JP2008273631A - Albumin in flexible polymeric container - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method which is inexpensive and packages a solution containing a protein, and also to provide a container which is obtained. <P>SOLUTION: A flexible polymeric container holds albumin. The container (12) is made of a sheet of a flexible polymeric film (34) formed into a bag. The flexible polymeric container has a cavity which is surrounded by a first wall, an opposing second wall, and seals about a periphery of these first and second walls. The seals join the inner parts of the opposing first and second walls, and create a fluid-tight chamber for storing the albumin with a certain concentration in the cavity of the container. The method for packaging the albumin protein in the flexible polymeric container is provided. A flexible polymeric material is converted into the bags, and a certain amount of the albumin is filled into the bag with a filling appliance (44) and the albumin is stored in the bag by sealing the sealing area of the bag. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

(Technical field)
The present invention relates generally to the packaging of proteins in flexible polymer containers, and more specifically to flexible polymers in the sterile environment of form-fill-seal packaging machines. It relates to the packaging of an amount of albumin in a container.

(Background of the Invention)
Many peptides and proteins are known for pharmaceutical or other use, including glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins, and hormones.

  One type of such compound is albumin. Albumin is a sulfur-containing water-soluble protein that clots when heated and is present in egg whites, milk, blood, and other animal and plant tissues and secretions. Albumin is often used as a blood dilator to help maintain a patient's blood pressure, or sometimes to help raise the patient's blood pressure during blood loss.

  Proteins (eg, albumin) are adsorbed by most artificial materials, including liquid containers made from various polymers. Protein adsorption on the artificial polymer surface results in a decrease in the protein content of the solution. Some protein solutions can be adversely affected by the adsorption of proteins onto artificial surfaces through a process called denaturation. Denaturation refers to a process in which protein molecules are not adsorbed permanently on a polymer container, but rather protein molecules are adsorbed on this container and then released. This adsorption and release can change the shape of the molecule (ie, modify its shape). Often, when protein molecules in a protein drug solution undergo denaturation, their effectiveness and utility can be lost. Thus, to date, proteins such as albumin have been stored for individual use in glass bottles to avoid the risk of denaturation. In order to eliminate the above disadvantages as much as possible due to the costs incurred by manufacturing, packaging, boxing, transporting and storing glass bottles, as well as the cost and weight of glass bottles, and the fragility of glass bottles, such as albumin A more efficient, less expensive and user friendly means of packaging proteins is desired.

  One type of packaging utilized to package non-protein pharmaceuticals is a polymer bag formed by a form-fill-seal packaging machine. Form-fill-seal packaging machines are typically utilized for packaging products in flexible containers. This form-fill-seal packaging machine provides an apparatus for packaging certain pharmaceuticals and many other products in an inexpensive and efficient manner.

  In accordance with FDA requirements, certain pharmaceuticals packaged in form-fill-seal packages are traditionally sterilized in a post-packaging autoclave process. This post-packaging step involves placing the sealed package containing the pharmaceutical product in an autoclave and the required temperature (this temperature is often about 250 ° F.) for the time period described above. Including steam sterilizing or heating the contents. This sterilization process operates to kill bacteria and other contaminants found in the package, whether on the inner layer of the film or within the pharmaceutical itself.

  However, certain packaged pharmaceuticals (including certain proteins such as albumin) generally cannot be sterilized in this manner. This is because certain drugs are destroyed or made useless by the heat required to kill bacteria in the autoclave process. Furthermore, in the case of albumin proteins, heat can act to coagulate the protein.

  Form-fill-seal can also cause other problems besides sterilization issues when packaging certain proteins such as albumin. Specifically, conventional form-fill-seal packaging machines introduce heat to specific areas of the polymeric material of the package for sealing. If this heat comes into contact with the protein during the sealing process, the protein will solidify or otherwise denature during, for example, high temperature sterilization. Furthermore, because certain proteins (eg, albumin) act as insulation, all seal areas must be away from the protein to heat seal the polymer material together. If any protein (eg, albumin) is present in the seal area prior to sealing, the integrity of the seal can be compromised.

  Therefore, a convenient and cost effective means for packaging certain proteins (including proteins such as albumin) is desired.

(Summary of the Invention)
The present invention provides a flexible polymer container for holding peptide and / or protein concentrations. Such peptides and proteins include: glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins, and hormones. Furthermore, the present invention provides a method for packaging such compounds in flexible polymer containers. In general, the flexible polymer container includes a sheet of flexible polymer film formed in a bag. The bag has a cavity surrounded by a first wall and an opposing second wall. The bag further provides a seal connecting the inside of the opposing first and second walls around the first and second walls to form a fluid tight chamber within the cavity of the container. This compound concentrate is stored in a fluid tight chamber. In one embodiment, the compound is albumin.

  In accordance with one aspect of the present invention, a flexible polymer container includes a sheet of flexible polymer material to retain the concentration of water-soluble albumin, and the material is first converted into a tube using a molding agent, And then change to a series of adjacent bags. The bag has a first side member, a second side member sealed around the first side member, and a cavity between the inside of the first side member and the second side member. A quantity of a population of a certain concentration of water-soluble albumin is placed in the cavity of the bag. The bag opening is subsequently sealed to create a fluid tight chamber.

  In accordance with another aspect of the present invention, the container has a plurality of peripheral edges. Three peripheral edges are heat sealed and one in the peripheral edge includes a fold that separates the first wall or first side member from the opposing second wall or second side member. .

  According to another aspect of the invention, the attachment is coupled to a container adjacent to the fold. The attachment extends from the outer shell of the container in the fold and has a sealed passage that cooperates with the fluid tight chamber of the container. The sealed passage extends into the cavity of the container and allows albumin to be released from the fluid tight chamber. A chevron can be placed at a constant distance from the opposite side of the attachment and along the fold to assist in the discharge of albumin from the container.

  According to another aspect of the invention, the peripheral edge of the container opposite the fold comprises a first seal and a second seal. The first seal and the second seal join the first wall and the opposing second wall. An opening is disposed between the first seal and the second seal and extends through the first wall and the opposing second wall.

  In accordance with another aspect of the present invention, the flexible polymer sheet material is a laminate having a low density linear polyethylene outer layer, a gas barrier layer, a polyamide core layer, and a low density linear polyethylene inner layer. Provide a film. This layer is bonded together by a polyurethane adhesive.

  According to another aspect of the present invention, 20% and 25% concentrations of albumin are packaged in flexible polymer containers. Thus, the flexible polymer container can have a volume of 50 ml or 100 ml.

  In accordance with another aspect of the present invention, a method for packaging albumin protein provides a flexible polymer container having an opening extending from the cavity of the polymer container, providing an amount of albumin in a sterile solution. Inserting albumin into the cavity of the polymer container through the opening under constant pressure, and sealing the opening to seal the liquid albumin in the fluid tight chamber of the cavity of the polymer container. Include.

  In accordance with another aspect of the invention, a filler is used to insert albumin into a flexible container. The filler has a distal tip adjacent to the first internal path and the second internal path. The first internal path has a larger cross-sectional area than the second internal path. The second internal path extends adjacent to the first internal path to the outside of the tip and the albumin is dispensed from the filler through the second internal path.

  In accordance with another aspect of the present invention, the interface between the first internal path and the second internal path is inside the outside of the tip and the second internal path extends to the outside of the tip. The albumin is retained at the interface between the first internal path and the second internal path during stoppage of the bag filling.

  In accordance with another aspect of the present invention, a sheath is disposed outside a portion of the filler adjacent to the tip. This sheath prevents contact between the polymer container and the filler.

  In accordance with another aspect of the invention, the sheath is coaxial with the filler. An air passage extends between the inside of the sheath and the outside of the filler. In addition, sterilized air passes through the air passage and is released next to the tip of the filler and upstream of the albumin outlet.

  In accordance with another aspect of the present invention, albumin is packaged in a series of flexible polymer containers using a form-fill-seal packaging machine. An amount of filtered albumin and flexible polymer material is provided and the form-fill-seal packaging machine converts the flexible polymer material into a series of bags. The bag is filled with a quantity of albumin in a form-fill-seal packaging machine, and the sealing area of the bag is sealed with a packaging machine to enclose a quantity of albumin in the bag. Is done.

  In accordance with another aspect of the present invention, adjacent bags in this series of bags are first combined, subsequently filled with an amount of albumin, and separated after filling of each bag.

  In accordance with another aspect of the present invention, a form-fill-seal packaging machine has a sterile area. The sterile flexible polymeric material is provided in a sterile area and formed into a bag in this sterile area. In addition, filtered albumin is inserted into the bag in this sterile area, and the bag is sealed in the sterile area to form a fluid tight container.

  In accordance with another aspect of the invention, albumin is packaged in a series of flexible polymer containers in a form-fill-seal packaging machine with the following process: in the form-fill-seal packaging machine Converting the flexible polymeric material into a tube using a molding agent; converting the tube into a series of bags in a forming-fill-seal packaging machine; followed by a forming-fill-seal packaging machine In which the bag is filled with a quantity of albumin; and the packaging machine is used to seal the sealing area of the bag to enclose a quantity of albumin in the bag. The bag can be filled from the filler into the bag using a filler that releases albumin without contacting the sealing area of the bag opening.

  In accordance with yet another aspect of the invention, albumin was packaged in a flexible polymer container using the following process: providing a concentration of albumin; forming assembly, filling assembly, and sealing assembly (these Providing a flexible polymer film; each of which is disposed within an interior aseptic environment of the packaging machine; providing a flexible polymer film; Using a sealing assembly to seal a portion of the elongated tube of polymeric film, wherein the sealed polymeric film has dimensions in the shape of a bag having a sealing region around it. There is a cavity in the bag and between the sealing areas, An opening extending from the cavity to the exterior of the bag; filling the bag with albumin under pressure through the filling assembly, the filling assembly passing through the bag opening and into the bag cavity; An extending filling tube and a sheath concentric with the exterior of the filling tube, the filling tube directing albumin into the interior of the bag at a distance from the periphery of the bag, and the sheath comprising the filling tube and the bag Sealing the opening of the bag to retain the albumin within the bag cavity.

  More specifically, the present invention can relate to the following items.
(Item 1) A method of packaging albumin protein comprising the steps of: providing a flexible polymer container, the polymer container having an opening extending from a cavity of the polymer container; Providing an amount of albumin in a sterile solution; inserting the albumin through the opening into a cavity of the polymer container under a solution line pressure of about 4 psig to about 20 psig; And sealing the opening to secure the liquid albumin in the hollow fluid tight chamber of the polymer container.
2. The method of claim 1, wherein the albumin is maintained at a temperature of about 68 ° F. prior to insertion of the container into the cavity.
3. The method of claim 1, wherein the albumin is inserted into the cavity of the flexible polymer container under a solution line pressure of about 12 psig to about 16 psig.
(Item 4) The flexible polymer container is provided in an aseptic environment of a form-fill-seal packaging machine, wherein the albumin is provided in the aseptic environment of the form-fill-seal packaging machine. The method of claim 1, wherein the container is inserted into the cavity of the flexible polymer container and the opening of the container is sealed within the sterile environment of the forming-fill-seal packaging machine.
5. The method of claim 1, further comprising providing a filler having a distal tip, wherein the distal tip includes adjacent first and second internal passages. The first internal passage has a larger cross-sectional area than the second internal passage, wherein the second internal passage is adjacent to the first internal passage, Extending outward and the albumin is dispensed from the filler through the second internal passage.
6. The method of claim 1, further comprising providing a filler having a tip, the distal tip having a coaxial first internal passage and a second internal passage, The first internal passage has an inner diameter that is larger than the inner diameter of the second internal passage, wherein the interface between the first internal passage and the second internal passage is the tip. The second internal passage extends outside the tip and the albumin exits the filler through the second internal passage.
(Item 7) The method according to item 1, further comprising the step of providing a sheath outside the portion adjacent to the tip of the filler, wherein the sheath comprises the polymer container and the filler. A method to prevent contact between.
(Item 8) The method according to item 1, wherein the albumin is provided at a concentration of 20%.
(Item 9) The method according to item 1, wherein the albumin is provided at a concentration of 25%.
(Item 10) The method according to item 1, wherein the flexible plastic container is provided having a capacity of 50 ml.
(Item 11) The method according to item 1, wherein the flexible plastic container is provided having a capacity of 100 ml.
(Item 12) The method according to item 1, further comprising the step of providing a flexible polymer container comprising a laminate film, wherein the laminate film is an outer layer of linear low density polyethylene, gas barrier A method having a layer, a polyamide core layer, and an inner layer of linear low density polyethylene, wherein the layers are bonded together by a polyurethane adhesive.
(Item 13) A method of packaging albumin protein in a series of flexible polymer containers, comprising the steps of: providing a quantity of filtered albumin; providing a flexible polymer material; Providing a fill-seal packaging machine and converting the flexible polymeric material into a series of bags in the form-fill-seal packaging machine; in the form-fill-seal packaging machine, the bag Filling a quantity of albumin; and using the packaging machine to seal the sealing area of the bag and containing the quantity of albumin in the bag.
14. The method of claim 13, wherein adjacent bags in the series of bags are initially connected and separated following filling of each bag.
15. The method of claim 14, further comprising providing a forming mandrel in the forming-fill-seal packaging machine.
16. The method of claim 15, further comprising using the forming mandrel to form the flexible polymeric material into a tube and further forming the tube into a series of adjacent bags.
(Item 17) The method according to item 13, wherein the bag is continuously filled with the amount of albumin.
(Item 18) The method according to item 13, further comprising the step of heat-sealing the periphery of the bag and containing the amount of albumin in the bag.
(Item 19) The method according to item 13, further comprising the step of providing a flexible polymer container comprising a laminate film, wherein the laminate film comprises an outer layer of linear low density polyethylene, a gas barrier. A method having a layer, a polyamide core layer, and an inner layer of linear low density polyethylene, wherein the layers are bonded together by a polyurethane adhesive.
20. The method of claim 13, wherein the form-fill-seal packaging machine has a sterile field, wherein the sterilized flexible polymeric material is provided in the sterile field. The sterilized flexible polymeric material is formed into a series of adjacent bags within the sterile region, wherein the albumin is continuously inserted into the bag at the sterile region; And the bag is continuously sealed in the aseptic area to form a fluid tight container.
21. The method of claim 13, further comprising providing a repeat filler, the repeat filler having a tip having a coaxial first internal passage and a second internal passage. The first internal passage has a cross-sectional area greater than that of the second internal passage, wherein the interface between the first internal passage and the second internal passage is Inside the outside of the tip, the second inside passage extends beyond the outside of the tip, the albumin exits the filler through the second inside passage, and the albumin fills Maintained at the interface between the first internal passage and the second internal passage during the stop.
(Item 22) The method according to item 21, further comprising the step of providing a sheath outside the portion adjacent to the tip of the filler, the sheath comprising the polymer container, the filler, Method to limit contact between.
23. The method of claim 21, further comprising providing an outer sheath coaxial with the filler and an air passage extending between the inside of the sheath and the outside of the filler. Wherein the sheath restricts contact between the polymer container and the filler, and sterilized air passes through the air passage and adjacent the tip of the filler. Discharged in the upstream of the outlet of the.
24. The method of claim 13, further comprising filtering the albumin through a 0.2 micron filter.
25. A method of packaging albumin protein in a series of flexible polymer containers, the method comprising the steps of: providing a quantity of filtered albumin; providing a flexible polymer material Providing a forming-fill-seal packaging machine and, in the forming-fill-seal packaging machine, using a molding agent to convert the flexible polymeric material into a tube; forming-fill- In a seal packaging machine, converting the tube into a series of bags; in the forming-fill-seal packaging machine, filling the bag with an amount of albumin through an opening in the bag; and Using a packaging machine, seal the sealing area of the opening of the bag, and A step of accommodating the amount of albumin in Tsu the grayed including, method.
(Item 26) The method according to item 25, wherein the bag is continuously filled with the amount of albumin.
(Item 27) The method according to item 25, further comprising a filler, and discharging albumin from the filler into the bag without contacting the sealing area of the opening of the bag. .
28. A process for packaging albumin in a flexible polymer container comprising the steps of: providing a concentration of albumin; providing a packaging machine having a filling assembly and a sealing assembly. The filling assembly and the sealing assembly are located within an internal aseptic environment of the packaging machine; providing a sterile flexible polymer container having an opening extending into the cavity; Filling the container with albumin under pressure through the filling assembly within the sterile region of the machine, the filling assembly being spaced apart from the wall of the flexible polymer container The outlet of the filling tube has the albumin around the opening of the container. Directed into the cavity of the container and the filling tube is spaced from the filling tube outlet during filling stop to maintain the albumin in the filling tube; and the package Sealing the opening of the container and retaining the albumin in the cavity of the container within the aseptic area of the machine.
29. The method of claim 28, further comprising providing a sheath outside a portion of the filling assembly, wherein the sheath provides contact between the polymer container and the filling assembly. How to limit.
30. A process for packaging albumin in a flexible polymer container, comprising the following steps: providing a concentration of albumin; forming machine, filling assembly, and sealing assembly Each of the assemblies is located within an aseptic environment inside the packaging machine; providing a flexible polymer film; using the forming assembly, the flexible Forming a polymer film into an elongated tube; sealing a portion of the elongated tube of the polymer film with the sealing assembly, wherein the sealed polymer film has a sealing region around it The size of the bag shape, where the cavity is sealed within the bag. And the opening extends from the cavity to the outside of the bag; filling the bag with the albumin through the filling assembly under solution line pressure, the filling assembly Has a filling tube extending through the opening of the bag to the cavity of the bag, and a coaxial sheath on the outside of the filling tube, the filling tube on the inside of the bag A distance from the periphery of the opening of the bag to direct the albumin, and the sheath restricts contact between the filling tube and the bag; and seals the opening of the bag Holding the albumin in the cavity of the bag.
31. The process of claim 30, wherein the sealing area is provided around the entire perimeter of the bag except for the opening.
32. The process of claim 30, further comprising converting the tube into a plurality of adjacent bags.
33. The process of claim 32, further comprising sealing at least three sides of the bag.
(Item 34) The process according to item 32, further comprising the step of continuously filling the bag with the amount of albumin.
35. The process of claim 34 further comprising continuously sealing the opening of the bag.
36. The process of claim 30, wherein the filling step includes providing a filler having a tip, the tip comprising a coaxial first internal passage and a second interior. A first internal passage having a cross-sectional area greater than a cross-sectional area of the second internal passage, wherein an interface between the first internal passage and the second internal passage. Is inside the outside of the tip, the second internal passage extends outside the tip, the albumin exits the filler through the second internal passage, and the albumin A process maintained at the interface between the first internal passage and the second internal passage during stoppage of filling.
(Item 37) A flexible polymer container for holding a concentrate of water-soluble albumin, comprising: a bag made of a sheet of flexible polymer material, wherein the sheet uses a forming agent The tube is first converted into a tube, and the tube is subsequently converted into an adjacent series of bags in the aseptic area of the form-fill-seal packaging machine, the bag being the first face member, the first A second face member sealed around one face member and a cavity between the inside of the first face member and the inside of the second face member, where an amount is A concentration of water-soluble albumin is to continuously fill albumin into the cavity of the adjacent bag through the opening of the bag with a filler in the sterilization area of the form-fill-seal packaging machine. A flexible polymer that enters the cavity of the bag and the opening of the bag is continuously sealed in the sterile area of the form-fill-seal packaging machine to create a fluid tight chamber. container.
(Item 38) The flexible polymer container according to item 37, wherein the flexible polymer sheet material comprises a laminate film, wherein the laminate is an outer layer of linear low density polyethylene, a gas barrier layer. A flexible polymer container having a core layer of polyamide, and an inner layer of linear low density polyethylene, the layers being bonded together by a polyurethane adhesive.
(Item 39) The flexible polymer container according to Item 38, wherein the gas barrier layer is polyvinylidene chloride.
(Item 40) The flexible polymer container according to item 37, wherein the polyamide core layer is nylon.
(Item 41) The flexible polymer container according to Item 38, wherein the gas barrier layer is made of SARAN.
(Item 42) A flexible polymer container filled with albumin, wherein:
  An outer shell made of a flexible polymer sheet material, the material comprising a laminate film, the laminate film having an outer layer of linear low density polyethylene, the outer layer being a polyurethane adhesive , Bonded to the first side of the polyvinylidene chloride layer, the second side of the polyvinylidene chloride layer is bonded together to the first side of the SARAN layer, and the second side of the SARAN layer The second side is bonded with polyurethane adhesive to the inside of the layer of linear low density polyethylene, and the outer shell is heat sealed together around the outer shell and the first side and A fluid tight channel having opposing second surfaces and a cavity located between the first surface and the second surface, the cavity having a concentration of albumin secured therein. Wherein the fixture extends from the outer shell, the fixture has a sealed passage extending into the cavity of the container, and the albumin is released from the fluid tight chamber. A flexible polymer container.
(Item 43) A container for holding albumin, the following:
  A sheet of flexible polymer film formed on the bag, the bag comprising a first wall, an opposing second wall, and a seal around the perimeter of the first and second walls Enclosed, having a cavity, the seal joining the inner portions of the opposing first and second walls and creating a fluid tight chamber within the cavity of the container, wherein A container in which a concentration of albumin mixed with a solution of sterile water and stabilizer is stored in the fluid tight chamber.
44. The bag has a plurality of peripheral edges, three of the peripheral edges are sealed with heat, and one of the peripheral edges is the first wall. 44. The container of item 43, comprising a fold that isolates the second wall from the opposing second wall.
45. The container of claim 44, wherein the fixture is connected to the vessel adjacent to the fold, and the fixture has a passage that cooperates with the fluid tight chamber of the vessel.
(Item 46) The peripheral edge facing the fold includes a first longitudinal seal and a second longitudinal seal, and the first longitudinal seal and the second longitudinal seal are Joining the first and second opposing walls, and an opening is located between the first longitudinal seal and the second longitudinal seal, and the opening is 45. A container according to item 44, extending through the first and second opposing walls.
(Item 47) The container according to item 45, further comprising at least one chevron seal in the folding.
(Item 48) A container according to item 45, which includes a chevron seal in the folding on the opposite surface of the equipment.

  Thus, a flexible polymer container for storing albumin made in accordance with the present invention is inexpensive, easily manufacturable, provides an efficient package, and is a predecessor for packaging albumin. Eliminate drawbacks associated with technology packaging and processes.

  Other features and advantages of the present invention will become apparent from the following specification, taken in conjunction with the following drawings.

  For an understanding of the present invention, it will now be described by way of example with reference to the accompanying drawings.

Detailed Description of Preferred Embodiments
While the present invention allows embodiments in many different forms, the present disclosure should be considered as illustrative of the principles of the invention and to limit the broad aspects of the invention to the illustrated embodiments. With the understanding that they are not intended to be illustrated in the drawings and described herein in the detailed preferred embodiments of the invention.

  As identified above, the scope of the present disclosure encompasses packaging any type of specific pharmaceutical compounds (eg, peptides and proteins for pharmaceutical or other uses). Such compounds are known and include the following: glycoproteins, lipoproteins, immunoglobulins, monoclonal antibodies, enzymes, blood proteins, receptor proteins, and hormones. However, for illustrative purposes, the detailed description of the present invention focuses on the packaging of albumin in a flexible polymer container.

  Referring now in detail to FIG. 3, a flexible polymer container 12 holding a constant concentration of albumin of the present invention is shown. The flexible polymer container 12 is preferably manufactured by an aseptic form-fill-seal packaging machine 10 as shown in FIG. 1 and utilizes the process schematically shown in FIG.

  The aseptic forming-fill-seal packaging machine 10 generally includes an unwind section 14, a film sterilization section 16, a film drying section 18, an idler / dancer roller section 20, a nip drive roller assembly section (not shown), A forming assembly section 22, a fin seal assembly section 24, a fixture mounting assembly section 26, a filling assembly section 30, an end seal / cutting assembly section 32, and a delivery section (not shown). Each of these assemblies downstream of the unwind section 14 is contained within the aseptic form-fill-seal packaging machine 10 internal aseptic environment.

  One of the functions of each of the various assemblies of the form-fill-seal packaging machine 10 is, for example: The unwind section 14 is a roll of flexible polymeric film 34 that is ultimately formed into a container. The film sterilization section 16 provides a peroxide bath for sterilizing the film 34; the film drying section 18 provides means for drying and cleaning the peroxide from the film 34; The forming assembly 22 provides a forming mandrel 36 for turning the web of film into a tube 38 (which ultimately becomes a flexible container or bag 12); the fin seal assembly 24 is a longitudinal seal 40. On the tube 38, this seal eventually becomes a longitudinal seal 40 on the flexible container 12, to which Thus, the formed tube 38 is longitudinally sealed: the fixture attachment assembly section 26 attaches fixture 42 to the tube 38; the filling assembly 30 attaches the flexible container 12 to the material (this is preferred for the present invention). The end seal / cut assembly 32 includes a flexible polymer container 12 for encapsulating albumin within the flexible polymer container 12. Cutting seal jaws 46 forming end seals 76, 78.

  In a preferred embodiment, the albumin used to be packaged in the flexible polymer container 12 is either 20% human albumin or 25% human albumin. To achieve the required concentration level, albumin is typically combined with sterile water and stabilizers. Furthermore, prior to packaging, the albumin concentrate is pasteurized and stored at about 2-8 ° C. in a large stainless steel holding tank (not shown) having a volume of about 500-600 liters. . Just prior to packaging, the albumin tank is removed from refrigeration and allowed to equilibrate to packaging room temperature (approximately 68 ° F.). It is important to treat albumin at a temperature that does not cause protein denaturation (less than about 60 ° C.). However, anywhere between 0 ° C. and 60 ° C., more preferably between 20 ° C. and 45 ° C. is appropriate. Further, in one embodiment, the process temperature is 68 ° F. to 77 ° F. Further, when entering the packaging machine 10, the albumin is filtered through a 0.2 micron filter.

  The flexible polymeric film 34 utilized in the preferred embodiment of the present invention is a linear low density polyethylene laminate. It has been found that such films having a gas barrier are particularly suitable for accommodating oxygen labile solutions (eg, identified proteins, including albumin). Specifically, it has been found that this film reduces or eliminates the denaturation process previously associated with placing proteins (eg, albumin) in plastic containers. As shown in FIG. 9, in a preferred embodiment, the laminate film 34 comprises a linear low density polyethylene (LLDPE) outer layer 52, a gas barrier layer 54, a polyamide core layer 56, and a linear low density polyethylene. The inner layers 58 are bonded together by a polyurethane adhesive 60. Most preferably, the material requirements of the laminated structure have the following characteristics: LLDPE layer (about 61 ± 10 μm) 52, polyurethane adhesive layer 60, nylon layer (about 15 ± 5 μm) 56, polyurethane adhesive layer 60, poly Vinylidene chloride (PVDC) layer (about 19 ± 5 μm) 54, polyurethane adhesive 60, and LLDPE layer (about 61 ± 10 m) 52. In total, the film thickness is about 160 ± 25 μm. Furthermore, the PVDC layer 54 is most preferably manufactured by Dow Chemical and sold under the trademark SARAN. Such a film is disclosed in US Pat. No. 4,629,361. U.S. Pat. No. 4,629,361 is assigned to the assignee of the present invention and is incorporated herein and made a part of this specification by reference. This film 34 is manufactured by Fujimori under the trade name FTR-13F.

  Prior to use, the internal aseptic area of the packaging machine must be sterilized each day. This is accomplished using a hydrogen peroxide spray that is passed through the sterile area of the packaging machine.

  As seen in FIG. 1, a roll of film 34 is disposed within the unwind section 14 of the packaging machine 10. During use, the film 34 is moved through the hydrogen peroxide bath 16 to sterilize the film before entering the sterile area of the packaging machine 10. This sterilization step cleans the web of film so that it can be used to make a sterile product. Film sterilization and cleaning is important in the pharmaceutical industry when packaging parenteral or enteral products. This sterilization step is particularly important when the resulting product is not sterilized at the end, i.e. when the packaging machine is an aseptic packaging machine. After the film is washed, washed and sterilized liquids and other residues (eg, chemical sterilants or wetting agents (eg, hydrogen peroxide)) remain on the film. Accordingly, it is necessary to remove the liquid and / or residue from the film 34. An air knife located in the film drying section 18 (the flow of air blown over the web of the film so that the liquid contained therein is blown away from the film) is applied to the film as it enters the aseptic area of the packaging machine. 34 is used to remove liquids and other residues.

  In the sterile area of the packaging machine 10, the film 34 passes through the dancer roller section 20 and the drive roller section before entering the forming assembly section 22. Prior to entering the forming assembly 22, the web of film 34 is substantially planar and has a first surface 62 and a second surface 64. The first surface 62 faces down when the film enters the forming assembly 22 and eventually becomes inside the container 12, while the second surface 64 faces up when the film enters the forming assembly 22. And finally the outside of the container 12.

  As shown in FIGS. 3 and 4, the film 34 further has a theoretical crease line that is located approximately around the center line of the web length of the film 34. The theoretical crease line becomes a fold area 67 that separates the first side member 66 or the first wall from the second side member 68 or the second wall of the container 12.

  A forming mandrel 36 is disposed within the forming assembly section 22. The forming mandrel 36 assists in turning the substantially planar web of polymeric material 34 into an elongated substantially tubular member 38. It will be appreciated that the elongated tubular member 38, or tube, is not generally cylindrical, but rather has an oblong shape, as shown in FIG. The first surface 62 of the first side member 66 faces the first surface 62 of the second side member 68 after the film 34 has traveled through the forming assembly 22 with the identification of the web region of the film. .

  Once the tubular member 38 is formed, the tubular member receives a longitudinal seal 40 within the fin seal assembly section 24 and a fixture 42 is connected to the tube 38 at the fixture mounting assembly 26. Specifically, the fixture 42 is attached to and extends from the outer shell of the container 12 at the folding region 67 using a heating assembly to seal the fixture 42 to the folding region 67 of the vessel 12. Typically, fixture sealers operate at temperatures from about 415 ° F. to about 450 ° F. and pressures from about 55 psig to about 70 psig, although any range within these identified ranges is acceptable. As shown in FIG. 4, fixture 42 has a sealed path that cooperates with the interior of tube 38. In particular, the pathway can extend into the cavity 82 of the container and create fluid communication with the cavity to release albumin from the fluid-tight chamber. It should be understood that in some embodiments, albumin may be injected into the cavity 82 of the container 12 through the fixture 42.

  The fin seal assembly 24 introduces heat and pressure into the film 34 to create a longitudinal seal 40 at the peripheral edge of the tube 38 opposite the folding region 67. Typically, the fin seal assembly operates at a temperature of about 350 ° F. to about 380 ° F. and a pressure of about 40 psig to about 80 psig, although any range within these specified ranges is acceptable. is there. In the preferred embodiment of the container 12 shown in FIG. 3, the longitudinal seal 40 includes a first longitudinal seal 70 and a 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 side of the first surface 62 of the second wall 68. Typically, an opening 74 used to suspend the formed container 12 is created between the first longitudinal seal 70 and the second longitudinal seal 72. Thus, the opening 74 extends through the opposing first and second walls 66 and 68.

  Sealed tubular member 38 traverses from fin seal assembly 24 to filling assembly 30 and end sealing assembly 32. At the end sealing member 32, the form-fill-seal packaging mechanism 10 utilizes heat and pressure to turn the sealed tube 38 into a series of bags 12 (also referred to as containers 12). . Typically, the end sealing assembly operates at a temperature of about 375 ° F. to about 405 ° F. and a pressure of about 500 psig to about 850 psig, although any range within these specified ranges is acceptable. . The sealed tube 38 initially receives the bottom seal 76 and cavities 82 located between the first side 66 and the second side 68 of the container 12 and the bottom seal 76 of the container, and the cavity 82 of the container 12. A bag 12 having an opening 80 extending from the container 12 to the outside of the container 12 is first formed. It should be understood that this opening 80 extends from the cavity 82 of the container 12 to the center of the tube 38 during the form-fill-seal manufacturing process. Once the bottom seal 76 is made, the bag 12 is filled with albumin through the opening 80, and then a top seal 78 is formed, thus sealing or closing the opening 80 and the fluid in which the albumin is retained. A closed chamber 82 is produced. In addition, once the bottom seal 76 is made, the polymeric film 34 can be said to be sized to the shape of the open bag 12, which is open to its periphery (opposite the folding region 67). A longitudinal seal 34, a bottom seal 76) connecting the folding area 67 and the longitudinal seal 40) and having a sealing area in the bag 12 and between the sealing areas 40, 76 and the folding area 67; A cavity 82 is provided. Thus, using a form-fill-seal packaging process, the completed container 12 has regions sealed to the three sides of the bag 12 (top seal 78, bottom seal 76, and longitudinal seal 40). The longitudinal seal 40 connects the top seal 78 and the bottom seal 76. In the preferred process, the top seal 78 of the first bag 12 is formed simultaneously with the bottom seal 76 of the adjacent upstream bag 12 using the end sealing assembly 32. Thus, adjacent bags 12 in a series of bags 12 are both part of the tubular member 38 forming the bag 12 and have an end seal formed using the same end sealing assembly 32. At first it is connected.

  In a preferred embodiment of the process for making a container of the present invention and filling with albumin, as shown in FIGS. 1 and 2, the container 12 is albumin via a filling assembly 30 that extends a tube 38 down. Filled with. Thus, the filling assembly 30 fills the cavity 82 of the bag 12 through the opening 80 of the three side open bag 12 being manufactured.

  A preferred embodiment filling assembly 30 is illustrated in FIGS. As such, the filling assembly 30 comprises a compression filler 44 made from the filling tube 84 and a sheath 86 positioned coaxially around the filling tube 84. Filler 44 typically operates under a solution line pressure of about 4 psig to about 20 psig, but any range of pressures within these specified ranges is acceptable. In a preferred embodiment, the filler operates at a solution line pressure of about 10 psig to about 16 psig, most preferably a solution line pressure of about 12 psig to about 16 psig. The identified range is utilized in an attempt to reduce turbulence and splashing of albumin or other proteins when inserted into the container 12. As described above, after the bottom seal 76 is made, the bag 12 is filled with albumin by the filling assembly 30 and the top seal 78 is made at the same time as the bottom seal 76 of the next bag, The next bag 12 is subsequently filled, and so on. Thus, adjacent bags 12 in a series of bags 12 are initially connected and then separated after successive filling and sealing of each respective bag 12.

  As shown in FIG. 5, in a preferred embodiment, the filler 44 of the filling assembly 30 is configured as a tube 86 around a tube 84. The sheath tube 86 is coaxially disposed around the filling tube 84, and the air passage 88 extends into a space between the inner diameter of the sheath tube 86 and the outer diameter of the filling tube 84. Sterilized air passes through this air passage and is exhausted from near the tip of the fill tube 84 upstream of the fill tube outlet 92.

  In a preferred embodiment of the fill tube 84 as shown in FIG. 5, the fill tube 84 has a venturi 85 that is tapered over its length from a first diameter to a second, wider diameter. Further, as shown in FIG. 6, the distal end 90 of the fill tube 84 has a first internal passage 94 that is coaxial with and adjacent to the second internal passage 96. And in a preferred embodiment of the present invention, the first internal passage 94 is generally annular in cross section and has a first inner diameter, and the second internal passage 96 is generally annular in cross section; Having a second inner diameter; The inner diameter (and hence the cross-sectional area of the first internal passage 94) is sized larger than the internal diameter (and hence the cross-sectional area of the second internal passage 96). The interface 98 connects the first internal passage 94 and the second internal passage 96 at a position inside the outside of the outlet 92 at the tip 90 of the filler 44. In a preferred embodiment, the interface comprises a chamfered step 98 between the first internal passage 94 and the second internal passage 96 to rapidly reduce the diameter from the first internal passage 94 to the second internal passage 96. The interface 98 between the first passage 94 and the second passage 96 provides an important function in the operation of the filler. Since albumin is dispensed from the outlet of the second internal passage 96 of the filler 44, the capillary force in the filling tube is in contact with the first passage 94 during the stop of filling instead of the outlet 92 of the second passage. It is manipulated to have an albumin meniscus present at the interface 98 with the second passage 96. Thus, albumin is dispensed from the filler 44 through the second internal passage 96 during each stop of filling between successive fillings of the bag 12, but albumin exits into the outlet of the filler 44. And is maintained at the interface 98 of the first passage 94 and the second passage 96. Such a configuration greatly assists in preventing migration of albumin from the outlet of the filler. Any movement allows albumin to move out of the filler and to contact the film 34. As explained above, albumin acts as an insulator. If albumin migrates onto the film, this can jeopardize the integrity of the upper seal area. Therefore, the arrangement of the present invention provides a means for eliminating this drawback. In tests performed on the seal integrity of the container 12 of the present invention, 99.90% of the formed container 12 exceeded the minimum seal strength value of 20 psi in the burst test evaluation.

  As explained above, the sheath 86 exists coaxially around the circumference of the fill tube 84 and the air passage 88 extends into the space between the inner diameter of the sheath tube 86 and the outer diameter of the fill tube 84. . In a preferred embodiment, the distal end portion 100 of the sheath 86 is an adapter mounted on the sheath 86, but the distal end portion 100 does not compromise the intended function of the sheath 86. Can be manufactured as part. As shown in FIGS. 7 and 8, the distal end portion 100 of the sheath 86 has a chamfered end 104. A plurality of exhaust holes 102 are disposed adjacent to the distal end of the distal end portion 100 of the sheath 86. The sterilized air is discharged from the air passage 88 to the outside of the exhaust hole 102. Since the outlet of the exhaust hole 102 is at the chamfered end 104 of the sheath 86, the sterilization air flow pattern is around the outside of the flow pattern of albumin discharged from the filling tip so as not to interfere with the flow of albumin. . This reduces the opportunity for sterilized air to introduce turbulence effects on the distributed albumin. Moreover, since the air flow pattern is outside and away from the albumin liquid flow pattern, any possible foam formation of albumin that occurs in contact with air is minimized. Similar to the benefits found using the dual internal diameter of the fill tube 84, the benefits found using sterile air flow are very useful. Such a configuration greatly assists in preventing albumin splatter and foam formation from the outlet of the filler. This prevents albumin from contacting the part of the film that is converted into the upper seal area, thereby also assisting in continuously creating a stronger upper seal.

  The first inner diameter 106 of the distal end portion 100 of the sheath 86 is sized to fit over the sheath 86 and be secured to the sheath 86 using a set screw 110. The second inner diameter 108 of the distal end portion 100 of the sheath 86 is sized to provide an air passage 88 between the sheath 86 and the fill tube 84. As shown in FIG. 7, the chamfer 112 is positioned at the distal end of the second inner diameter 108 to further reduce the inner diameter of the sheath 86. The reverse chamfer 114 is positioned on the outer portion of the distal portion of the sheath 86.

  The sheath 86 and fill tube 84 are shown assembled in FIG. As can be seen in this figure, the outer diameter of the fill tube 84 is sized at the chamfer 112 to be the same or slightly less than the reduced inner diameter of the sheath 86. In a preferred embodiment, the second inner diameter of the sheath 86 is about 0.584 inches and is increased to 0.500 inches at the chamfer 112. Further, the preferred embodiment of the fill tube 84 of the present invention has an outer diameter of about 0.500 inches. In this way, the interface between the chamfer 112 and the fill tube 86 closes the air passage 88 and allows sterile air to pass from the exhaust hole 102 located upstream of the outlet 92 of the second internal passage of the albumin fill tube 84. Operates to go out.

  As can be seen in FIG. 10, the outer diameter of the sheath 86 is larger than the outer diameter of the filling tube 84 protruding through the sheath 86. Often during filling, the film tube 38 contacts the filling assembly 30. With the specified configuration of the filling tube and sheath, but during part of the filling process, the filling tube 84 of the filling assembly 30 extends through the bag opening 80 into the bag cavity 82, The sheath 86 is external to a portion of the fill tube 84 so that only the sheath 86 can contact the tube 38, thereby preventing contact between the polymer container and the fill tube 84. Thus, the outlet 92 of the fill tube 84 is located away from the inner wall of the flexible polymer container 12. Thus, the position and size of the sheath 86 in combination with the internal interface 98 of the first and second internal passages, and the reverse chamfer 114, allows any albumin to move outside the filling assembly 30 and ultimately. Contact with the sealing area of the tube 38 which becomes the top seal 78 of the finished container is prevented. Since albumin acts as an insulator, it is necessary to maintain the entire seal area free of protein in order for the polymeric material to be heat sealed together. If some albumin is present in the seal area prior to sealing, the integrity of the seal can be compromised. Thus, using the specified configuration, albumin is drained from the fill tube 84 to the bottom of the bag 12 without contacting the sealing area of the opening of the bag 12 that will eventually become the top seal 78. .

  While specific embodiments have been illustrated and described, numerous modifications can be devised without significantly departing from the spirit of the invention, and the scope of protection is limited only by the appended claims.

FIG. 1 is a cross-sectional elevation view of a form-fill-seal packaging machine for producing a flexible polymer container holding a constant concentration of albumin of the present invention. FIG. 2 is a schematic diagram of a process for producing a flexible polymer container holding a constant concentration of albumin of the present invention. FIG. 3 is a front elevation view of a flexible polymer container holding a constant concentration of albumin of the present invention. FIG. 4 is a partial side elevational view of the flexible polymer container holding the constant concentration of albumin of FIG. FIG. 5 is a side elevational view of the partially filled assembly of the present invention. 6 is an enlarged side elevational view of a portion of the filling assembly of FIG. FIG. 7 is a cross-sectional side elevational view of the sheath of the filling assembly of the present invention. 8 is an end elevation view of the sheath of FIG. FIG. 9 is a schematic cross-sectional view of an embodiment of the film laminate structure of the present invention. FIG. 10 is a cross-sectional view of the end of the filling tube and sheath of the present invention.

Explanation of symbols

10 Packaging machine
12 Container (bag)
14 Rewind section
16 Hydrogen peroxide bath
18 Film drying section
22 Forming assembly section
24 Fin seal assembly
26 Fixture mounting assembly
30 Filling assembly
32 End sealing assembly
34 Roll of film
36 Formation Mandrels
38 Tubular members (tubes)
40 Longitudinal seal
42 Equipment
44 Compression filler
62 First surface of film
64 Second surface of film
67 Film folding area
76 Top seal
78 Bottom seal
84 Filling tube
86 sheath
92 Filling tube outlet

Claims (1)

A flexible polymer container containing a protein solution, made by a form-fill-seal packaging machine as shown in FIG.

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