MANUFACTURING A FLEXIBLE CONTAINER

Abstract

A method of manufacturing a flexible container (1) housing a drug substance, comprises: forming a first compartment (11) of the container (1) out of a flexible sheet-like material, filling a liquid (2) into the first compartment (11) of the container (1), sealing the first compartment (11), forming a second compartment (12) of the container (1) out of the flexible sheet-like material, filling a dry drug formulation (3) into the second compartment (12), and sealing the second compartment (12). The method further involves lyophilizing the drug formulation inside a tubular cartridge such that the dry drug formulation (3) is generated and held in the tubular cartridge, wherein filling the dry drug formulation (3) into the second compartment (12) comprises: introducing the tubular cartridge holding the dry drug formulation (3) through an opening of the second compartment (12) of the container (1) such that an open end of the tubular cartridge is positioned distant from the opening of the second compartment (12), providing the dry drug formulation (3) out of the open end of the tubular cartridge into the second compartment (12), and withdrawing the tubular cartridge out of the opening of the second compartment (12) of the container (1). The first compartment (11) is separated from the second compartment (12) by a frangible seal (14) which opens when the first compartment (11) is compressed.

Claims

1. A method of manufacturing a flexible container housing a drug substance, the method comprising: forming a first compartment of the container out of a flexible sheet-like material; filling a liquid into the first compartment of the container; sealing the first compartment; forming a second compartment of the container out of the flexible sheet-like material; filling a dry drug formulation into the second compartment; sealing the second compartment; and lyophilizing the drug formulation inside a tubular cartridge such that the dry drug formulation is generated and held in the tubular cartridge, wherein filling the dry drug formulation into the second compartment comprises introducing the tubular cartridge holding the dry drug formulation through an opening of the second compartment of the container such that an open end of the tubular cartridge is positioned distant from the opening of the second compartment, providing the dry drug formulation out of the open end of the tubular cartridge into the second compartment, and withdrawing the tubular cartridge out of the opening of the second compartment of the container, and wherein the first compartment is separated from the second compartment by a frangible seal which opens when the first compartment is compressed.

2. The method of claim 1, wherein the drug formulation is a high potency drug formulation.

3. The method of claim 1, wherein the liquid comprises a solvent for dissolving the dry drug formulation.

4. The method of claim 1, wherein the tubular cartridge has a conical shape widening towards the open end of the tubular cartridge.

5. The method of claim 1, wherein the tubular cartridge is essentially cylindrical.

6. The method of claim 1, wherein an inner wall of the tubular cartridge is coated with a friction reducing material.

7. The method of claim 1, wherein providing the dry drug formulation out of the open end of the tubular cartridge into the second compartment comprises forwarding a plunger through the tubular cartridge towards the open end such that the dry drug formulation is pushed out of the open end of the cartridge.

8. The method of claim 1, wherein forming the first compartment of the container comprises sealing the flexible sheet-like material such that a firm seal is generated which does not open when the first compartment is compressed.

9. The method of claim 8, wherein the firm seal is generated by sealing the flexible sheet-like material at first conditions and the frangible seal is generated by sealing the flexible sheet-like material at second conditions different from the first conditions.

10. The method of claim 1, wherein the second compartment has an opposite end at a maximum distance to the opening of the second compartment, and the dry drug formulation is provided out of the open end of the tubular cartridge into the second compartment near the opposite end of the second compartment.

11. The method of claim 1, wherein forming the second compartment of the container comprises sealing a port to the flexible sheet-like material such that a content of the second compartment can be expelled through the port.

12. The method of claim 1, further comprising: forming a third compartment of the container out of the flexible sheet-like material, lyophilizing a dry further drug formulation inside a further tubular cartridge such that the dry further drug formulation is generated and held in the further tubular cartridge, filling the dry further drug formulation into the third compartment by introducing the further tubular cartridge holding the dry further drug formulation through an opening of the third compartment of the container such that an open end of the further tubular cartridge is positioned distant from the opening of the third compartment, providing the dry further drug formulation out of the open end of the further tubular cartridge into the third compartment, and withdrawing the further tubular cartridge out of the opening of the third compartment of the container, and sealing the third compartment.

13. The method of claim 1, wherein the container is an infusion bag.

14. The method of claim 1, comprising visually inspecting the first compartment and the second compartment; for particulate matter, after sealing the first compartment and the second compartment.

15. The method of claim 14, wherein the first compartment; and the second compartment are at least partially transparent.

16. The method of claim 1, implemented in a blow fill and seal process.

17. The method of claim 2, wherein the high potency drug formulation comprises a biological component.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] The method according to the invention and the thereby manufactured flexible containers are described in more detail herein below by way of exemplary embodiments and with reference to the attached drawings, in which:

[0051] FIG. 1 shows a flow scheme of a first embodiment of a method of manufacturing a flexible container according to the invention;

[0052] FIG. 2 shows a flexible container manufactured by the method of FIG. 1;

[0053] FIG. 3 shows a flow scheme of a second embodiment of a method of manufacturing a flexible container according to the invention;

[0054] FIG. 4 shows a flexible container manufactured by the method of FIG. 3;

[0055] FIG. 5 shows a tubular cartridge as it can be used in the first method of FIG. 1 or in the second method of FIG. 3 before lyophilization;

[0056] FIG. 6 shows the tubular cartridge of FIG. 5 after lyophilization.

DESCRIPTION OF EMBODIMENTS

[0057] In the following description certain terms are used for reasons of convenience and are not intended to limit the invention. The terms “right”, “left”, “up”, “down”, “under” and “above” refer to directions in the figures. The terminology comprises the explicitly mentioned terms as well as their derivations and terms with a similar meaning. Also, spatially relative terms, such as “beneath”, “below”, “lower”, “above”, “upper”, “proximal”, “distal”, and the like, may be used to describe one element's or feature's relationship to another element or feature as illustrated in the figures. These spatially relative terms are intended to encompass different positions and orientations of the devices in use or operation in addition to the position and orientation shown in the figures. For example, if a device in the figures is turned over, elements described as “below” or “beneath” other elements or features would then be “above” or “over” the other elements or features. Thus, the exemplary term “below” can encompass both positions and orientations of above and below. The devices may be otherwise oriented (rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein interpreted accordingly. Likewise, descriptions of movement along and around various axes include various special device positions and orientations.

[0058] To avoid repetition in the figures and the descriptions of the various aspects and illustrative embodiments, it should be understood that many features are common to many aspects and embodiments. Omission of an aspect from a description or figure does not imply that the aspect is missing from embodiments that incorporate that aspect. Instead, the aspect may have been omitted for clarity and to avoid prolix description. In this context, the following applies to the rest of this description: If, in order to clarify the drawings, a figure contains reference signs which are not explained in the directly associated part of the description, then it is referred to previous or following description sections. Further, for reason of lucidity, if in a drawing not all features of a part are provided with reference signs it is referred to other drawings showing the same part. Like numbers in two or more figures represent the same or similar elements.

[0059] FIG. 1 shows a first embodiment of a method of manufacturing an infusion bag as a flexible container housing a drug substance according to the invention. The method is embodied in a side fill and seal process or in a blow fill and seal (BFS) process in an at least partially aseptic environment. It comprises a step A in which two rectangular sheets of flexible plastic foil are arranged with their surfaces contacting each other as flexible sheet-like material. Thereby, the at least one of the sheets of foil is coated with an adhesive which is thermo- and pressure-activatable, wherein the coated surface of the sheets contacts the surface of the other sheet.

[0060] In a step B, two edges of the composition of the two sheets are pressurized at a first pressure and heated at a first temperature such that the sheets are bonded and sealed together at their edges. In particular, the first temperature and pressure are adjusted such that the seals generated in step B are firm seals. In a step C, a second pressure and a second temperature are applied which are lower than the first pressure and temperature, respectively. More specifically, the second temperature and pressure are applied such that two frangible seals are generated. By the two firm seals and the two frangible seals, a first compartment and a second compartment are formed between the sheets, which are separated from each other by one of the frangible seals. The first compartment extends over about half of the two sheets. The first and second compartment are open towards the same longitudinal side of the container. In a step D a diluent is filled in liquid form into the first compartment.

[0061] Preferably in parallel to any of steps A to D, a dry drug formulation is prepared. Thereby, in a step E.sub.i a highly potent biopharmaceutical drug formulation is positioned inside a tubular cartridge. In a step E.sub.ii, the drug formulation is lyophilized inside the tubular cartridge in a way that the dry drug formulation is generated and held in the tubular cartridge. Then the lyophilized or dry drug formulation is filled into the second compartment by, in a step E.sub.iii, introducing the tubular cartridge holding the dry drug formulation through an opening established by the open edges of the two sheets into the second compartment such that an open end of the tubular cartridge is positioned near an end of the second compartment opposite to the opening or compartment opening. Filling of the dry drug formulation further comprises a step E.sub.iv of providing the content of the tubular cartridge by advancing a plunger through it, and a step E.sub.v of withdrawing the tubular cartridge out of the opening of the second compartment as well as out of the container.

[0062] Following step E.sub.iv, the first and second compartments are closed or sealed. In particular, in a step F the open side edge of the container is pressurized to the first pressure and heated to the first temperature such that the first and second compartments are closed by a firm seal. Then in a step G a rigid port is positioned between the non-sealed fourth edges of the two sheets. In a step H, these fourth edges are pressurized at the first pressure and heated at the first temperature such that the sheets are bonded and sealed together at their fourth edges. Thereby, a firm seal is established at the fourth edges. Alternatively, the rigid port can also be mounted in step B above.

[0063] In FIG. 2 a first embodiment of a flexible container according to the invention in the form of an infusion bag 1 is shown as it results from the method described above in connection with FIG. 1. The infusion bag 1 has a first compartment 11 housing a liquid diluent 2, a second compartment 12 housing a highly potent lyophilized drug formulation 3 and an outlet compartment 16. The compartments 11, 12, 16 are formed by generating firm seals 13 and frangible seals 14 in two sheets of a flexible plastic material in an appropriate manner. In particular, the first compartment 11 is formed by a lower longitudinal firm seal 131 extending along the infusion bag, a back firm seal 132, an upper longitudinal firm seal 133 and a right frangible seal 142. The second compartment 12 is formed by the lower longitudinal seal 131, the right frangible seal 142, the upper longitudinal seal 133 and a left frangible seal 141. The outlet compartment 16 is formed by a front firm seal 134 and the left frangible seal 141.

[0064] Centrally in the front firm seal 134 a port 4 is mounted which is in fluid connection with the outlet compartment 16. The port 4 is embodied to be connected to a structure or device for intravenous administration. In the back firm seal 132 a hole 15 is provided for hanging the infusion bag 1 on an appropriate support.

[0065] In use of the infusion bag 1, a user manually compresses the first compartment 11 such that the pressure inside the first compartment 11 is raised. Caused by this pressure raise, the right frangible seal 142 ruptures such that the first compartment 11 and the second compartments 12 form a common compartment. In the common compartment, the diluent 2 and the lyophilized drug formulation 3 are then mixed. Such mixing can be assisted by manually shaking the infusion bag 1. Thereby, the lyophilized drug is diluted and a solution is generated as drug substance. The infusion bag 1 is then hanged port 4 down on the support and an intravenous device is attached to the port 4. Now, the left frangible seal 141 is raptured by manually applying a pressure to the common compartment. Thereby, the infusion bag 1 is changed to a single compartment infusion bag and can be applied as known in the art.

[0066] FIG. 3 shows a second embodiment of a method of manufacturing an infusion bag as a flexible container housing a drug substance according to the invention. The method is embodied in a side fill and seal process or in a blow fill and seal (BFS) process in an at least partially aseptic environment. The method of FIG. 3 comprises generally the same steps as the method described above in connection with FIG. 1. Thus, for aspects not described in the following, it is referred to the description relating to FIG. 1 above.

[0067] In contrast to the method of FIG. 1, in step B, firm seals are provided in the two sheets by appropriately pressurizing and heating the two sheets such that a first compartment, a third compartment and a fourth compartment are created. The two sheets are also pressurized and heated at lower pressure and temperature such that the third and fourth compartments are closed towards the first compartment by frangible seals. At the end of step B, the first compartment is open towards a front end as well as the third and fourth compartments are open towards opposing lateral ends of the two sheets.

[0068] Further, in contrast to the method of FIG. 1, the method of FIG. 3 repeats steps E and F. More specifically, by repeatedly or parallelly performing steps E.sub.i and E.sub.ii plural tubular cartridges of two different sizes holding a lyophilized highly potent biopharmaceutical drug formulation are provided. Then the lyophilized dry drug formulation is filled into the second, third and forth compartments by, in a step E.sub.iii, introducing the tubular cartridges holding the dry drug formulation through respective openings of the second, third and fourth compartments. Then, in a step E.sub.iv the content of the tubular cartridges is forwarded into the respective compartments, and in a step E.sub.v the tubular cartridges are withdrawn out of the openings of the second, third and fourth compartments and out of the container.

[0069] Following step E, the second, third and fourth compartments are closed or sealed in a step F. In particular, the second pressure and the second temperature are applied such that a second frangible seal is generated closing the second compartment. Further, the first pressure and the first temperature are applied such that firm seals are generated closing the third and fourth compartments.

[0070] In FIG. 4 a second embodiment of a flexible container according to the invention in the form of an infusion bag 10 is shown as it results from the method described above in connection with FIG. 3. The infusion bag 10 has a first compartment 110 housing a liquid diluent 20, a second compartment 120 housing two large portions of a highly potent lyophilized drug formulation 310, a third compartment 160 housing one small portion of the highly potent lyophilized drug formulation 320, a fourth compartment 170 housing two small portions of the highly potent lyophilized drug formulation 330, and an outlet compartment 180.

[0071] The compartments 110, 120, 160, 170, 180 are formed by generating firm seals 130 and frangible seals 140 in an appropriate manner. In particular, a lower longitudinal firm seal 1310 extending along the infusion bag 10, a back firm seal 1320, an upper longitudinal firm seal 1330 and a front firm seal 1340 are generated. The first compartment 110 is separated from the second compartment 120 by right frangible seal 1410, from the third compartment 160 by an upper non-continuous frangible seal 1430, and from the fourth compartment 170 by a lower non-continuous frangible seal 1440. The second compartment 120 is separated from the outlet compartment by a left frangible seal 1420.

[0072] Centrally in the front firm seal 1340 a port 40 is mounted which is in fluid connection with the outlet compartment 180. The port 40 is embodied to be connected to a structure or device for intravenous administration. In the back firm seal 1320 a hole 150 is provided for hanging the infusion bag 10 on an appropriate support.

[0073] In use of the infusion bag 10, a practitioner manually presses the first compartment 110 such that the pressure inside the first compartment 110 raises. Caused by this pressure raise, the right frangible seal 1410 ruptures such that the first compartment 110 and the second compartment 120 together form a common compartment. As the need may be, the dosage is adjusted by additionally rupturing the upper non-continuous frangible seal 1430 and/or the lower non-continuous frangible seal 1440. Like this, any or none of the small portions of the highly potent lyophilized drug formulation 320, 330 can be added to the common compartment. In the common compartment, the diluent 20 and the lyophilized drug formulation 30 are mixed. Thereby, the lyophilized drug is diluted and a solution is generated as final drug substance. After being visually inspected for proper mixing and absence of any visual particles, an intravenous device is attached to the port 40 and the left frangible seal 1420 is raptured by manually applying a pressure to the common compartment. Then, the infusion bag 10 is hanged port 40 down on the support.

[0074] In FIG. 5 a tubular cartridge 5 as it can be used in a method according to the invention is shown. The tubular cartridge 5 has a hollow and essentially cylindrical body 51 made of a material having a high thermal conductivity. Towards its lower end, the body 51 widens such that it comprises a conical section. Into the conical section of the body 51 a stopper 52 is provided for tightening the interior of the body 51. Inside the interior above the stopper 52 a liquid drug formulation is positioned.

[0075] The drug formulation is then lyophilized inside the tubular cartridge 5 such that a dry drug formulation 39 is generated as shown in FIG. 6. and held in the tubular cartridge. Before, filling the lyophilized or dry drug formulation 39 into a compartment of a flexible container the stopper 52 is removed. The dry drug formulation 39 is still held inside the body 51 by friction. The conical section of the body allows on one hand an efficient manipulation of the stopper 52 and on the other hand an efficient transfer of the dry drug formulation out of the tubular cartridge 5. By using the tubular cartridge 5, it can be assured that the dry drug formulation 39 is provided inside the interior of the compartment distant from an edge thereof. Like this, contamination of the edge to be sealed or even loss of dry drug formulation out of the compartment can be prevented.

[0076] This description and the accompanying drawings that illustrate aspects and embodiments of the present invention should not be taken as limiting the claims defining the protected invention. In other words, while the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. Various mechanical, compositional, structural, electrical, and operational changes may be made without departing from the spirit and scope of this description and the claims. In some instances, well-known circuits, structures and techniques have not been shown in detail in order not to obscure the invention. Thus, it will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below.

[0077] The disclosure also covers all further features shown in the Figs. individually although they may not have been described in the afore or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the invention or from disclosed subject matter. The disclosure comprises subject matter consisting of the features defined in the claims or the exemplary embodiments as well as subject matter comprising said features.

[0078] Furthermore, in the claims the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single unit or step may fulfil the functions of several features recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. The terms “essentially”, “about”, “approximately” and the like in connection with an attribute or a value particularly also define exactly the attribute or exactly the value, respectively. The term “about” in the context of a given numerate value or range refers to a value or range that is, e.g., within 20%, within 10%, within 5%, or within 2% of the given value or range. Components described as coupled or connected may be electrically or mechanically directly coupled, or they may be indirectly coupled via one or more intermediate components. Any reference signs in the claims should not be construed as limiting the scope.