas of the polymeric packaging material to create seals. If heat contacts the protein during the sealing process, the protein can harden or otherwise denature, such as during high temperature sterilization. In addition, since certain proteins such as albumin operate as insulators, all sealing areas must be free of the protein in order for the polymeric materials to be heat sealed together. If any protein, such as albumin, is present in the sealing area prior to sealing, the integrity of the sealing may be endangered.

[0009] Thus, a convenient and cost-effective means of packaging certain proteins, including proteins such as albumin, is desirable.

Summary of the Invention [0010] The present invention provides a flexible polymeric container for containing a concentration of peptides and / or proteins. Such peptides and proteins include: glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins and hormones. In addition, the present invention provides a method of packaging such a compound in a flexible polymeric container. Generally, the flexible polymeric container comprises a sheet of flexible polymeric film formed into a bag. The bag has a cavity surrounded by a first wall and a second opposite wall. The bag also has seals around the periphery of the first and second walls that join an internal part

Petition 870180058002, of 07/04/2018, p. 11/40 / 21 of the first and second opposite walls, to create a fluid impermeable chamber within the container cavity. A concentration of the compound is stored within the fluid impermeable chamber. In one version, the compound is albumin.

[0011] According to one aspect of the present invention, the flexible polymeric container, to contain a concentrate of water soluble albumin, comprises a sheet of flexible polymeric material, which is initially converted into a tube with a former and is subsequently converted into a series of adjacent bags. The bags have a first side member, a second side member peripherally sealed to the first side member, and a cavity between an interior of the first and second side members. An amount of a concentration of water-soluble albumin is located within the cavity of the bag. The openings of the bags are subsequently sealed to create a fluid impermeable chamber.

[0012] According to another aspect of the present invention, the container has a plurality of peripheral edges. Three of the peripheral edges are heat sealed and one of the peripheral edges contains a fold that separates the first wall or first side member from the second wall or second side member opposite.

[0013] According to another aspect of the present invention, an accessory is connected to the container, adjacent to the fold. The accessory extends from the outer casing of the container in the fold and has a sealed passage that cooperates with the fluid-impermeable chamber of the container. The sealed passage extends into the container cavity to allow the albumin to be released from the fluid-impermeable chamber. A V-shaped border can be located at a distance from the opposite sides of the accessory and along the fold, to assist in draining the albumin from the container.

[0014] According to another aspect of the present invention, the edge

Petition 870180058002, of 07/04/2018, p. The peripheral 12/40 / 21 of the container opposing the fold contains a first seal and a second seal. The first and second seals join the first and second opposite walls. An opening is located between the first seal and the second seal and extends through the first and second opposite walls.

[0015] According to another aspect of the present invention, the flexible polymer sheet material comprises a laminated film, having an outer layer of low density linear polyethylene, a gas barrier layer, a polyamide core layer and an inner layer linear low-density polyethylene. The layers are joined together by a polyurethane adhesive.

[0016] According to another aspect of the present invention, albumin, in concentrations of 20% and 25%, is packaged in the flexible polymeric container. In addition, flexible polymeric containers can have a volume of 50 ml or 100 ml.

[0017] According to another aspect of the present invention, a method of packaging the protein albumin comprises providing a flexible polymeric container, having an opening extending from a cavity of the polymeric container, to provide an amount of a concentration of albumin in a solution sterile, insert the albumin under pressure into the polymeric container cavity through the opening and seal the opening to keep the liquid albumin inside a fluid impermeable chamber of the polymeric container cavity.

[0018] In accordance with another aspect of the present invention, a filler is used to insert the albumin into the flexible container. The filler has a distal tip with adjacent first and second internal passages. The first internal passage has a larger cross-sectional area than the second internal passage. The second internal passage extends adjacent the first internal passage to the outside of the tip and the

Petition 870180058002, of 07/04/2018, p. 13/40 / 21 albumin is dispersed from the filler through the second internal passage.

[0019] According to another aspect of the present invention, the interface between the first and second internal passages is internal to an outside of the tip, and the second internal passage extends to the outside of the tip. Albumin is maintained at the interface between the first and second internal passages, during the suspension of filling the bags.

[0020] According to another aspect of the present invention, a coating is located external to a part of the filler adjacent to the tip. The coating prevents contact between the polymeric container and the filler.

[0021] According to another aspect of the present invention, the coating is concentric with the filler. An air passage extends between an interior of the liner and an exterior of the filler. In addition, sterile air passes through the air passage and is expelled adjacent to the tip of the filler and upstream of the albumin outlet.

[0022] According to another aspect of the present invention, albumin is packaged in a series of flexible polymeric containers with a forming-filling-sealing packaging machine. A quantity of filtered albumin and a flexible polymeric material are provided and the forming-filling-sealing packaging machine converts the flexible polymeric material into a series of bags. The bags are filled with an amount of albumin inside the fill-seal forming machine and a sealing area of the bags is sealed with the packaging machine, to enclose the amount of albumin inside the bags.

[0023] According to another aspect of the present invention, the adjacent bags of the bag series are initially connected, are sequentially filled with an amount of albumin and the filling of each bag is then separated.

[0024] According to another aspect of the present invention, the machine

Petition 870180058002, of 07/04/2018, p. 14/40 / 21 forming-filling-sealing packaging has an aseptic area. The sterile flexible polymeric material is provided inside the aseptic area and is formed into bags inside the aseptic area. In addition, the filtered albumin is inserted into the bags in the aseptic area and the bags are sealed inside the aseptic area to form a fluid-tight container.

[0025] According to another aspect of the present invention, albumin is packaged in a series of flexible polymeric containers, in a forming-filling-sealing packaging machine, with the following process: converting a flexible polymeric material into a tube with a forming-filling-sealing packaging machine; converting the tube into a series of bags on the forming-filling-sealing packaging machine; sequentially, filling the bags with an amount of albumin inside the forming-filling-sealing packaging machine; and sealing an area for sealing the bags with the packaging machine, to enclose the amount of albumin inside the bags. The bags can be filled with a filler that discharges albumin from the filler and into the bag, without contacting the sealing area of the opening of the bag.

[0026] In accordance with yet another aspect of the present invention, the albumin is packaged in a flexible polymeric container with the following process: providing an albumin concentrate; providing a packaging machine having a forming assembly, a filling assembly and a sealing assembly, each of which is located within an internal aseptic environment of the packaging machine; providing a flexible polymeric film; conformation of the flexible polymeric film in an elongated tube with the sealing assembly; sealing a portion of the elongated polymeric film tube with the sealing assembly, the sealed polymeric film being sized in the shape of a bag having sealing areas around its periphery, a

Petition 870180058002, of 07/04/2018, p. 15/40 / 21 cavity located inside the bag and between the sealing areas and an opening extending from the cavity to the outside of the bag; filling the bag with albumin under pressure through the filling assembly, the filling assembly having a filling tube extending through the opening of the bag and into the cavity of the bag, and a concentric coating to the outside of the filling tube, the filling tube directing the albumin into the bag at a distance away from the periphery of the bag opening and the coating limiting contact between the filling tube and the bag; and, sealing the opening of the bag, to retain albumin within the cavity of the bag.

[0027] Accordingly, a flexible polymeric container for storing albumin, produced in accordance with the present invention, provides an inexpensive, easily manufactured and efficient packaging and process that eliminates the inconveniences associated with previous packaging and processes for packaging albumin.

[0028] Other aspects and advantages of the invention will be evident from the following specification, taken in conjunction with the following drawings. Brief Description of the Drawings [0029] To understand the present invention, it will now be described by way of example, with reference to the accompanying drawings, in which:

[0030] Figure 1 is a cross-section elevation view of a more specifically forming-filling-sealing, for manufacturing a flexible polymeric container containing a concentration of albumin of the present invention;

[0031] Figure 2 is a schematic view of the process for manufacturing the flexible polymeric container containing a concentration of albumin of the present invention;

[0032] Figure 3 is a front elevation view of the flexible polymeric container containing a concentration of albumin of the present

Petition 870180058002, of 07/04/2018, p. 16/40 / 21 invention;

[0033] Figure 4 is a partial side elevation view of the flexible polymeric container containing a concentration of albumin in Figure 3;

[0034] Figure 5 is a side elevation view of a partial filler assembly of the present invention;

[0035] Figure 6 is an enlarged side elevation view of part of the filling assembly of Figure 5;

[0036] Figure 7 is a side elevation view in cross section of a liner for the filler assembly of the present invention;

[0037] Figure 8 is a side elevation view of the

Figure 7;

[0038] Figure 9 is a schematic cross-sectional view of a version of the laminated film structure of the present invention; and [0039] Figure 10 is a cross-sectional view of the end of the fill and liner tube of the present invention.

Detailed Description of the Preferred Version [0040] Although this invention is susceptible to versions in many different forms, it is shown in the drawings and preferred versions of the invention will be described here in detail, with the understanding that the present description is to be considered as a exemplification of the principles of the invention and is not intended to limit the broad aspect of the invention to the illustrated versions.

[0041] As identified above, the scope of this description includes the packaging of any type of certain pharmaceutical compounds, such as peptides and proteins for pharmaceutical or other uses. Such compounds are known and include: glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins and

Petition 870180058002, of 07/04/2018, p. 17/40 / 21 hormones. For example, however, the detailed description of the present invention focuses on packaging albumin in a flexible polymeric container.

[0042] With reference now in detail to Figure 3, there is shown a flexible polymeric container 12, containing a concentration of albumin of the present invention. The flexible polymeric container 12 is preferably manufactured by a fill-seal forming machine 10, as shown in Figure 1, and using the process schematically illustrated in Figure 2.

[0043] The aseptic forming-filling-sealing packaging machine 10 generally includes a unwinding section 14, a film sterilization section 16, a film drying section 18, an intermediate roll / dancer roll section 20, a attached drive roller set section (not shown), forming set section 22, ribbed seal assembly section 24, accessory attachment assembly section, filler assembly section 30, assembly section end seal / cut 32 and a supply section (not shown). Each of these assemblies downstream of the unrolling section 14 is contained within the internal aseptic environment of the aseptic forming-filling-sealing packaging machine 10.

[0044] One of the functions of each of the various sets of the forming-filling-sealing packaging machine 10 is as follows: the unrolling section 14 contains a roll of flexible polymeric film 34, which is finally shaped in the container; the film sterilization section 16 provides a peroxide bath to sterilize the film 34; the film drying section 18 provides a means for drying and cleaning the peroxide from the film 34; the forming assembly 22 provides a forming mandrel 36 for converting the film web into a tube 38, which finally becomes the flexible container or bag 12; the ribbed seal assembly 24 provides the

Petition 870180058002, of 07/04/2018, p. 18/40 / 21 longitudinal sealing 40 on tube 38, which finally becomes the longitudinal sealing 40 of flexible container 12, thereby longitudinally sealing shaped tube 38; accessory attachment assembly 26 secures accessory 42 to tube 38; the filling assembly 30 includes a filler 44, which fills the flexible containers 12 with a substance, which is a water-soluble albumin concentration of the present preferred application; and the extreme sealing / cutting assembly 32 contains cutting and sealing claws 46, which form the end seals 76, 78 of the flexible polymeric containers 12, to enclose the albumin within the flexible polymeric container 12.

[0045] In the preferred version, the albumin used, to be packaged in the flexible polymeric container 12, is a 20% human albumin or a 25% human albumin. To obtain the required concentration level, albumin is typically combined with water and sterile stabilizers. In addition, prior to packaging, the albumin concentration is pasteurized and stored in large stainless steel holding tanks (not shown), having a volumetric capacity of approximately 500 600 liters, at approximately 2 ^o C to 8 ^o C. Immediately before packaging, the albumin tanks are removed from the refrigeration and allowed to equilibrate at the ambient packaging temperature (approximately 20 ^o C). It is important to process albumin at temperatures that do not result in protein denaturation, approximately below 60 ^o C. However, anywhere between 0 ^o C and 60 ^o C and, more preferably, between 20 ^o C and 45 ^o C, is appropriate . Additionally, in one version, the processing temperatures of 20 ^o C to 25 ^o C. Additionally, albumin is filtered through a 0.2 micro filter, when it enters the packaging machine 10.

[0046] The flexible polymeric film 34, used in the preferred version of the present invention, is a low density linear polyethylene laminate. It has been found that such a film with a gas barrier is particularly

Petition 870180058002, of 07/04/2018, p. 19/40 / 21 suitable for housing oxygen unstable solutions, such as the identified proteins, including albumin. Specifically, it has been found that this film reduces or eliminates the denaturation process previously associated with placing proteins, such as albumin, in a plastic container. As shown in Figure 9, in the preferred version the laminated film 34 has an outer layer of linear low density polyethylene (LLDPE) 52, a gas barrier layer 54, a layer of polyamide core 56 and an inner layer of linear polyethylene of low density 58, the layers being joined together by a polyurethane adhesive 60. Most preferably, the material requirements of the laminated structure have the following characteristics: a LLDPE layer (approximately 61 ± 10 μm) 52, a polyurethane adhesive layer 60 , a polyvinylidene chloride (PVDC) layer (approximately 19 ± 5 μm) 54, a polyurethane adhesive layer 60, a nylon layer (approximately 15 ± 5 μm) 56, a polyurethane adhesive layer 60, a LLDPE layer ( approximately 61 ± 10 μm) 52. In total, the film thickness is approximately 160 ± 25 μm. In addition, the PVDC 54 layer is most preferably manufactured by Dow Chemical and sold under the trademark SARAN. Such a film is described in U.S. Patent No. 4,629,361. U.S. Patent No. 4,629,361 is assigned to the assignee of the present invention and is incorporated herein and made part of it by this reference. This film 34 is manufactured by Fujimoro under the trade name FTR-13F.

[0047] Before use, the internal aseptic area of the packaging machine must be sterilized every day. This is done with a hydrogen peroxide haze, which is passed through the aseptic area of the packaging machine.

[0048] As seen in Figure 1, the film roll 34 is located in the unwinding section 14 of the packaging machine 10. During use, the film 34 is transferred through a hydrogen peroxide bath 16, to sterilize the film before entering the aseptic area of the

Petition 870180058002, of 07/04/2018, p. 20/40 / 21 pack 10. This sterilization step cleans the film web so that it can be used to create a sterile product. Sterilization and film cleaning are critical in the medical industry when packaging parenteral or enteric products. This sterilization step is especially critical when the resulting product is not to be terminally sterilized, that is, when the packaging machine is an aseptic packaging machine. After the film has been washed, cleaned or sterilized, liquid and other residues, for example, a chemical sterilizer or wetting agent, such as hydrogen peroxide, typically remain on the film. Thus, it is necessary to remove the liquid and / or residue from the film 34. A pneumatic knife (an air stream blown through the continuous film sheet, so that the liquid contained in it is blown out of the film), located in the section of film drying 18, is used to remove liquid and other residues from film 34, when the film penetrates the aseptic area of the packaging machine.

[0049] In the aseptic area of the wrapping machine 10, the film 34 passes through the dancer roller section 20 and the driving roller section, before entering the forming set section 22. Before entering the forming set 22, the film web 34 is substantially flat and has a first surface 62 and a second surface 64. The first surface 62 faces downwards when the film penetrates the forming assembly 22 and finally becomes the inner part of the container 12, while the second surface 64 faces upwards when the film penetrates the forming assembly 22 and finally becomes the inner part of the container 12.

[0050] As shown in Figures 3 and 4, the film 34 additionally has a theoretical fold line, located approximately close to a central line of the length of the film web 34. The theoretical fold line becomes a fold area

Petition 870180058002, of 07/04/2018, p. 21/40 / 21

67, which separates the first side member 66 or first wall from the second side member 68 or second wall of the container 12.

[0051] A forming mandrel 36 is located in the forming assembly section 22. The forming mandrel 36 assists in converting the substantially flat web of polymeric material 34 into an elongated and substantially tubular member 38. It should be understood that the member elongated tubular 38, or tube, is generally not cylindrical, but more precisely, it has an oblong shape, as shown in Figure

4. With regard to the identification of the areas of the film web described above, after the film passes through the forming assembly 22, the first surface 62 of the first side member 66 is opposed to the first surface 62 of the second side member 68.

[0052] Once the tubular member 38 is shaped, the tubular member receives a longitudinal seal 40 in the ribbed seal assembly section 24, and an accessory 42 is connected to tube 38 in the accessory fixation set 26. Specifically, the accessory 42 is attached to and extends from the outer envelope of the container 12 in the folding area 67, using a heated set, to seal the accessory 42 to the folding area 67 of the container 12. Typically, the accessory sealer operates in a temperature of about 213 ^o C to about 232 ^o C and a pressure of about 4 kg / cm ² man. at about 5 kg / cm ² man., although any range within these identified ranges is acceptable. As shown in Figure 4, fitting 42 has a sealed passageway that cooperates with the inside of tube 38. Specifically, the passageway extends into and creates a communication fluid with cavity 82 of the container, to allow albumin to be released from the fluid impermeable chamber. It should be understood that, in some versions, albumin can be injected into the cavity of the container 12 through the accessory 42.

[0053] The ribbed seal assembly 24 introduces heat and pressure to the

Petition 870180058002, of 07/04/2018, p. 22/40 / 21 film 34, to create the longitudinal seal 40 at the peripheral edge of the tube 38, which opposes the bend area 67. Typically, the ribbed seal assembly operates at a temperature of about 177 ^o C to 193 ^o C and with a pressure of about 3 kg / cm ² man. at 6 kg / cm ² man., although any band within these identified bands is acceptable in the preferred version of the container 12, as shown in Figure 3, the longitudinal seal 40 comprises a first longitudinal seal 70 and a second longitudinal seal 72. The first and second longitudinal seals 70, 72 join the first surface 62 of the first wall 66 to the first opposite surface 62 of the second wall 68. An opening 74, typically used to suspend a shaped container 12, is created between the first longitudinal seal 70 and the second longitudinal sealing 72. Therefore, opening 74 extends through the first and second opposite walls 66, 68.

[0054] The sealed tubular member 38 passes through the ribbed sealing set 24 to the filling set 30 and the end sealing set 32. In the end sealing set 32, the forming-filling-sealing packaging machine 10 uses heat and pressure to convert the sealed tube 38 into a series of bags 12, also referred to as containers 12. Typically, the end seal assembly operates at a temperature of about 191 ^o C to about 207 ^o C and with a pressure about 35 kg / cm ² man. at about 60 kg / cm ² man., although any range within these identified ranges is acceptable. The sealed tube 38 first receives a base seal 76, to initially form the bag 12, having a cavity 82 located between the first and second sides 66, 68 of the container 12 and the base seal 76 of the container, and an opening 80 that extends from cavity 82 of container 12 to the outside of container 12. It should be understood that, during the fill-seal manufacturing process, opening 80 extends from cavity 82 of container 12 into the center of tube 38. Once the base seal 76 is created, the

Petition 870180058002, of 07/04/2018, p. 23/40 / 21 bag 12 is filled with albumin through opening 80 and then the top sealing 78 is carried out, thus sealing or closing opening 80 and creating a fluid impermeable chamber 82, in which albumin is retained. In addition, once the base seal 76 is created, the polymeric film 34 can be said to be dimensioned in the shape of the open bag 12, having sealing areas close to its periphery (the longitudinal seal 34, opposite the fold area 67, the base seal 76, joining the fold area 67 and the longitudinal seal 40) and having a cavity 82 located inside the bag 12 and between the seal areas 40, 76 and the fold area 67. Thus, with a process of forming-filling-sealing packaging, the finished container 12 has sealed areas on the three sides of the bag 12: the top seal 78, the base seal 76 and the longitudinal seal 40. The longitudinal seal 40 joins the top seal 78 and the base seal 76. In the preferred process, the top seal 78 of a first bag 12 is carried out at the same time as the base seal 76 of an adjacent upstream bag 12 with the end seal assembly 32. As such, adjacent bags 12, in the bag series 12, are initial connected, both because they are part of the tubular member 38, which forms the bags 12, as well as because they have end seals which are formed with the same end sealing set 32.

[0055] In the preferred version of the process for creating and filling containers of the present invention with albumin, as illustrated in Figures 1 and 2, containers 12 are filled with albumin through a filling assembly 30, which extends tube 38 below. The filling assembly 30 thus fills the cavity 82 of the bag 12 through the opening 80 of the open three-sided bag in processing 12.

[0056] The filling set 30 of the preferred version is illustrated in Figures 5-8 and 10. As such, the filling set 30 comprises a pressurized filler 44, made of a filling tube 84 and a liner

Petition 870180058002, of 07/04/2018, p. 24/40 / 21 located concentrically around the perimeter of the fill tube 84. The filler 44 typically operates under a solution line pressure of about 0.281 kg / cm ² man. at about 1.406 kg / cm ² man., however, any pressure range within the identified range is acceptable. In the preferred version, the filler operates under a line pressure and solution of about 0.703 kg / cm ² man. at about 1.125 kg / cm ² man. and, most preferably, under a solution line pressure of about 0.844 kg / cm ² man. at about 1.125 kg / cm ² man .. The identified bands are used in an attempt to reduce the turbulence and splash of albumin or other protein when it is inserted into container 12. As explained above, after bottom sealing 76 be created, the bag 12 is filled with albumin through the filling set 30, the top seal 78 is created simultaneously with the bottom seal 76 of the next bag, the next bag 12 of tube 38 is filled sequentially and so on . Thus, adjacent bags 12 of the bag series 12 are initially connected and are then separated in sequence, followed by the filling and sealing of each respective bag 12 sequentially.

[0057] As shown in Figure 5, in the preferred version, the filler filler 30 is configured as a tube 86 over a tube 84. The liner tube 86 is located concentric to the fill tube 84, with an air passage 88 extending in the space between the inner diameter of the casing tube 86 and the outer diameter of the fill tube 84. Sterilized air passes through the air passage and is expelled adjacent to one end of the fill tube 84, upstream of a a filling tube outlet 92.

[0058] In a preferred version of the fill tube 84, as shown in Figure 5, the fill tube 84 has a Venturi 85 that tapers from a first diameter to a second larger diameter around its length. In addition, as shown in Figure 6, the tip 90 of the

Petition 870180058002, of 07/04/2018, p. 25/40 / 21 filling 84 has a first inner passage 94 concentric with and adjacent to a second inner passage 96. And, in a preferred version of the present invention the first inner passage 94 is generally circular in cross-sectional shape, having a first inner diameter, and the second inner passage 94 is generally of circular cross section, having a first inner diameter, and second passage 96 is generally circular in shape of the cross section, having a second inner diameter. The inner diameter, and thus the cross-sectional area of the first inner passage 94, is dimensioned larger than the inner diameter and thus the cross-sectional area of the second inner passage 96. An interface 98 connects the first inner passage 94 and the second internal passage 96 at a location that is internal to the outside of outlet 92 of tip 90 of filler 44. In a preferred version, the interface comprises a beveled step 98 between the first and second internal passages 94, 94, to pronounce reduce the diameter of the first internal passage 94 to the second internal passage 96. The interface 98, between the first and second passages 94, 96, provides an important function in the operation of the filler. Since the albumin is distributed through the outlet of the second internal passage 96 of the filler 44, capillary forces from the filling tube operate to cause the meniscus of the albumin to reside at the interface 98, between the first and second passages 94, 96, during a filling stop, instead of at exit 92 of the second passage. Thus, even though the albumin is distributed by the filler 44 through the second internal passage 96, during each suspension of the filling in the middle of the sequential filling of the bags 12, the albumin is kept internal to and at a distance from the outlet of the filler 44, and in the interface 98 of the first and second passages 94, 96. Such a configuration greatly assists in preventing migration of albumin from the filler outlet. Any migration can allow the albumin to be transferred to the outside of the filler and contact film 34. As explained above, the

Petition 870180058002, of 07/04/2018, p. 26/40 / 21 albumin operates as an insulator. If albumin migrates to film it will also endanger the integrity of the top sealing area. Thus, the configuration of the present invention provides a means of eliminating this drawback. In a test conducted on the integrity of the sealing of the containers 12 of the present invention, 99.90% of the formed containers 12 were above the minimum sealing resistance value of 1.406 kg / cm ² in a burst test evaluation.

[0059] As explained above, the liner 86 is located concentrically around a perimeter of the filling tube 84 and an air passage 88 extends in the space between the inner diameter of the liner tube 86 and the outer diameter of the tube to fill 84. While in the preferred version the distal end 100 of the liner 86 is an adapter that is attached to the liner 86, the distal end portion 100 can be manufactured as part of the liner 86, without destroying the intended function of the liner 86 As shown in Figures 7 and 8, the distal end part 100 of the liner 86 has a chamfered end 104. A plurality of vent holes 102 are located adjacent to the end of the distal end part 100 of the liner 86. The sterile air is dispersed of the air passage 88 through the ventilation holes 102. Since the exit of the ventilation holes is at the chamfered end 104 of the liner 86, the flow pattern of the Sterilized air is circumferentially external to the flow pattern of albumin and is dispersed by the filling tip, so as not to interfere with the flow of albumin. This decreases the chances of the sterile air introducing a turbulent effect on the distributed albumin. Additionally, since the airflow pattern is external to and away from the liquid flow pattern of albumin, any possible foaming of the albumin that may come into contact with the air is minimized. Similar to the benefits revealed with the sterile air flow, they are extremely useful. Such a configuration greatly helps in preventing

Petition 870180058002, of 07/04/2018, p. 27/40 / 21 of the splash and defoaming of albumin through the filler outlet. This prevents contact of the albumin with the part of the film that is converted into the top seal area, thereby also helping to continuously create a stronger top seal.

[0060] The first inner diameter 106 of the distal end 100 of the liner 86 is sized to fit into the liner 86 and be secured to it with a retaining screw 110. The second inner diameter 108 of the distal end 100 of the liner 86 is sized to provide air passage 88 between liner 86 and fill tube 84. As shown in Figure 7, a chamfer 112 is located at the end of the second inner diameter 108, to further reduce the inner diameter of liner 86. An inverse chamfer 114 it is located on an outside of the end of the liner 86.

[0061] The liner 86 and the fill tube 84 are shown as assembled in Figure 10. As seen in the illustration, the outer diameter of the fill tube 84 is sized to be the same as or slightly smaller than the reduced inner diameter of the coating 86 on chamfer 112. In the preferred version, the second inner diameter of coating 86 is approximately 1.483 cm and is decreased on chamfer 112 to approximately 1.270 cm. In addition, the outer diameter of the filling tube 84 of the preferred version of the present invention is approximately 1.270 cm. As such, the interface between the chamfer 112 and the filling tube 86 operates to close the air passage 88 and force the sterilized air through the ventilation holes 102, located upstream of the outlet 92 of the second inner passage of the albumin filling tube. 84.

[0062] As seen in Figure 10, the outer diameter of the liner is greater than the outer diameter of the filling tube 84 projecting beyond the liner. With the identified configuration of the filling and coating tube, even though during a part of the filling process

Petition 870180058002, of 07/04/2018, p. 28/40 / 21 filling the filling tube 84 of the filling assembly 30 extends through the opening 80 of the bag and into the cavity 82 of the bag, the liner 86 is external to a part of the filling tube 84 and thus , only the liner 86 can contact the tube 38, thereby preventing contact between the polymeric container and the filler tube 84. As such, the outlet 92 of the filler tube 84 is positioned at a distance away from the inner wall of the flexible polymeric container 12. Thus, the position and size of the coating 86, in combination with the internal interface 98 of the first and second internal passages, and the reverse bevel 114 prevent any albumin from migrating outside the filling set 30 and contacting the sealing areas of tube 38, which finally become the top seal 78 of the finished container. Since albumin operates as an insulator, it is necessary to keep all sealing areas free of the protein in order for the polymeric materials to be thermally sealed together. If any albumin was present in the sealing area prior to sealing, the integrity of the sealing could be endangered. As such, with the identified configuration, the albumin is discharged from the filling tube 84 and into the bottom of the bag 12, without contacting the sealing area of the opening of the bag 12, which finally becomes the top seal 78.

[0063] Although specific versions have been illustrated and described, numerous modifications come to mind without significantly departing from the spirit of the invention, and the scope of protection is only limited by the scope of the appended claims.

Petition 870180058002, of 07/04/2018, p. 29/40 / 5

Claims (20)

1. Method of packing protein albumin, characterized by the fact that: providing a flexible polymeric container (12) having an opening extending from a cavity (82) of the polymeric container (12); providing an amount of a concentration of albumin in a sterile solution; providing a filler (44) having an outer liner (86) concentric to the filler (44) and an air passage (88) extending between an interior of the liner (86) and an exterior of the filler (44), where the coating (86) limits contact between the opening of the polymeric container (12) and the filler (44), and in which the sterilized air passes through the air passage and is expelled adjacent to the tip (90) of the filler (44) and the output amount of albumin; insert the albumin under a solution line pressure of about 0.281 kg / cm ² man. at 1.406 kg / cm ² man. inside the cavity (82) of the polymeric container (12), through the opening therein; and sealing the opening to trap the liquid albumin inside a fluid impermeable chamber of the cavity (82) of the polymeric container (12). Method according to claim 1, characterized in that the albumin is maintained at a temperature of 20 ^o C before insertion into the cavity (82) of the container (12). Method according to claim 1, characterized in that the albumin is inserted into the cavity (82) of the flexible polymeric container (12) under a solution line pressure of about 0.844 kg / cm ² man. at about 1.125 kg / cm ² man. Method according to claim 1, characterized in that the flexible polymeric container (12) is provided within an aseptic environment of a forming-filling packaging machine Petition 870180058002, of 07/04/2018, p. 30/40 sealing (10), in which the albumin is inserted into the cavity (82) of the flexible polymeric container (12), within the aseptic environment of the forming-filling-sealing packaging machine (10) and in which the opening The container (12) is sealed within the aseptic environment of the forming-filling-sealing packaging machine (10). 5. Method according to claim 1, characterized in that the albumin is provided in a concentration of 20%. 6. Method according to claim 1, characterized in that the albumin is provided in a concentration of 25%. Method according to claim 1, characterized in that the flexible plastic container (12) is provided having a volume of 50 ml. Method according to claim 1, characterized in that the flexible plastic container (12) is provided having a volume of 100 ml. Method according to claim 1, characterized in that it further comprises providing a flexible polymeric container (12) comprising a laminated film having an outer layer of low density linear polyethylene (52), a gas barrier layer (54) , a layer of polyamide core (56) and an inner layer of low density linear polyethylene (58), the layers being joined together by a polyurethane adhesive (60). 10. Method of packaging protein albumin in a series of flexible polymeric containers, characterized by the fact that it comprises: providing an amount of filtered albumin; providing a flexible polymeric material (34); providing a forming-filling-sealing packaging machine (10) and converting the flexible polymeric material (34) into a series of bags in the forming-filling-sealing packaging machine (10); Petition 870180058002, of 07/04/2018, p. 31/40 3/5 provide a repeat filler (44) having an outer liner (86) concentric to the filler (44) and an air passage (88) extending between an inner liner (86) and an outer liner (44) ), where the liner (86) limits contact between the opening of the polymeric container (12) and the filler (44), and where the sterile air passes through the air passage and is expelled adjacent to the tip (90) of the filler (44) and upstream of the albumin outlet; fill the bags with an albumin amount of about a solution line pressure of about 0.281 kg / cm ² man. at about 1.406 kg / cm ² man. inside the filling-sealing forming machine (10); and sealing an area for sealing the bags with the packaging machine (10), to enclose the amount of albumin inside the bags. 11. Method according to claim 10, characterized in that the adjacent bags of the series of bags are initially connected and are separated after the filling of each bag. Method according to claim 11, characterized in that it further comprises providing a forming mandrel (36) in the forming-filling-sealing packaging machine (10). 13. Method according to claim 12, characterized in that it also comprises forming the flexible polymeric material (34) in a tube (38) with the forming mandrel (36) and also forming the tube (38) in the series of bags adjacent. 14. Method according to claim 10, characterized in that the bags are sequentially filled with the amount of albumin. 15. Method according to claim 10, characterized in that it also comprises thermal sealing of the periphery of the bags, to enclose the amount of albumin inside the bags. Petition 870180058002, of 07/04/2018, p. 32/40 4/5 Method according to claim 10, characterized in that it comprises providing a flexible polymeric container (12), comprising a laminated film having an outer layer of low density linear polyethylene (52), a gas barrier layer (54) , a layer of polyamide core (56) and an inner layer of low density linear polyethylene (58), the layers being joined together by a polyurethane adhesive (60). 17. Method according to claim 10, characterized in that the forming-filling-sealing packaging machine (10) has an aseptic area, in which the sterile flexible polymeric material (34) is formed in a series of adjacent bags inside the aseptic area, in which the albumin is sequentially inserted into the bags in the aseptic area and in which the bags are sequentially sealed inside the aseptic area to form a fluid impermeable container (12). 18. Method according to claim 10, characterized in that it also comprises the step of filtering albumin through a 0.2 micro filter. 19. Method of packaging protein albumin in a series of flexible polymeric containers, characterized by the fact that it comprises: providing an amount of filtered albumin; providing a flexible polymeric material (34); providing a seal-forming-packing machine (10) and converting the flexible polymeric material (34) into a tube (38) with a seal-forming-packing machine (10); converting the tube (38) into a series of bags in the forming-filling-sealing packaging machine (10); fill the bags, through an opening in the bags, with an amount of albumin under a solution line pressure of about Petition 870180058002, of 07/04/2018, p. 33/40 5/5 0.281 kg / cm ² man. At about 1.406 kg / cm ² man. inside the forming-filling-sealing packaging machine (10); and sealing a sealing area of the opening of the bags with the packaging machine (10), to enclose the amount of albumin inside the bags, wherein the filling step comprises providing a filler (44) having a concentric outer coating (86) to the filler (44) and an air passage (88) extending between an interior of the liner (86) and an exterior of the filler (44), where the liner (86) limits contact between the opening of the polymeric container (12 ) and the filler (44), and the sterile air passes through the air passage and is expelled adjacent to the tip (90) of the filler (44) and upstream of the albumin outlet. 20. Method according to claim 19, characterized in that the bags are sequentially filled with the amount of albumin. Petition 870180058002, of 07/04/2018, p. 34/40 1/5 Petition 870180058002, of 07/04/2018, p. 36/40 2/5 FIGURE 3 Petition 870180058002, of 07/04/2018, p. 37/40 3/5 Petition 870180058002, of 07/04/2018, p. 38/40 4/5 Petition 870180058002, of 07/04/2018, p. 39/40 5/5 Z77TZ FIGURE 9 FIGURE 10 j · C t \ os ί | K ΙΠPetition 870180058002, of 07/04/2018, p. 40/40 1/1