Apparatus and method for vacuum sealing medicament into container

Abstract

The present invention relates to a sterilizable vacuum chamber (10) providing fluid sealing of a medicament into a plurality of containers (60), the chamber comprises a vertically movable container nest holder (70) for holding a container nest (62) carrying a plurality of drug containers filled with a drug fluid, a container closure nest holder for holding a closure nest (82) carrying a plurality of corresponding container closures (80) and for positioning a closure vertically above each corresponding container, a pressure head (25) for vertically moving the container nest to engage the container with the corresponding closure, and an elastically deformable closure nest constraining element (28, 28 ') provided on a side of the closure nest opposite the container nest. A method for fluid sealing of a drug into a container is provided. The method includes a closure nest constraining element acting on the closure nest to resist any vertical upward movement of any of the plurality of containers after engagement of the containers with the closure.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is an international application filed under the Patent Cooperation Treaty, claiming priority to U.S. Provisional Patent Application Serial Number 63 / 355,640 filed on June 26, 2022, priority to U.S. Provisional Patent Application Serial Number 63 / 358,143 filed on July 3, 2022, and priority to U.S. Provisional Patent Application Serial Number 63 / 412,404 filed on October 1, 2022, the disclosures of which are incorporated by reference in their entirety. Technical Field

[0003] The present invention relates to the medical field as exemplified by IPC classification A61, and more particularly to apparatus and associated methods for sterilizing and aseptically handling pharmaceutical materials and containers for pharmaceuticals, including putting the pharmaceuticals into a form for administration to a medical or veterinary patient. In one aspect, the present invention relates to filling pharmaceutical containers with a predetermined amount of liquid or other material and for sealing such material into the container. Background Art

[0004] Controlled environment enclosures are known in the art. Such enclosures are used, for example, to contain hazardous materials. In other examples, controlled environment enclosures are used to provide a controlled environment with a limited number of particles.

[0005] In the art, controlled environment enclosures are typically equipped with ports for transferring materials into and out of the enclosure, and the ports are equipped with gloves for manual manipulation of equipment, parts or materials inside the enclosure. Such gloves are subject to significant puncture risks.

[0006] In some examples known in the art, controlled environment enclosures are also used to limit exposure to live particles. Such controlled environment enclosures may be required for aseptic processing of cell cultures and the manufacture of pharmaceutical products, medical devices, foods or food ingredients. In these cases, it is necessary to decontaminate the controlled environment enclosure. This can be done thermally using steam or chemically using chemical reagents. Suitable chemical reagents known in the art include hydrogen peroxide, ozone, β-propiolactone, aziridine, formaldehyde, chlorine dioxide, ethylene oxide, propylene oxide and peracetic acid. In most cases, a cleaning process must be performed before decontamination and sterilization operations. Such a cleaning process has the function of removing major contaminants by simple mechanical and chemical actions.

[0007] In some examples in the prior art, the controlled environment also contains automated equipment. Such automated equipment includes machines for filling vials. Automated equipment located in a controlled environment is typically of such size and complexity that it cannot be operated fully automatically without human intervention. Such human intervention typically requires the use of gloves with associated puncture risks.

[0008] In view of the above, there remains a need for a controlled environment that does not require manual intervention via the use of gloves and in which drug fluids can be accurately and aseptically dispensed and sealed into containers. This is particularly true in the case of drug fluids that need to be vacuum sealed into syringes or cartridges. This is an area where mechanical challenges remain in the sealing process and where much effort must be invested to prevent any trapped air bubbles that are potentially harmful to the patient being injected with the drug fluid. Summary of the invention

[0009] A method for sealing a plurality of containers with corresponding closures in a sterilizable chamber is provided, the method comprising: transferring a plurality of containers held in a container nest and a plurality of corresponding closures held in a closure nest to an isolator connected to a chamber space via a sealable portal; establishing aseptic conditions in both the chamber and the isolator; filling a plurality of containers with a pharmaceutical fluid under aseptic conditions in the isolator; transferring a container nest holding the pharmaceutically filled containers and a closure nest holding the corresponding closures to the chamber; placing the closure nest in the chamber; The invention relates to a method of mechanically engaging a plurality of containers with corresponding closures by vertically pushing the container nest upward under the container nest so that each container to be sealed is aligned and / or concentrically positioned under the corresponding closure; vacuum-tightly sealing the chamber by means of the port; reducing the air pressure in the chamber to a predetermined level to form a vacuum condition; mechanically engaging the plurality of containers with the corresponding closures by vertically pushing the container nest upward under the vacuum condition; after engagement, resisting any vertical upward movement of any one of the plurality of containers by means of the closure nest; and increasing the air pressure in the chamber to push the plurality of closures deeper into the corresponding plurality of containers to establish physical contact between the closures and the drug fluid.

[0010] Resisting any vertical upward movement of any of the plurality of containers may include constraining the closure nest by means of a mechanical element of a sterilizable chamber disposed on a side of the closure nest opposite the container nest. Resisting any vertical upward movement of any of the plurality of containers may include constraining the closure nest by elastic deformation of a mechanical element of a sterilizable chamber disposed on a side of the closure nest opposite the container nest. The elastic deformation may include elastic compression or spring-based compression. Resisting any vertical upward movement of any of the plurality of containers may include mechanically restraining the closure nest along a vertical axis.

[0011] The vacuum-tight sealing of the chamber may include vacuum-tight sealing to a leak rate equal to or less than 1.54 millibars·liters per second. In some embodiments, vacuum-tight sealing of the chamber may include vacuum-tight sealing to a leak rate equal to or less than 0.3 millibars·liters per second. In yet other embodiments, vacuum-tight sealing of the chamber may include vacuum-tight sealing to a leak rate equal to or less than 0.02 millibars·liters per second.

[0012] A sterilizable vacuum chamber is provided for sealing drug fluid into a plurality of containers using corresponding plurality of closures, the chamber comprising: a vertically movable container nest holding facility arranged to receive a container nest carrying a plurality of drug containers filled with drug fluid; a container closure nest holding facility arranged to receive a closure nest carrying a plurality of corresponding container closures and for positioning a closure vertically above each corresponding container in the container nest; a pressure head for vertically moving the container nest holding facility to engage the containers in the container nest with the closures in the closure nest; and a closure nest restraining element disposed on a side of the closure nest opposite to the container nest.

[0013] The sterilizable vacuum chamber may be capable of sealing to a leakage rate equal to or less than 1.54 millibars per second. In other embodiments, the chamber may be capable of sealing to a leakage rate equal to or less than 0.3 millibars per second. In yet other embodiments, the chamber may be capable of sealing to a leakage rate equal to or less than 0.02 millibars per second. The closure nest restraining element may be elastically deformable so as to be able to move between a first undeflected configuration to a second deflected configuration and back again when the container nest moves toward and away from the closure nest. The closure nest restraining element may be elastically compressible or may include at least one compressible spring. The closure nest restraining element may be arranged to deform elastically when the closure nest is pushed vertically upward against the restraining element. The closure nest restraining element may be arranged to mechanically limit the closure nest along a vertical axis.

[0014] The elastically deformable closure nest restraining element may be arranged to engage the container nest. The container nest holding facility and the closure nest holding facility may be aligned. The container nest holding facility and the closure nest holding facility may be arranged to hold the container nest and the closure nest in alignment. The alignment of the container nest holding facility and the closure nest holding facility may be arranged to concentrically position the corresponding container nest and closure nest.

[0015] The sterilizable vacuum chamber may further comprise a sealable port configured to receive a container nest carrying a plurality of drug containers and a closure nest carrying a plurality of corresponding container closures.

[0016] Another aspect of the present invention relates to an elastically deformable closure nest restraining element that positions relative elements near a closure nest and a container nest. Such a device relates to a sterilizable vacuum chamber for sealing a drug fluid into a container (such as, but not limited to, a tubular and / or cylindrical container). Such a deflectable flexure element may extend near a closure nest and a container nest. It may provide a surface facing oppositely to one of the closure nest and the container nest, such as, but not limited to, a concave surface, a convex surface, and / or an undulating surface. Such a deflectable element may further include a second deflectable element, which, for example, but not limited to, has a concave surface, a convex surface, and / or an undulating surface facing oppositely to at least one of the closure nest and the container nest. Such a flexure may mechanically bias the closure nest and the container nest, such as, but not limited to, by moving between a first undeflected configuration to a second deflected configuration when the container nest moves toward the closure nest. In other embodiments, the closure nest may be pushed against the container, and in some cases, the closure nest may be pushed against the container nest indirectly (via the container) if the container nest is dragged upward with the container by return air pressure acting on the closure. Such an arrangement may position, engage, insert and / or seal at least one closure of the closure nest within an opening of a corresponding container in the container nest to facilitate handling of the nest. Such a flexure may be further moved back to an undeflected configuration as the nest moves away from the closure nest, and may be mounted to and / or mounted with one of the closure nest and the container nest or a corresponding portion of a holding facility.

[0017] Other features, elements, steps, characteristics and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In the drawings, which are not necessarily drawn to scale, the same numerals may describe similar components in different views. The same numerals with different letter suffixes may represent different instances of similar components. The drawings generally illustrate various embodiments discussed in this document by way of example and not by way of limitation.

[0019] Figure 1A is a schematic diagram of an apparatus for filling a syringe with a medical fluid and vacuum sealing the fluid into the syringe with the aid of a closure.

[0020] Figure 1B Show Figure 1A Detail of one chamber of the device.

[0021] Figure 1C yes Figure 1B A cross-section in a vertical plane of an embodiment of a container sealing arrangement is shown in FIG.

[0022] Figure 1D yes Figure 1B 0026 is an isometric view of a cross-section in a vertical plane of an alternative embodiment of a container sealing arrangement shown in 0026 employing an alternative closure nest restraining element.

[0023] Figure 1E yes Figure 1B A cross-section in a vertical plane view of another embodiment of a container sealing arrangement shown in FIG. 1, wherein the container sealing arrangement adopts a method for mechanically limiting the container sealing arrangement along the vertical axis. Figure 1B The closure nest restraining element of the closure nest is provided as part of the closure nest frame.

[0024] Figure 2 is a flow chart of a method for filling a syringe with a medical fluid and vacuum sealing the fluid into the syringe with a closure.

[0025] Throughout the several views, corresponding reference characters indicate corresponding parts. Although the drawings represent embodiments of the invention, the drawings are not necessarily drawn to scale, and certain features may be enlarged to better illustrate and explain the invention. The flow charts are also representative in nature, and actual embodiments of the invention may include additional features or steps not shown in the drawings. The illustrations set forth herein illustrate embodiments of the invention in one form, and such illustrations are not to be construed as limiting the scope of the invention in any way. DETAILED DESCRIPTION

[0026] The embodiments disclosed below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can utilize the teachings of these embodiments.

[0027] Figure 1A , Figure 1B and Figure 1C An embodiment of a device 100 for filling a container with a drug fluid and vacuum sealing the fluid into the container by means of a closure is shown. Device 100 includes at least two chambers 10 and 20. Chamber 20 can be vacuum-tightly sealed relative to chamber 10 by a port 30. The interiors of chambers 10 and 30 can be sterilized with port 30 open and are configured to maintain aseptic conditions established by sterilization. Chamber 20 can be equipped with an air pressure control subsystem (not shown) for controlling the air pressure inside chamber 20. The air pressure control subsystem can include suitable pumps and valves. Suitable pressure control subsystems are well known to those skilled in the art.

[0028] For the purpose of this specification, the terms "aseptic" and "sterilization" and their derivatives will be understood as follows. Establishing aseptic conditions in the interior of a chamber should be understood to mean establishing the conditions throughout the interior atmosphere of the chamber and on substantially all exposed inner surfaces of the chamber. This should include the surfaces of all articles, containers, subsystems, etc., exposed to the interior atmosphere of the chamber. For example, to the extent that extremely airtight cracks or tiny cracks may exist in the interior of the chamber so that sterilizing gases or steam may not fully penetrate into such a closed area, the degree of sterilization may not be complete in actual circumstances. This is recognized in both the industry and the standards set for the industry. The action of establishing aseptic conditions in the interior of the chamber and "sterilizing the interior of the chamber" should have the same meaning in this specification.

[0029] Introducing the article that its surface is not properly sterilized into the inside of the chamber with aseptic condition will destroy the existing aseptic condition in the chamber.On the contrary, introducing aseptic or sterilized articles into the inside that does not have aseptic condition in the inside of the chamber will not make the inside sterile.In fact, what it does is only to destroy the aseptic condition on the surface of the article introduced in this way.Similarly, even when all biological entities are filtered out, introducing filtered air into the unsterilized chamber will not sterilize the chamber in any way or make it aseptic to an acceptable degree in the pharmaceutical industry.The reason is that the inner surface of the chamber will not be sterilized by introducing such air.What is achieved is just to pollute the filtered air with the active biological species that reside on the inner surface of the unsterilized chamber.

[0030] For clarity and completeness, it should also be stated that in the art, the term "sterile" is sometimes also used in association with introducing a drug fluid into a body in a controlled chamber along a sterile tube. In such a case, the term in the art refers to the condition of the tube interior or to the fact that the drug fluid can be filtered to a suitable degree. This will never sterilize the interior of the chamber in question or make it sterile. In such a case, the sterile condition is limited to the interior of the tube carrying the drug flow. Such a flow is usually filtered to a high degree, but such filtration only affects the interior of a specific tube and will not sterilize the interior of the chamber in any way.

[0031] In some prior art systems, containers introduced into a chamber for the purpose of filling with a drug are guided through a sterilization subsystem. This kills biological species on the container. When such a sterilized container is introduced into a chamber when the chamber itself is not sterile, the container loses its sterile condition because the biological species contained in the chamber will be deposited on the previously sterile container.

[0032] It should also be noted that even when laminar flow hoods or the like or any quality HEPA (High Efficiency Particulate Air) filters or ULPA (Ultra Low Particulate Air) filters are employed, pharmaceutical or semiconductor clean rooms of any quality level, including "Class 100", "Class 10" or "Class 1", cannot constitute a sterile chamber because they do not have reliable means to sterilize or aseptically sterilize the surfaces of the chamber. There are standards for clean rooms from both the U.S. federal government and ISO (International Organization for Standardization). These standards specify in great detail the particle content allowed in a cubic volume of air in such a clean room facility for different standards. None of these standards address the problem of biological species present on surfaces in the chamber. This serves to show that a chamber cannot be sterilized by simply managing the atmosphere or air flow of the chamber. Conversely, a chamber cannot be sterilized by simply sterilizing the surfaces of the interior of the chamber.

[0033] The article "Guideline for Disinfection and Sterilization in Healthcare Facilities" by Rutala et al., 2008, from the Centers for Disease Control, lists a summary of mechanisms and methods for sterilization. We are specifically concerned in this specification with those mechanisms for sterilizing the interior of a chamber (i.e., sterilizing both the interior surfaces and the atmosphere within the chamber). In view of the requirements, steam-based methods are best suited for this task. These methods include, but are not limited to, treatment with heated water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, ethylene oxide, glutaraldehyde vapor, or other suitable sterilizing gases and vapors. In one suitable method suitable for the present invention, sterilization is performed with the aid of hydrogen peroxide vapor, which is then flushed with ozone before the chamber is employed in the filling of the drug container.

[0034] As used herein, the term "decontamination" refers to a process for removing or inactivating contaminants (including but not limited to viruses, bacteria, spores, prions, molds, yeasts, proteins, pyrogens, and endotoxins) to acceptable levels. As used herein, "decontamination" includes sterilization (i.e., destroying all microorganisms including bacterial spores to a concentration typically less than 1:10). 6 probability of survival of organisms) and disinfection (i.e., the destruction and removal of specific types of microorganisms).

[0035] Return to Figure 1A , Figure 1B and Figure 1C, the chamber 10 includes a filling station 40 within its interior, which is arranged and configured to hold one or more drug containers 60 arranged in one or more container nests 62. A filling needle 50 is disposed within the interior of the first chamber 10 and is configured to dispense drug fluid into the one or more containers 60. The port 30 provides access to the second chamber 20 described in more detail below. The drug fluid can be dispensed via a fluid path ( Figure 1A , Figure 1B and Figure 1C (not shown) is supplied from a suitable source of drug fluid. Such a source ( Figure 1A , Figure 1B and Figure 1C ) may be disposed within the chamber 10 or may be disposed outside the chamber 10. Figure 1A , Figure 1B and Figure 1C The container 60 shown in the figure is a syringe, but can be generally any other suitable drug container, including but not limited to a cartridge. Suitable first chambers are described in detail in U.S. Patent Application Nos. 13 / 744,408, 15 / 680,114, 16 / 356,734, 17 / 005,606, and 17 / 681,810, all of which are hereby incorporated by reference in their entirety.

[0036] As used herein, the term "fluid" means any liquid and any mixture of solids in a liquid having fluid properties, such as flowability or appreciable fluidity at ambient temperature and pressure, including but not limited to dispersions, emulsions, slurries, microemulsions, colloidal suspensions, suspensions, liposomal suspensions, and micellar suspensions of one or more solids in a liquid.

[0037] As used herein, the term "fluid path" refers to any single-channel or multi-channel conduit or other pathway or structure (rigid or flexible) for conveying fluids. Examples of suitable fluid paths are described in detail in U.S. Patent Application Nos. 14 / 890,223, 15 / 898,641, 16 / 799,767, and 17 / 502,884, the disclosures of all of which are hereby incorporated by reference in their entirety.

[0038] Return to Figure 1A The robot arm 70 with the end effector 72 in the first chamber 10 is configured to move and reposition the container nest 62 carrying the container 60 (see Figure 1B ). To this end, the container nest 62 can be held in the container nest frame 22. The robot arm 70 can also be configured to move and reposition the closure nest 82 carrying the closure 80 (see Figure 1B). To this end, the closure nest 82 may be retained in the closure nest frame 24. The robotic arm 70 may be hermetically sealed within and to the chamber 10 and thus function to move the nesting material. Suitable robotic arms 10 have been described in detail in U.S. Patent Application Nos. 14 / 377,696, 16 / 223,003, and 17 / 486,693, the disclosures of all of which are hereby incorporated by reference in their entirety.

[0039] Figure 1B The second chamber 20 is shown in more detail. A container nest 62 carrying containers 60 can be held in the container nest frame 22. During filling, sealing and subsequently until its use, the container 60 (which can be, for example, but not limited to, a tubular syringe body) is sealed at its lower end with a cap 64. The container nest frame 22 can be moved in a vertical direction by a ram 25. The ram 25 is driven along a vertical axis by a linear motion shaft 27, as shown by arrow 23. The ram 25 can be hermetically sealed to the second chamber 20 by a bellows 29. A closure nest 82 carrying container closures 80 can be held in the closure nest frame 24, wherein each closure 80 is positioned above a corresponding container 60, for example, but not limited to, wherein the closure 80 is aligned with the corresponding container 60 and / or the closure 80 is arranged concentrically with the corresponding container 60. For each closure positioning position in the closure nest 82, the chamber 20 further includes a closure push pin 26 mounted to the inner top plate of the second chamber 20 and configured to prevent the corresponding closure 80 from being further vertically pushed when the ram 25 is pushed upward. The chamber 20 further includes a closure nest restraining element 28. Figure 1B In the embodiment shown in the drawings, the closure nest restraining element 28 is an arcuate flexure, however other shapes and configurations of such flexures may alternatively be employed, such as but not limited to cantilever, leaf spring, coil spring, etc. arrangements. Such flexures are positioned to resiliently engage at least one of the nest and / or nest retaining facility, rather than engaging with elements involved in filling and sealing. The closure nest restraining element 28 and its method of use are described in more detail below.

[0040] When the ram 25 is pushed upward, the closure nest restraining element 28 contacts the closure nest 82 and ensures that the closure nest 82 is firmly restrained within the closure nest frame 24 along the vertical axis while the closure 80 is pushed into the corresponding container 60 by the closure push pin 26, thereby restraining the closure nest 82 from vertical movement relative to the container nest 62 during sealing. In other embodiments, alternative restraining mechanisms may be used to restrain the closure nest 82 from being lifted out of the frame 24. In other embodiments, alternatives to the bellows 29 may be used to obtain a sterile and vacuum-tight seal between the ram 25 and the second chamber 20.

[0041] Figure 1C yes Figure 1B A cross section in a vertical plane of some of the embodiments of the elements of the container sealing arrangement shown in Figure 1C All numbered elements in correspond to Figure 1B Those elements given in . Figure 1C The full vertical extent of the container nest frame 22 is not shown. Figure 1C Also not shown are any elements of the ram 25 or elements driving the ram 25. For the sake of clarity and focus, Figure 1C The container nest 62 and closure nest 82 , one container 60 , one closure 80 , two nest frames 22 and 24 , one closure push pin 26 , and the closure nest restraining element 28 are shown.

[0042] The closure nest restraining element 28 may include one or more elastically deformable portions. Figure 1C In the embodiment shown in FIG. 1 , the closure nest restraining element 28 includes two elastically deformable portions 282A and 282B. The closure nest restraining element 28 may further include one or more closure nest engaging portions. Figure 1C In the embodiment shown in FIG, the closure nest restraining element 28 includes two closure nest engaging portions 284A and 284B. The closure nest restraining element 28 may further include one or more mounting portions. Figure 1C In the embodiment shown in FIG. 8 , the closure nest restraining element 28 includes a mounting portion 286 configured to mount the closure nest restraining element 28 to the interior ceiling of the second chamber 20 .

[0043] In operation, with the chamber 20 under a suitable vacuum, the linear motion shaft 27 extends vertically and in doing so maintains a sterile and vacuum-tight seal to the chamber 20 via the bellows 29. In the process, the ram 25 moves upward and vertically displaces the container nest frame 22 carrying the container nest 62 with the container 60 together with the closure nest frame 24 carrying the closure nest 82 and the closure 80. This displacement causes the closure 80 to come into contact with the corresponding closure push pin 26. As the ram 25 continues its upward movement and the closure nest restraining element 28 secures the closure nest 82 in the closure nest frame 24 by means of the closure nest engagement portions 284A and 284B, the closure push pin 26 pushes the closure 80 out of the closure nest 82 and into the container 60 to a predetermined depth. During the upward vertical displacement of the ram 25, the elastically deformable portions 282A and 282B of the closure nest restraining element 28 are elastically deformed. However, during this process, the closure 80 may become stuck on the closure push pin 26 .

[0044] The term "elastically deformable" is used herein to describe an object or part of an object that (i) changes shape from an original shape to a deformed shape under the action of a force applied externally to the object or part of the object, and (ii) returns to its original shape due to its own elastic material properties when the applied force is removed. The term "elastically compressible" is used herein to describe an object or part of an object that (i) reduces its original range along the axis of the applied force under the action of a force applied externally to the object or part of the object, and (ii) returns to its original range along the axis due to its own elastic material properties when the applied force is removed. This behavior is maintained as long as the material of the object or part of the object is deformed only within the limits determined by the specific material of the object or part of the object. An object may have but does not necessarily have both "elastically deformable" and "elastically compressible" properties, because these properties are compatible with each other. By way of non-limiting example, many polymer materials are elastically deformable and elastically compressible. Coil springs of various materials are elastically compressible along the longitudinal axis within the limits of their individual elastic material properties. As the degree of elastic deformation or compression increases due to an applied force, the object or portion of the object exerts a comparable reaction force that resists the deformation or compression.

[0045] When the air pressure is increased again in the chamber 20 as part of the vacuum sealing process and the pressure head 25 is reduced, the closures 80 are held in the containers by the pressure differential, but can potentially remain stuck on the closure push pins 26. In the absence of the closure nest restraining element 28, a plurality of containers 60, now held on the closures 80 by air pressure and friction, can potentially be lifted out of the container nest 62, they can come into contact with the (now empty) closure nest 82, and they can lift the closure nest 82 out of the closure nest frame 24. Thus, the closure nest 82 will also become indirectly stuck on the closure push pins 26. In these cases, some of the containers 60 can fall and break when they hit the floor of the chamber 20, resulting in wasted product and a process stoppage.

[0046] The closure nest restraining element 28 restrains the closure nest 82 from being lifted out of the closure nest frame 24. The thus restrained closure nest 82 then acts as a vertical movement restraint for the container 60, thereby resisting vertical movement of the container 60 and ensuring that the container 60 remains located in the container nest 62 during the sealing process. This arrangement does not require any mechanical elements of the apparatus 100 to be inserted between the closure nest 82 and the container 60 in order to prevent lifting of the container 60 and the lifting of the container nest 62 that may be associated with such movement. This greatly simplifies the sealing process, thereby reducing expensive process failures. Figure 1B , Figure 1C and Figure 1DResistance to any vertical upward movement of any of the plurality of containers 60 is shown including, for example, but not limited to, restraining the closure nest 82 by means of a sterilizable chamber mechanical element 28 disposed on a side of the closure nest 82 opposite the container nest 62 .

[0047] In another embodiment, the system 100 may use Figure 1D 28'. In this embodiment, the closure nest restraining element 28' includes two elastically deformable portions 282A' and 282B'. The closure nest restraining element 28' includes a single nest engaging portion 284' and a mounting portion 286', which is configured to mount the closure nest restraining element 28' to the interior ceiling of the second chamber 20. In this embodiment, the closure nest restraining element 28' functions as a Figure 1C The closure nest restraining element 28 has the same function as the closure nest restraining element 28 of the embodiment of the present invention, except that the closure nest restraining element 28' fixes the closure nest 82 in the closure nest frame 24 by means of the engagement portion 284'. During the upward vertical displacement of the ram 25, the elastically deformable portions 282A' and 282B' of the closure nest restraining element 28' are elastically deformed to generate the force required to restrain the closure nest 82 in the closure nest frame 24.

[0048] The flexures 28 and 28' can mechanically bias the closure nest 82 and the container nest 62, for example but not limited to, by moving between a first undeflected configuration to a second deflected configuration as the container nest 62 moves toward the closure nest 82. In other embodiments, the closure nest 82 can push against the container 60, and in some cases, the closure nest 82 can push against the container nest 60 indirectly (via the container 60) if the container nest 62 is dragged upward with the container 60 by return air pressure acting on the closure 80.

[0049] In another embodiment, the system 100 may use Figure 1E 00143] The closure nest restraining arrangement shown in . In this embodiment, the closure nest restraining element need not include any elastically deformable portions. In this embodiment, the closure nest 82 is releasably retained in the closure nest frame 24' by means of closure nest engaging elements 242A' and 242B', which are hinged to the closure nest frame 24' of the system 100 by hinges 244A' and hinges 244B', respectively. The closure nest engaging elements 242A' and 242B' engage with the closure nest 82 before the closure nest 82 is transferred to the chamber 20 in the associated method described below. Figure 1EIn the embodiment, only two closure nest engagement elements 244A', 244B' and hinges 242A', 242B' are shown, which respectively engage the left and right peripheral regions of the closure nest 82. In other embodiments, the closure nest frame 24' may have at least two additional closure nest engagement elements for engaging the proximal and distal peripheral regions of the closure nest 82 (at the left and right peripheral regions). Figure 1E (not visible in the cross-sectional view in Figure 2). Figure 1E In the embodiment of the present invention, the closure nest restraining element 242' includes closure nest engagement elements 242A' and 242B', optionally together with corresponding proximal and distal closure nest engagement elements as described herein.

[0050] Figure 1C , Figure 1D and Figure 1E The three embodiments shown in the drawings have the common feature of spatially securing the closure nest 82 within the closure nest frame 24, 24', whether by elastically deformable closure nest restraining elements (such as closure nest restraining elements) attached to the interior ceiling of the chamber 20. Figure 1B , Figure 1C and Figure 1D ), or by mechanical restraint along a vertical axis by a closure nest engagement element attached to a closure nest frame, such as Figure 1E In all three cases, the elements of the system 100 are arranged to allow the closure nest 82 to move the closure away from the closure push pin 26. This will be explained in more detail below.

[0051] In one embodiment, the airtight seal provided by the chamber 10 is sufficient to meet the predetermined requirements according to the ISO standard ISO10648-2 entitled "Containment Enclosures Part 2-Classification According to Leak Tightness and Associated Checking Methods". Specifically, the seal is preferably sufficient to meet Level 3, or more preferably to meet Level 2, or even more preferably to meet Level 1. In another embodiment, the airtight seal provided by the chamber 10 is sufficient to meet the predetermined requirements according to the PDA Journal of Pharmaceutical Science and Technology Technical Report No. 34 entitled "Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products" (September / October 2001). The disclosures of both documents are incorporated herein by reference.

[0052] On page 2 of the ISO 10648-2 document, four leak tightness levels for containment enclosures are defined according to the leak rate as follows. "Level 4" describes an enclosure with a leak rate of less than 10 per hour. -1 "Level 3" describes systems with a leakage rate of less than 10 -2 "Level 2" describes systems with a leakage rate of less than 2.5 × 10 -3 "Class 1" describes systems with a leakage rate equal to or less than 5 × 10 -4 PDA document No. 34 does not define the class, but specifies on page 8 a single leak rate of “not more than 0.5% of the isolator’s internal volume in one hour.” Therefore, PDA document No. 34 specifies a leak rate equal to or less than 5×10 -3 The leakage rate is 2.5%, which places it exactly between Class 2 and Class 3 of the ISO 10648-2 document.

[0053] In some embodiments, the second chamber 20, which must maintain an active vacuum during the sealing process, may have a leakage rate equal to or less than 1.54 mbar·liter per second. In other embodiments, the second chamber 20 may have a leakage rate equal to or less than 0.3 mbar·liter per second. In still other embodiments, the chamber 20 may have a leakage rate equal to or less than 0.02 mbar·liter per second. These leakage rates also apply in particular to the bellows 29 and the port 30.

[0054] according to Figure 2 The flowchart in the method

[200] includes: (i) providing

[210] a first chamber 10 capable of maintaining aseptic conditions, the first chamber being attached to a second chamber 20 also capable of maintaining aseptic conditions and vacuum conditions via a sealable port 30, the first chamber 10 including a device 70 for moving nesting material, a filling station 40 and a filling needle 50 configured to dispense a drug fluid, the second chamber 20 including a device for establishing vacuum conditions, a vacuum sealing device for sealing a closure 80 into a drug container 60, and a nest restraining device 28, 28', 242' for resisting vertical upward movement of a closure nest 82 during sealing; (ii) transferring

[220] at least one empty drug container 60 arranged in at least one container nest 62 and at least one corresponding drug closure 80 arranged in at least one closure nest 82 into the first chamber 10; (iii) transferring the drug closure 80 into the first chamber 10 and the second chamber 20 with the sealable port 30 open. and (ix) sealing

[290] at least one closure 80 into the corresponding at least one filled container 60 by means of a vacuum sealing device, while restraining the closure nest 82 from moving vertically away from the container nest 62 by means of a restraining device 28, 28', 242'.

[0055] Resisting any vertical upward movement of any of the plurality of containers 60 includes restraining the closure nest 82 by means of a mechanical element, such as, but not limited to, a closure nest restraining element 28, 28' or 242' of the sterilizable chamber 20 disposed on a side of the closure nest 82 opposite the container nest 62. Figure 1B , Figure 1C and Figure 1DIn the particular embodiment shown in FIG. 1 , any vertical upward movement of any of the plurality of containers 60 is resisted by a mechanical element of the sterilizable chamber 20 (such as, but not limited to, Figure 1C or Figure 1D The closure nest 82 is constrained by elastic deformation of a corresponding closure nest constraining element 28 or 28') which is disposed on the side of the closure nest 82 opposite to the container nest 62. Figure 1E In the particular embodiment shown in , resisting any vertical upward movement of any of the plurality of containers 60 includes constraining the closure nest 82 along a vertical axis by mechanical restriction provided by closure nest engagement elements attached to the closure nest frame 24' and acting on the side of the closure nest 82 opposite the container nest 62.

[0056] Repositioning

[260] may include: repositioning the container nest 62 having at least one filled container 60 to the second chamber 20 while the container nest 62 is maintained in the container nest frame 22; and repositioning the closure nest 82 having at least one corresponding closure 80 while the closure nest 82 is maintained in the closure nest frame 24, 24'.

[0057] Sealing

[290] may include: (i) inserting the closure 80 into the corresponding container under vacuum conditions; and (ii) increasing the air pressure in the second chamber 20 after insertion. Increasing the air pressure in the second chamber 20 may include equalizing the air pressure in the second chamber 20 with the air pressure in the first chamber 10. Equalizing the air pressure in the second chamber 20 with the air pressure in the first chamber 10 may include at least partially opening the sealable port 30. The increased air pressure in the second chamber 20 pushes the closure 80 along the interior of the container 60 until the closure 80 contacts the meniscus of the drug fluid in the container 60. Inserting the closure under vacuum conditions as described herein ensures that potentially harmful air bubbles are not trapped between the closure and the meniscus of the drug fluid in any of the containers 60 during sealing

[290] .

[0058] Providing

[210] may further include providing a ram 25 within the second chamber 20 that provides a vacuum-tight seal to the chamber 20, thereby allowing the chamber 20 to be sterilized and free of mechanical debris despite having a mechanical ram operating within the chamber 20 driven by a motor located outside the chamber 20.

[0059] Repositioning

[260] to the second chamber 20 may include positioning the closure nest frame 24 having the closure nests 82 and closures 80 above the container nest frame 22 having the container nests 62 carrying the containers 60 , with each closure 80 positioned vertically aligned with a corresponding container 60 .

[0060] Inserting the closure 80 into the container 60 may include pushing the container 60 vertically upward along the axis of arrow 23 to abut, engage or otherwise contact the corresponding closure 80 by operating the ram 25 to vertically displace the nest frame 22 so as to press the closure 80 against the closure push pin 26.

[0061] Inserting the closure 80 into the container 60 may include (e.g. Figure 1B , Figure 1C and Figure 1D ) achieving downward pressure on the closure nest 82 to prevent the closure 80 from being punctured, impacted, or otherwise connected to the closure push pin 26. Achieving downward pressure on the closure nest 82 may include elastically deforming a mechanical component. Elastically deforming the mechanical component may include elastically deforming the closure nest restraining elements 28, 28'. In other embodiments, different arrangements of elastically deformable mechanical components may be used, including but not limited to spring-based components, elastically compressible components, etc. In general, the method includes resisting any vertical upward movement of any of the plurality of containers 60 by means of the closure nest 82 after engagement.

[0062] Additional Notes

[0063] The above detailed description includes references to the accompanying drawings, which form part of the detailed description. The accompanying drawings show by way of illustration specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples". All publications, patents, and patent documents cited in this document are incorporated herein by reference in their entirety, as if individually incorporated by reference. In the event of inconsistencies in usage between this document and those documents so incorporated by reference, the usage in the incorporated reference(s) should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document shall prevail.

[0064] In this document, as is common in patent literature, the terms "a" or "an" are used to include one or more than one, independent of any other instance or usage of "at least one" or "one or more". In this document, unless otherwise indicated, the term "or" is used to refer to a non-exclusive or, such that "A or B" includes "A but not B", "B but not A", and "A and B". In the appended claims, the terms "including" and "wherein" are used as the plain English equivalents of the respective terms "including" and "wherein". In addition, in the following claims, the terms "including" and "comprising" are open-ended, that is, systems, devices, articles, or processes that include elements other than those listed after such terms in the claims are still considered to fall within the scope of the claim. In addition, in the following claims, the terms "first", "second", and "third", etc. are used merely as labels and are not intended to impose numerical requirements on their objects.

[0065] The method examples described herein may be at least partially machine or computer implemented. Some examples may include a tangible computer readable medium or machine readable medium encoded with instructions, which may be operable to configure an electronic device to perform the method described in the example above. The implementation of such a method may include code, such as microcode, assembly language code, high-level language code, etc. Such code may include computer readable instructions for performing various methods. The code may form part of a computer program product. In addition, the code may be tangibly stored on one or more volatile or non-volatile computer readable media during execution or at other times. These computer readable media may include, but are not limited to, hard disks, removable disks, removable optical disks (e.g., compact disks and digital video disks), cassettes, memory cards or memory sticks, random access memories (RAM), read-only memories (ROM), etc.

[0066] The above description is intended to be illustrative, not restrictive. For example, the examples described above (or one or more aspects thereof) may be used in combination with each other. Other embodiments may be used, such as by a person of ordinary skill in the art when reviewing the above description. An abstract is provided to comply with the provisions of Section 1.72 (b) of Section 37 of the Code of Federal Regulations of the United States, to allow readers to quickly determine the essence of the disclosure of the present technology. Submitting this abstract is based on such an understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the above detailed description, various features may be grouped together to simplify the disclosure. This should not be interpreted as an intention that the disclosed features that are not claimed for protection are necessary for any claim. On the contrary, the subject matter of the invention may lie in the partial features of a specific disclosed embodiment. Therefore, the following claims are thus incorporated into the detailed description, wherein each claim exists independently as a separate embodiment. The scope of the present invention should be determined with reference to the full scope of the equivalents given by the attached claims together with such claims.

Claims

1. A method for sealing a pharmaceutical fluid into a plurality of containers (60) within a sterilizable chamber (10) using a corresponding plurality of closures (80), the method being characterized by: transferring (220) the plurality of containers held in the container nest (62) and the corresponding plurality of closures held in the closure nest (82) into an isolator in communication with the chamber space via a sealable port (30); establishing (230) sterile conditions within both the chamber and the isolator; filling (250) the plurality of containers with the pharmaceutical fluid under the aseptic conditions in the isolator; transferring (260) the container nest holding the drug-filled containers and the closure nest holding the corresponding closures into the chamber; arranging the closure nest above the container nest within the chamber so that each container to be sealed is aligned and / or concentrically positioned beneath a corresponding closure; vacuum-tightly sealing (270) the chamber via the port; reducing (280) the air pressure in the chamber to a predetermined level to create a vacuum condition; mechanically engaging the plurality of containers with the corresponding closures by vertically pressing the container nest upward under the vacuum; resisting (290) any vertical upward movement of any of the plurality of containers by means of the closure nest after said engagement; as well as The air pressure in the chamber is increased to push the plurality of closures deeper into the corresponding plurality of containers to establish physical contact between the closures and the medical fluid.

2. The method according to claim 1, characterized in that Resisting any vertical upward movement of any of the plurality of containers includes restraining the closure nest by means of a mechanical element of the sterilizable chamber disposed on a side of the closure nest opposite the container nest.

3. The method according to any one of the preceding claims, characterized in that Resisting any vertical upward movement of any of the plurality of containers includes restraining the closure nest by elastic deformation of a mechanical element of the sterilizable chamber disposed on a side of the closure nest opposite the container nest.

4. The method according to any one of the preceding claims, characterized in that The elastic deformation includes elastic compression.

5. The method according to any one of the preceding claims, characterized in that Elastic deformation includes spring-based compression.

6. The method according to any one of the preceding claims, characterized in that Resisting any vertical upward movement of any of the plurality of containers includes mechanically restraining the closure nest along a vertical axis.

7. The method according to any one of the preceding claims, characterized in that Vacuum-tightly sealing the chamber includes vacuum-tightly sealing to a leak rate equal to or less than 1.54 mbar·liter per second.

8. The method according to any one of the preceding claims, characterized in that Vacuum-tightly sealing the chamber includes vacuum-tightly sealing to a leak rate equal to or less than 0.3 mbar·liter per second.

9. The method according to any one of the preceding claims, characterized in that Vacuum-tightly sealing the chamber includes vacuum-tightly sealing to a leak rate equal to or less than 0.02 mbar·liter per second.

10. A sterilizable vacuum chamber (10) for sealing a pharmaceutical fluid into a plurality of containers (60) using a corresponding plurality of closures (80), the chamber being characterized by: a vertically movable container nest holding facility (70) arranged to receive a container nest (62) carrying a plurality of drug containers filled with a drug fluid; a container closure nest holding facility (70) arranged for receiving a closure nest (82) carrying a plurality of corresponding container closures and for positioning a closure vertically above each corresponding container in the container nest, a ram (25) for vertically moving the container nest holding means to engage the containers in the container nest with the closures in the closure nest; A closure nest restraining element (28, 28') is provided on the side of the closure nest opposite the container nest.

11. The sterilizable vacuum chamber according to claim 9, characterized in that The chamber is sealable to a leak rate equal to or less than 1.54 mbar·liter per second.

12. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 11, characterised in that The chamber is sealable to a leak rate equal to or less than 0.3 mbar·liter per second.

13. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 12, characterised in that The chamber is sealable to a leak rate equal to or less than 0.02 mbar·liter per second.

14. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 13, characterised in that The closure nest restraining element is elastically deformable.

15. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 14, characterised in that The closure nest restraining element includes at least one compressible spring.

16. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 15, characterised in that The closure nest restraining element is arranged to deform elastically when the closure nest is urged vertically upwards against the restraining element.

17. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 16, characterised in that The closure nest restraining element is configured to mechanically constrain the closure nest along a vertical axis.

18. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 17, characterised in that A sealable through opening (30) is provided for receiving the container nest carrying the plurality of drug containers and the closure nest carrying the plurality of corresponding container closures.

19. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 18, characterised in that The closure nest restraining element is configured to engage the container nest.

20. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 19, characterised in that The container nest retaining facility and the closure nest retaining facility are aligned.

21. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 20, characterised in that The container nest holding facility and the closure nest holding facility are arranged to hold the container nest and the closure nest in alignment.

22. A sterilizable vacuum chamber according to any one of the preceding claims 10 to 21, characterised in that The alignment of the container nest holding means and the closure nest holding means is arranged to concentrically position the corresponding container nest and closure nest.

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