Methods, devices, and systems for filling medication containers

Abstract

The present invention relates to a stopper installation device for closing a plurality of pharmaceutical containers held in a container nest with a corresponding plurality of closures held in a closure nest. The device includes a controlled environment enclosure capable of maintaining sterility. Within the enclosure, an actuating driver having an upwardly facing horizontal driving surface is configured to move along a vertical path. A retaining plate is disposed within the controlled environment enclosure above the driver and includes a lower horizontal surface parallel to and facing the horizontal driving surface. A resilient, malleable element may be attached to the upwardly facing horizontal driving surface to be compressible between the container and the horizontal driving surface. A resilient, malleable vertical pin may be attached to the retaining plate to engage with the tops of the closures under actuation of the actuating driver. The resilient, malleable element compensates for differences in container height.

Description

[Technical Field]

[0001] The present disclosure relates to the medical field as exemplified by IPC Classification A61, and more particularly to devices, systems, and methods for filling and sealing pharmaceutical containers. In one aspect, the present disclosure relates to devices, systems, and methods for filling and sealing pharmaceutical containers in a controlled environment chamber. [Background technology]

[0002] By its very nature, human sterilization of pharmaceutical products is problematic. Humans can be a significant source of microbial contamination. Also, with increased potency, some drugs can be harmful in occupational exposure. For at least these reasons, robotics is attractive in pharmaceutical manufacturing to limit human contact. Isolator technology, which provides a solid barrier between the process and people, can also be used in pharmaceutical manufacturing to limit human contact.

[0003] Traditionally, equipment for filling, stoppering, and capping pharmaceutical containers has been designed to process singulated containers, typically using vibratory bowls for dispensing elastomeric closures and shrink caps. More recently, equipment has become available to process multiple containers in nested configurations. Such container configurations can be cleaned, depyrogenated, and sterilized on-site at the container manufacturer, simplifying equipment requirements and pharmaceutical manufacturer operations.

[0004] A significant portion of all filling equipment is of such complexity that it cannot be incorporated into a controlled environment enclosure. Such filling equipment can only be installed in a restricted access barrier system, the environment of which is far less secure than the complete physical barrier provided by a controlled environment enclosure such as an isolator. Another negative aspect of complex equipment is cleanliness, which can be a concern for the use of multiple products, particularly for very robust products. In particular, systems using conveyor belts to transport nested containers are known, and these pose considerable challenges in the pharmaceutical industry in terms of achieving an acceptable degree of cleanliness.

[0005] Handling and singulation of elastomeric stoppers and aluminum crimp caps has been known to be problematic at times. Blockages in the vibrating chute cannot always be prevented, occasionally requiring operator intervention to relieve the blockage. This has led to the use of nested drug containers.

[0006] Some of the newer filling equipment accepts nested containers but unnestrs them to process them in a singulated manner, just as is done with conventional equipment. These equipment thereby negates some of the inherent benefits provided by nesting the containers in the first place. Other equipment variations unnestr elastomeric closures and aluminum crimp caps and then apply them in a singulated manner.

[0007] It is good automation practice not to release a part, such as a drug container or closure, once it is properly held, and only to release the part once all processing involving the part has been completed. Most prior art vial filling machine designs deviate from this rule due to the perceived difficulty in placing stoppers and caps when containers are placed in a nest.

[0008] Another good practice is to avoid unnecessary handling of parts under sterile conditions. Stopper and closure elements are typically singulated in the industry using vibrating bowls and transported using vibrating chutes. The vibrating bowls and chutes contact the stoppers, and the surfaces of the stoppers ultimately come into direct contact with the product inside the container. To address this issue, it is generally considered necessary to steam sterilize the vibrating bowls and chutes. However, it is practically impossible to aseptically transport the stopper bowls and chutes from the sterilization autoclave to the processing environment.

[0009] With regard to specific closure nest designs, examples of prior art vial closure nests are described in US Patent No. 5,929,999. The specific examples are of limited practical use for at least three reasons.

[0010] First, commercially available trays typically have 60 to 120 containers, the number varying depending on vial diameter. A packing density of 60 to 120 containers with a footprint of 8 inches by 9 inches in the nest does not allow for a matching cap nest design, as shown in U.S. Patent No. 5,629,499, because its retention features would occupy too much space. The force required to cap each vial is typically in the range of 40 to 50 Newtons, and is therefore orders of magnitude greater than the force required for removal of the tamper-evident features shown in the same patent application.

[0011] Second, the closure needs to be held by the nest in such a way that the force required to cap the vial is directed so that the resulting force vector does not act on the tamper-evident features. When simultaneous capping is considered, the forces can be up to 6000N, further strengthening the demand for a closure nest design that does not deform or flex under the load.

[0012] Third, the closure needs to be retained in the nest in such a way that its accidental release is prevented during shipping and handling, yet should allow the cap to be removed without risk of removing the tamper-evident feature. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] US Patent Application Publication No. 20120248057 Summary of the Invention [Problem to be solved by the invention]

[0014] In summary, while the use of nested containers is established in the industry, challenges remain as to how to manage such containers in a controlled environment while ensuring that the equipment used in the process is cleanable to a degree acceptable in the highly regulated pharmaceutical industry.

[0015] Certain additional aspects of using nested containers and closures require attention. Dimensional inconsistencies in glass containers are problematic in automated filling, particularly for smaller vials. While large volumes of containers can be processed in a nested configuration, differences in height from container to container can potentially result in costly failures in stoppering the filled containers. There is a clear need for a solution to this problem. [Means for solving the problem]

[0016] In a first aspect, the present disclosure provides a method for aseptically filling a first plurality of containers with a pharmaceutical product in a first controlled environment enclosure, the method comprising the steps of decontaminating at least one of first and second sealed and nested materials in a first transfer chamber; placing the first controlled environment enclosure in spatial communication with the first transfer chamber; aseptically grasping at least one of the first and second sealed and nested materials; transferring at least one of the first and second sealed and nested materials to the controlled environment enclosure; removing a container nest holding the first plurality of containers from one of the first and second sealed and nested materials and removing a closure nest releasably holding a plurality of closures from the other of the first and second sealed and nested materials; filling the first plurality of containers with the pharmaceutical product in the first controlled environment enclosure; and at least partially closing the first plurality of containers with a plurality of closures. The method may further include maintaining sterility in the first controlled environment chamber and weighing the first plurality of containers while the plurality of containers are in the container nest.

[0017] The first plurality of containers may be in the closure nest during at least partial closure. The aseptic gripping step may include manipulating a first articulated arm device. The closing step may include manipulating the articulated arm device to place the first plurality of containers in a stoppering device. The filling step may include manipulating a second articulated arm device. The filling step may include filling at least a portion of the first plurality of containers simultaneously.

[0018] Filling the first plurality of containers may include manipulating an articulated arm device to move one of the container nest and a fill needle system that dispenses the pharmaceutical product. Dispensing the pharmaceutical product may include simultaneously dispensing the pharmaceutical product from the plurality of fill needles. Removing the container nest holding the first plurality of containers may be by manipulating a second articulated arm device.

[0019] The method may further include returning the filled container to the transfer chamber and terminating spatial communication between the transfer chamber and the first controlled environment chamber.

[0020] At least partially closing the first plurality of containers may include partially inserting the first plurality of containers, lyophilizing the pharmaceutical product in the first plurality of containers, and at least partially sealing the first plurality of containers by exerting pressure on at least a portion of a plurality of caps associated with the plurality of stoppers. Lyophilizing the pharmaceutical product may include lyophilizing the pharmaceutical product in a stopper fitting device having an interior that may be isolated from an interior of the first controlled environment enclosure.

[0021] Partially closing the first plurality of containers may include partially closing at least a portion of the first plurality of containers simultaneously. In other embodiments, partially closing the first plurality of containers may include partially closing all of the containers in the container nest simultaneously.

[0022] The at least partially closing step can include fully closing, and the method can further include transferring the filled containers to a second controlled environment enclosure. In some embodiments, the partially sealed first plurality of containers can be transferred to the second controlled environment enclosure.

[0023] In another aspect, the present disclosure provides a method for aseptically sealing a pharmaceutical product into a plurality of containers, the method including the steps of introducing a first plurality of containers into a controlled environment enclosure, releasably suspending a plurality of sterile closures from a closure nest in the controlled environment, filling at least a first portion of the first plurality of containers with the pharmaceutical product, and simultaneously sealing at least partially a second portion of the first plurality of containers with a portion of the plurality of sterile closures while releasably retaining the sterile closures in the closure nest. The method may further include lyophilizing the pharmaceutical product in the second portion of the first plurality of containers while releasably retaining the sterile closures in the closure nest.

[0024] The releasably suspending and releasably retaining steps may include releasably engaging a retention feature of each of the plurality of sterile closures. Releasably engaging the retention feature may include resiliently engaging the retention feature. Resilient engaging the retention feature may include engaging the retention feature with a spring-loaded retention structure portion of the closure nest.

[0025] Some or all of the plurality of sterile closures held by the closure nest can be used to either fully or partially seal a pharmaceutical product into a container. The number of containers can be equal to the number of sterile closures releasably suspended by the closure nest. Two or more containers can be filled simultaneously.

[0026] In another aspect, the present disclosure provides a closure nest for releasably retaining a plurality of closures for a drug container, the closure nest including a substantially planar support structure and a plurality of closure retention structures disposed on the planar support structure, each of the plurality of closure retention structures including a plurality of closure engagement structures disposed to engage retention features on one of the plurality of closures and including at least one spring-loaded arm. The closure retention structure may further include a plurality of bung structures configured to trap one of the plurality of closures and exert a force on one of the plurality of closures when the closure and the closure nest are pressed together in a vertical direction.

[0027] The at least one spring-loaded retention structure can be integrally integrated with the closure nest, and the closure nest can be a polymeric closure nest. The at least one spring-loaded retention structure can be a flexible retention structure, and in some embodiments, the flexible retention structure can be a polymeric structure. The plurality of closure engagement structures can be arranged in a geometric pattern, and in some embodiments, the geometric pattern can be a closely spaced pattern. The geometric pattern can be center-to-center aligned with the pattern of container retention structures in the container nest.

[0028] A stopper attachment device is provided for closing a plurality of pharmaceutical containers held in a container nest with a corresponding plurality of closures held in a closure nest, the stopper attachment device comprising: a controlled environment enclosure capable of maintaining a sterility state; an actuated driving machine having an upwardly facing horizontal driving surface and configured to move along a vertical path within the controlled environment enclosure; a fixed plate positioned within the controlled environment enclosure above the driving machine, the fixed plate having a lower horizontal surface parallel to and facing the horizontal driving surface; and at least one resiliently compliant element positioned so as to be compressible between at least one of the containers and the horizontal driving surface.

[0029] The at least one resilient, compliant element may be a single resilient, compliant pad arranged to be compressible between all of the containers and the horizontal installation surface. The at least one resilient, compliant element may comprise a plurality of resilient, compliant pads, each pad aligned center-to-center with a corresponding container in the container nest along the vertical axis and arranged to be compressible between the corresponding container and the horizontal installation surface. The at least one resilient, compliant element may comprise a single resilient, compliant pad, the surface of the pad facing the lower horizontal surface of the fixture plate shaped to provide a distribution of apexes of resilient, compliant material arranged to be elastically compressible between the containers and the horizontal installation surface. A portion of the apex of the resilient, compliant material may be arranged to pass through an opening in the lowermost surface of the container nest to engage the container. The at least one resiliently compliant element may comprise a single resiliently compliant pad, the surface of the pad facing the horizontal driving surface being shaped to provide a distribution of tops of resiliently compliant material arranged to be resiliently compressible when the pad is pressed against the container under the action of the actuating driving tool.

[0030] In one embodiment, there is provided a stopper attachment device for closing a plurality of pharmaceutical containers held in a container nest with a plurality of corresponding closures held in a closure nest, the stopper attachment device comprising: a controlled environment enclosure capable of maintaining a sterility state; an actuating driver having an upward-facing horizontal driving surface and configured to move along a vertical path within the controlled environment enclosure; a fixture plate disposed within the controlled environment enclosure above the driver, the fixture plate having a lower horizontal surface parallel to and facing the horizontal driving surface; and a plurality of pins attached to the lower horizontal surface of the fixture plate and centered along a vertical axis to correspond to the plurality of closures, the plurality of pins being positioned and configured to pass through openings in the closure nest to engage with tops of the closures as the actuating driver presses the plurality of containers into the plurality of corresponding closures, and configured to resiliently compress the tops of the closures under actuation of the actuating driver.

[0031] In one embodiment, there is provided a stopper attachment device for closing a plurality of pharmaceutical containers held in a container nest with a plurality of corresponding closures held in a closure nest, the stopper attachment device comprising: a controlled environment enclosure capable of maintaining sterility; an actuated driver having an upward-facing horizontal driving surface configured to move along a vertical path within the controlled environment enclosure; a stationary plate positioned within the controlled environment enclosure above the driver, the stationary plate having a lower horizontal surface parallel to and facing the horizontal driving surface; and a plurality of pins attached to the lower horizontal surface of the stationary plate and corresponding to the plurality of closures along a vertical axis, the plurality of pins being centered relative to the plurality of closures, the plurality of pins being positioned and configured to pass through openings in the closure nest to engage with tops of the closures as the actuated driver drives the plurality of containers into the plurality of corresponding closures, each pin comprising a resiliently compliant element made of a resiliently compliant material positioned at a point along its length, the resiliently compliant element being positioned and configured to be resiliently compressible.

[0032] In one embodiment, a stopper attachment device is provided for closing a plurality of pharmaceutical containers held in a container nest with a corresponding plurality of closures held in a closure nest, the stopper attachment device comprising: a controlled environment enclosure capable of maintaining sterility; an actuated driver having an upward-facing horizontal driving surface configured to move along a vertical path within the controlled environment enclosure; a stationary plate positioned within the controlled environment enclosure above the driver, the stationary plate having a lower horizontal surface parallel to and facing the horizontal driving surface; and a plurality of resiliently compressible extendable pins attached to the lower horizontal surface of the stationary plate and corresponding to the plurality of closures along a vertical axis, the plurality of pins being positioned and configured to pass through openings in the closure nest to engage with tops of the closures as the actuated driver drives the plurality of containers into the corresponding closures.

[0033] A stopper attachment device is disclosed that provides a controlled environment for receiving nests of drug containers and nests of closures and for closing an array of drug containers held in the container nest with an array of corresponding closures held in the closure nest, the stopper attachment device comprising: first and second opposing rigid plates defining a space therebetween for receiving the array of closures in overlapping registration with the openings of the array of containers, the rigid plates being arranged for relative movement towards and away from each other to drive the array of containers and the array of closures together to seal the openings of each container in the array of containers with a corresponding closure in the array of closures, the second plate being in overlapping registration with the first plate; and at least one resiliently compliant element positioned between the array of containers and the first rigid plate, the at least one resiliently compliant element being locally deformable by each container in the array of containers during driving the containers into sealing engagement with the closures.

[0034] The at least one resilient, compliant element may be a single resilient, compliant pad arranged to be compressible between all of the containers and a first of the opposing rigid plates. The at least one resilient, compliant element may comprise a plurality of resilient, compliant pads, each pad aligned center-to-center with a corresponding container in the container nest along the vertical axis and arranged to be compressible between the corresponding container and a first of the opposing rigid plates. The at least one resilient, compliant element may comprise a single resilient, compliant pad, with one surface of the rigid plate facing the other of the rigid plates shaped to provide a distribution of apexes of resilient, compliant material arranged to be elastically compressible between the containers and the surface of the first of the rigid plates. A portion of the apex of the resilient, compliant material may be arranged to pass through an opening in the lowermost surface of the container nest to engage the container. At least one resiliently compliant element may comprise a single resiliently compliant pad, the surface of the pad facing the first of the opposing plates being shaped to provide a distribution of tops of resiliently compliant material that is arranged to be resiliently compressible when the pad is pressed against the container under the action of the actuation driver.

[0035] A stopper application device is disclosed that provides a controlled environment for receiving nests of drug containers and nests of closures and for closing an array of drug containers held in the container nests with a corresponding array of closures held in the closure nests, the stopper application device comprising first and second opposing rigid plates defining a space therebetween for receiving the array of closures in overlapping registration with openings in the array of containers, the rigid plates driving the array of containers and the array of closures together to close the openings of each of the containers in the array of containers with a corresponding opening in the array of closures. The device includes first and second rigid plates arranged for relative movement toward and away from each other to seal with the closures, the first plate in overlapping registration with the second plate; and a plurality of pins disposed on a surface of the first plate, centered on the plurality of closures and corresponding to each other, each pin extending along an axis parallel to the longitudinal axis of a corresponding container. The pins are arranged and configured to pass through corresponding openings in the closure nest to engage with the tops of the closures while driving the containers into sealing engagement with the closures. The pins may be configured to resiliently compress the tops of the closures. The device may include a resiliently compliant element disposed within or on the end of each of the plurality of pins, and arranged to be resiliently compressed while driving the containers into sealing engagement with the closures. Each pin may comprise a resiliently compressible telescoping pin arranged to be compressed while driving the containers into sealing engagement with the closures.

[0036] A method of operating a stopper applicator for closing a plurality of pharmaceutical containers held in a container nest with a plurality of corresponding closures held in a closure nest is disclosed. A controlled environment enclosure capable of maintaining sterility is provided, and an actuation driver is disposed within the controlled environment enclosure. The actuation driver has an upward-facing horizontal driving surface and is configured to move along a vertical path within the controlled environment enclosure. Also provided within the controlled environment enclosure is a fixture plate above the driver and having a lower horizontal surface parallel to and facing the horizontal driving surface. A plurality of pins are attached to the lower horizontal surface of the fixture plate and correspond center-to-center with the plurality of closures along the vertical axis. The pins are positioned and configured to pass through openings in the closure nest to engage with the tops of the closures when the actuation driver drives the plurality of containers into the corresponding closures, such that the pins are configured to resiliently compress the tops of the closures under actuation of the actuation driver. Finally, the articulating driver and the fixture plate are pressed together.

[0037] The foregoing and other features and objects of the present invention, and the manner in which they are accomplished, will become more apparent, and the invention itself will be better understood, by reference to the following description of embodiments thereof taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0038] [Figure 1] FIG. 1 is a diagram of a system for filling drug containers. [Figure 2] FIG. 1 shows the arrangement and contents of a sealed, nested container package used in the present invention, from bottom to top. [Figure 3] 1 is a bottom-up view of the layout and contents of a sealed, nested closure package used in the present invention. FIG. [Figure 4] FIG. 10 is a diagram of an alternative embodiment of a system for filling drug containers. [Figure 5A] FIG. 1 is a diagram of a medication container and its key dimensions. [Figure 5B] FIG. 1 is a diagram of a medication container and its key dimensions. [Figure 6A] 1A-1C are diagrams of embodiments of closures for drug containers. [Figure 6B] 1A-1C are diagrams of embodiments of closures for drug containers. [Figure 7A] 10A-10C are views of an embodiment of a closure retention structure for a closure nest. [Figure 7B] 10A-10C are views of an embodiment of a closure retention structure for a closure nest. [Figure 8] 7B is a diagram of an arrangement for closing the container of FIG. 5 with the closure of FIG. 6A using the closure retention structure of FIG. 7A. [Figure 9] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 10] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 11] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 12] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 13] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 14] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 15] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 16]1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. [Figure 17] 1A-1C are diagrams of an embodiment of a plug attachment device for closing a plurality of containers nested in a container nest with a plurality of closures nested in a closure nest. DETAILED DESCRIPTION OF THE INVENTION

[0039] Corresponding reference numerals indicate corresponding parts throughout the several views. While the drawings depict embodiments of the present invention, they are not necessarily to scale and certain features may be exaggerated to better illustrate and explain the present invention. The examples set forth herein illustrate embodiments of the present invention, in one form, and such examples are not to be construed as limiting the scope of the present invention in any way.

[0040] 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 their teachings.

[0041] A method and associated system for filling pharmaceutical containers is described through schematic depictions in FIG. 1 as well as FIGS. 2 and 3. A filling system 10 for filling pharmaceutical containers 90 with a pharmaceutical product is disposed within a controlled environment enclosure 20. The controlled environment enclosure 20 is configured to maintain sterility. In some embodiments, particularly the embodiment shown in FIG. 1, the pharmaceutical product may be a liquid product. In other embodiments, the product may be a solid pharmaceutical product. The pharmaceutical product may be potentially toxic or otherwise harmful. As described in more detail below, the filling system 10 may be configured to position, target, and fill containers 90 held in container nests 70 within container tubs 80 (see FIG. 2). Many types of containers 90 are contemplated herein, including, but not limited to, vials, syringes, bottles, and ampoules.

[0042] Pharmaceutical containers made from tubular glass are commercially available in a range of different sizes with dimensions according to the DIN / ISO 8362-1 standard. Molded glass vials are commercially available in a range of different sizes with dimensions according to the DIN / ISO 8362-4 standard. Often, vials with one or more additional custom specifications are used. In some cases, these specifications may deviate from the standard.

[0043] Glass has traditionally been the only choice for container materials, but problems with glass fracture, spalling, dimensional inconsistency, particulates from glass-on-glass collisions, and the stability of some products have led to the development and use of suitable polymeric materials. One example of such a polymeric material is TOPAS® cyclic olefin-based polymer. Vials made from polymeric materials are commercially available in a range of sizes and dimensions that typically closely mimic those of glass vials.

[0044] Polymeric materials are significantly less scratch resistant than glass materials, and existing aseptic processing equipment has not been redesigned to mitigate the risk of scratching. While scratched container surfaces are a significant concern for the sensory quality of the product, they also severely limit the ability to inspect the containers for particulates. Such inspection is typically a regulatory requirement for good manufacturing practice.

[0045] Handling vials in nests can be an effective solution to prevent vial abrasion that typically occurs during singulated handling of vials or during simultaneous handling of rows of vials. Handling vials in nests avoids collisions between all vials and tools, as well as between vials themselves. Nests are particularly well suited for handling polymeric vials, but can be used equally well for handling glass vials.

[0046] Nests for syringes have been commercially available for decades, but are a relatively new concept for managing medication containers beyond syringes. Suitable container nests, such as the 70, are available from Nuova Ompi of Newtown, PA, and Afton Scientific of Charlottesville, VA.

[0047] The container 90, tub 80, and container nest 70 are shown in more detail in FIG. 2 , which depicts the completed packaging of the container 90 from bottom to top. The container nest 70 and container tray or tub 80 may be, for example, but not limited to, the polystyrene EZ-FILL™ variety offered by Nuova Ompi of Newtown, PA. They are provided with a sealing Tyvek™ cover 82 that is permeable to ethylene oxide for sterilization purposes. The cover 82 may consist of a permeable Tyvek™ sheet 84 and a permeable Tyvek™ lid 86 that covers the Tyvek™ sheet 84. The combination of the tub 80 sealed with the cover 82 and the nest 70 containing the container 90 is referred to herein as the “sealed and nested container material” 88. The sealed and nested container material 88 may be supplied packaged in a Steribag 92. This entire combination, as shown in FIG. 2, is referred to herein as a "sealed and nested container package" 94.

[0048] Closures 120 for containers 90 may be supplied in a manner similar to container 90, as shown in FIG. 3. The closures may include caps 130 with integrated stoppers 140, as described in more detail below in FIGS. 6 and 7. The closures 120 are supplied in closure tubs 110 with ethylene oxide-permeable, sealing Tyvek™ covers 112 arranged within closure nests 100 for sterilization purposes. The covers 112 may comprise a Tyvek™ sheet 114 and a Tyvek™ lid 116 that is permeable and covers the Tyvek™ sheet 114. The combination of the tubs 110 sealed with the covers 112 and the closure nests 100 containing the closures 120 is referred to herein as the "sealed and nested closure material" 118. The sealed and nested closure material 118 may be supplied packaged in a Steribag 122. This entire combination, as shown in FIG. 3, is referred to herein as a "sealed and nested closure package" 124. The sealed and nested container material 88 and the sealed and nested closure material 118 are collectively referred to herein as the "sealed and nested material."

[0049] The tabs 80, 110 can be handled within the controlled environment enclosure 20 by an articulated arm device 22 disposed within the controlled environment enclosure 20. The articulated arm device 22 includes an end of an arm tool 24 configured to hold the tabs and nests. The articulated arm device 22 can be, but is not limited to, a robotic articulated arm. Suitable robotic articulated arms are described in U.S. Patent Application Publication No. 2009 / 0223592 and WIPO Publication No. WO 2013 / 016248, both of which are incorporated by reference herein in their entirety.

[0050] In contrast to prior art conveyor belt systems, the sealed and nested closure packages 92, 122, tabs 80, 110, and nests 70, 100 are grasped and held by the end of the arm tooling 24, which may be capable of gripping or holding. Furthermore, as described in co-pending U.S. Patent Application Publication No. 2009 / 0223592, entitled "Robotic Filling Systems and Methods," the articulated arm apparatus 22 allows the environmental enclosure 20 to be cleaned to a much greater extent than conveyor belt systems. The articulated arm apparatus 22 is fully automated, which allows for a greater degree of automation of the entire container filling process within the controlled environment enclosure 20 than would otherwise be achievable under such decontaminated or sterile conditions within the controlled environment enclosure 20. The use of the articulated arm apparatus 22 eliminates some of the difficulties described in the background of this specification. Specifically, because all handling operations can be performed using the nests 70, 100 or tabs 80, 110, the articulated arm device 22 can hold the associated nest in a single actuation, and not the container 90 or closure 120 itself, until processing is complete.

[0051] Regarding the method, the sealed and nested container package 94 or the sealed and nested closure package 124 can be opened outside of the filling system 10. The covers 82, 112 can be highly permeable to the atmosphere, so that removing the sealing tabs 80, 110 from their packaging 88, 118 can expose not only the sealing tabs 80, 110 but also their contents to the ambient atmosphere.

[0052] With the interior door 26 between the transfer chamber 30 and the controlled environment enclosure 20 closed, the exterior door 32 of the transfer chamber 30 can be opened so that the sealing tabs 80, 110 containing the containers 90 or nests 70, 100 with closures 120 can be transferred through the exterior door 32 of the transfer chamber 30 to the shelf 34 of the transfer chamber 30. The shelf 34 can be, but is not limited to, a rotating shelf.

[0053] In a next step, the sealing tabs 80, 110 may be decontaminated inside the transfer chamber 30. Suitable decontamination methods include, but are not limited to, exposure to hydrogen peroxide gas or ozone. Other suitable means of decontamination may include, but are not limited to, electron beam irradiation and ultraviolet radiation. The transfer chamber 30 may be any isolatable and decontaminable vessel, including, but not limited to, an autoclave or a radiation-based decontaminable vessel configured to be placed in spatial communication with the controlled environment enclosure 20. As used herein, the term "transfer chamber" may be used to describe any such vessel that is decontaminated and that may be placed in spatial communication with the controlled environment enclosure 20. Further examples of vessels suitable for use as the transfer chamber 30 are provided below.

[0054] In some cases, it may be advantageous to decontaminate the transfer chamber 30 along with the controlled environment enclosure 20. When decontaminated simultaneously, the seal on the interior door 26 will be decontaminated. In some other cases, the seal area of ​​the door 26 can be ignored.

[0055] The cover 82, 112 can be highly permeable to gases and decontaminating agents. Some materials can be susceptible to significant sorption of decontaminating agents during transfer chamber decontamination. Exposure of the pre-sterilized material of the tub 80, 110 to the decontaminating agent can be prevented by using an impermeable cover in place of the cover 82, 112 or by adding an impermeable layer on top of the cover 82, 112. Suitable methods for adding such an impermeable layer include, but are not limited to, adhesive film and heat sealing.

[0056] In another aspect of the invention, the transfer chamber 30 can be a vacuum chamber and configured to sterilize the contents of the tubs 80, 110. Thermal sterilization cycles and fast non-thermal sterilization cycles are well known in the art. The fast cycle times of non-thermal sterilization cycles can be particularly advantageous. Such cycles are typically used in hospital settings, for example, for sterilization of surgical instruments. The gaseous sterilant can be hydrogen peroxide, ozone, and combinations thereof.

[0057] The transfer chamber 30 may be equipped with a plasma generator for rapid application and removal of the sterilant. The addition of a non-thermal sterilization transfer chamber 30 to the controlled environment enclosure 20 is particularly well suited for processing nested drug container materials.

[0058] Once the tabs 80, 110 have been decontaminated, the interior door 26 can be opened to place the interior of the transfer chamber 30 in communication with the interior of the controlled environment enclosure 20, and the articulating arm apparatus 22 can be used to transfer the sealed and nested material 88, 118 from the transfer chamber 30 through the interior door 26 and into the controlled environment enclosure 20. The gripping of the tabs 80, 110 by the articulating arm apparatus 22 is referred to herein as "aseptic gripping" because the articulating arm apparatus 22 is of a decontaminated or sterile construction and grips the tabs 80, 110 in a decontaminated environment. In contrast, other methods of transfer may not involve gripping or may not be sterile, requiring the controlled environment enclosure 20 to be sterilized or decontaminated after transfer.

[0059] The articulating arm device 22 can be used to remove one or both of the lids 86, 116 and sheets 84, 114 within the controlled environment enclosure 20. A suitable method for using the articulating arm device 22 to remove the lids 86, 116 is described in co-pending International Patent Application PCT / US13 / 39455, published as WO 2013 / 166379 on July 11, 2013, which is incorporated herein in its entirety. The sheets 84, 114 may alternatively be removed using suitable suction. The articulating arm device 22 can then remove the container 90 or nest 70, 100 with closure 120 from the tub 80, 110.

[0060] The controlled environment enclosure 20 includes a filling station 60. In one embodiment shown in Figure 1, the filling station 60 includes a filling needle system 62 to which a liquid product is delivered from a fluid reservoir 50 via a flow path 64 under the action of a suitable pump 52. The pump 52 may be, but is not limited to, a peristaltic pump. The liquid product may be filtered via a suitable filter 54. The fluid may enter the controlled environment enclosure 20 along the flow path 64 via a suitable flow path coupler 56.

[0061] In one embodiment of the method shown in FIG. 1 , the articulated arm device 22 moves the opening of each container 90 sequentially under the fill needle system 62. The fill needle system 62 may include a single fill needle or may include multiple fill needles. If the fill needle system 62 includes a single fill needle, the containers 90 are filled sequentially by moving the container nest 70 and operating the fill needle system 62 to fill the containers 90. If the fill needle system 62 includes multiple fill needles, the containers 90 are filled multiple times, sequentially by moving the container nest 70 and operating the fill needle system to fill the containers 90. The end of the arm tool 24 can be rotated to align the containers 90 with the fill needles of the fill needle system 62.

[0062] 4, the container nest 70 with the containers 90 is located in a fixed position on the platform 28, and the filling needle system 62 is spatially manipulated by a suitable second articulated arm device 22' to position the filling needle system 62 over the opening of the container 90. The container 90 is then filled by moving and manipulating the filling needle system. The second articulated arm device may be of the same type as the articulated arm device 22. The second articulated arm device may have an end of an arm tool 24' configured to manipulate the filling needle system 62. Having a second articulated arm device dedicated to filling frees the articulated arm device 22 to handle the second tubs (of the tub 80, 110 configuration) and nests 70, 100 while the containers 90 from the first tub 80, 110 are being filled.

[0063] Filling system 10 includes a bung mounting apparatus 40 that may have an interior that may be isolated from the interior of controlled environment enclosure 20. The interior of controlled environment enclosure 20 communicates with the interior of bung mounting apparatus 40 via a bung mounting system door 42. In the embodiment depicted in FIG. 1 , bung mounting apparatus 40 is shown as being housed within controlled environment enclosure 20. In other embodiments, bung mounting apparatus 40 may be located in a room separate from controlled environment enclosure 20 and may communicate with controlled environment enclosure 20 via an appropriate bung mounting system door.

[0064] A container nest shelf 46 and a closure nest shelf 48 are positioned within the interior of the stopper application device 40. The container nest shelf 46 and the closure nest shelf 48 are positioned to center the closures 120 in the closure nest 100 over the openings of the containers 90 in the container nest 70 when the closure nest 100 and the container nest 70 are placed on the closure nest shelf 48 and the container nest shelf 46, respectively.

[0065] In one embodiment of the method shown in FIG. 1 , the bung attachment system door 42 is opened and the articulating arm device 22 moves the container nest 70 with filled containers 90 for placement on the container nest shelf 46. The articulating arm device 22 may also be used to move the closure nest 100 with closures 120 for placement on the closure nest shelf 48, so that each filled container 90 has a closure positioned concentrically immediately above it. The closure nest 100 with closures 120 may be placed on the closure nest shelf 48 either before or after the container nest 70 with filled containers 90 is placed on the container nest shelf 46. To this end, the container nest 70 and the closure nest 100 may have matching shapes to position each closure 120 concentrically with the opening of each corresponding container 90.

[0066] After the container nest 70 with containers 90 and the closure nest 100 with closures 120 are positioned on their respective shelves 46 and 48 within the stopper installation apparatus 40, the stopper installation system door 42 is closed. To the extent that some stopper installation procedures need to be performed under vacuum conditions or an inert atmosphere, the necessary vacuum or inert atmosphere can then be established within the interior of the stopper installation apparatus 40.

[0067] The bung attachment device 40 is configured to close all of the containers simultaneously, such as using an actuating driver 44. For some subsequent operations, such as freeze-drying, the bungs need only be partially inserted, and the actuating driver 44 may be configured to only partially insert the bungs 140. After insertion of the bungs 140, the articulating arm device 22 removes the nest 70 with the containers 90 from the bung attachment device 40.

[0068] In another embodiment of the articulating arm device 22, the articulating arm device 22 loads nested containers 90 and nested caps 130 with integrated stoppers 140 into the stopper application device 40. As previously described, the device 40 can simultaneously stopper and cap nests 70 of containers 90.

[0069] After the stoppering and capping are completed, the articulated arm device 22 moves the nested containers 90 back to the transfer chamber 30. In other embodiments, the articulated arm device 22 can move the nest 70 with the filled, stoppered, and capped containers 90 through a suitable access door (not shown) to an adjacent controlled environment enclosure (not shown). The nest 70 with the capped containers 90 may also be moved to the adjacent controlled environment enclosure with only a partially stoppered or partially closed container.

[0070] 5A and 5B show the general shape of a drug container 90, which in this example is a vial. The container comprises a cylindrical container body 96 and a neck 97. The neck 97 of the container 90 is shown in an enlarged view in FIG. 5B, where region 502 of FIG. 5A is presented in more detail. Diameters d1, d2, d3, and d4 of different portions of the container 90 are provided in FIGS. 5A and 5B, as are heights h1, h2, and h3 of different portions of the container 90. Symbols s1 and s2 provide the wall thickness and bottom thickness, respectively, of the cylindrical container body 96. Typically, the diameter 98 of the d2 neck of the container 90 is slightly smaller than the diameter 99 of the d1 main portion of the container 90. This allows for placement of a closure 120 on the container 90 without reducing the packing density of the containers 90 in the nest 70 of FIG. 2. Therefore, the packing density of the closures 120 in their tightest circle is exactly the same as the packaging of the containers. It is particularly advantageous that the closure nest 100 has exactly the same packaging shape as the container nest, so that the closure nest 100 can be stacked on the container nest 70 and the closures 120 can be applied without moving the container nest 70. The closures 120 may be applied one at a time, multiple in a row, or all at once.

[0071] In another aspect, the present disclosure provides a nest for retaining a closure. Consider a first general closure 120, provided in FIG. 6A . The closure 120 includes a cap 130 and a bung 140. The bung 140 has a thinner septum 142 that is pierceable by a withdrawal needle, such as a syringe withdrawal needle. The cap 130 includes a cylindrical cap body 132, at least a first set of barb retention features 134, and a tamper-evident flip-off cover 136. In the example of FIG. 6A , two sets of barb retention features 134 are shown, which may be arranged in a pattern around the inner circumference of the cap 130. The tamper-evident flip-off cover 136 is manufactured as an integral part of the cap 130 so that it cannot be replaced when the cover 136 is removed. This serves as evidence that the septum 142 of the bung 140 has been exposed. In this specific example, the cover 136 has a larger diameter than the body 132 of the cap 130. The cover 136 can serve as a retention feature 138 for the cap 130 and, in turn, as a retention feature 138 for the closure 120, which can be utilized to retain the closure 120 in the nest 100.

[0072] FIG. 6B illustrates another example closure 120'. The closure 120' includes a cap 130' and a stopper 140'. The stopper 140' has a thinner septum 142' that is pierceable by a withdrawal needle, such as a syringe withdrawal needle. The cap 130' includes a cylindrical cap body 132', at least a first set of barb retention features 134', and a tamper-evident flip-off cover 136'. In the example of FIG. 6B, two sets of barb retention features 134' are shown, which may be arranged in a pattern around the inner circumference of the cap 130'. The tamper-evident flip-off cover 136' is manufactured as an integral part of the cap 130' so that it cannot be replaced when the cover 136' is removed. This serves as evidence that the septum 142' of the stopper 140' has been exposed. The cover 136' has the same diameter as the body 132' of the cap 130' in this particular example. However, a recess 138' is provided at the junction between the cover 136' and the cap body 132'. The cover 136' can serve as a retention feature 138' for the cap 130', and in turn as a retention feature 138' for the closure 120', which can be utilized to retain the closure 120' in the nest 100. Considering FIGS. 6A and 6B, it can be seen that the retention feature extends radially outward from the radial periphery of the cap 130' at the top of the cap 130, similar to the retention feature 138 in FIG. 6A. In other embodiments, the retention feature can extend radially inward from the radial periphery of the cap 130' at the bottom of the cap 130', as shown in FIG. 6B. The retention feature can be the bottom of the cap 130'.

[0073] In the prior art, these vial caps are made of aluminum with a polymer flip-off cover. Capping with an aluminum cap typically generates a significant amount of invisible particles, which has made aluminum caps unacceptable in recent years. Currently, caps made of polymer materials are commercially available. Polymer caps are particularly well suited for use with polymer containers, but can also be used with glass containers.

[0074] The optimal shapes of the containers 90 in the nest 70 typically follow the mathematical theory of packing of equal sized circles, resulting in hexagons, triangles, squares, elongated triangles, twisted squares, and other related geometric patterns of container locations in the nest 70.

[0075] Presented herein is a closure nest 100 in which the geometric arrangement of closures 120, 120' closely matches the geometric pattern of container locations in nest 70. In some embodiments, closure nest 100 has the exact same packaging shape as container nest 70, and the distribution of closure centers in closure nest 100 lines up within processing tolerances with the distribution of container centers in container nest 70. This allows closure nest 100 to be stacked on container nest 70 and closures 120, 120' to be applied to containers 90 such that every closure 120, 120' in closure nest 100 can be applied to every corresponding container 90 in container nest 70 without substantial movement of either nest 70 or nest 100. The closures 120, 120' may be applied one at a time, a row at a time, or all substantially simultaneously.

[0076] FIG. 7A shows a schematic representation of a portion of a closure nest 100, depicting a closure retention structure 103 for a single cap 130 of the closure 120 of FIG. 6A positioned on a planar support structure 109. In FIG. 7A, the associated bung 140 is housed within the cap 130 and is therefore not visible (see FIG. 6A). It is understood that the portion of the closure nest 100 shown in FIG. 7A represents a plurality of such components, arranged two-dimensionally to concentrically align the plurality of containers 90 in the container nest 70 with the matching plurality of closures 120 held by the closure nest 100. The closure retention structure 103 includes a plurality of closure engagement structures 105 arranged in an annular configuration around the cylindrical axis 111 of the corresponding closure 120. Each closure engagement structure 105 includes a spring-loaded arm 102 that includes a suspended ledge 101 (triangular in the embodiment shown in FIG. 7A). Each of the plurality of closure engagement structures 105 is positioned to engage a retention feature 138 on the cover 136 of the cap 130 using the suspension shelf 101, thereby suspending the cap 130 by the retention feature 138 and allowing the cap 130 to be positioned substantially frictionlessly within the closure nest 100. No friction is required to retain the suspended cap 130, whereby the cap 130 hangs from the closure nest 100 as it is positioned and suspended within the closure retention structure 103. By appropriate selection of the dimensions of the cap 130 and the closure engagement structure 105, the cap 130 can be suspended by its retention feature 138 completely independent of friction, allowing the cap 130 to be held substantially frictionlessly within the closure nest 100. The term "friction-free suspension" is used herein to describe the suspension of the closure 120 by the closure retention structure 103 without the need for friction anywhere between the cap 130 of the closure 120 and any part of the closure retention structure 103. Each closure engagement structure 105 further comprises a stopper structure 104 against which the cap 130 can press when the cap 130 and the closure nest 100 are pressed together in a vertical direction.The cap 130' of FIG. 6B may be similarly retained by its particular retention feature 138'.

[0077] FIG. 7B shows a schematic representation of a portion of another closure nest 100′ depicting a closure retention structure 103′ for a single cap 130 of the closure 120 of FIG. 6A positioned on a planar support structure 109′. In FIG. 7B, the associated bung 140 is housed within the cap 130 and is therefore not visible (see FIG. 6A). It is understood that the portion of the closure nest 100′ shown in FIG. 7B represents a plurality of such components, arranged two-dimensionally to concentrically align the plurality of containers 90 in the container nest 70 with the matching plurality of closures 120 held by the closure nest 100′. The closure retention structure 103′ includes a plurality of closure engagement structures 105′ arranged annularly about the cylindrical axis 111′ of the corresponding closure 120. Each closure engagement structure 105' includes a spring-loaded arm 102' that includes a suspension ledge 101' (triangular in the embodiment shown in FIG. 7B). Each of the plurality of closure engagement structures 105' is arranged to engage the bottom of a cap 130 using the suspension ledge 101', thereby suspending the cap 130 by its bottom and allowing the cap 130 to be positioned within the closure nest 100' substantially without friction. In this arrangement, the bottom of the cap 130 serves as a general retention feature. No friction is required to retain the suspended cap 130, whereby the cap 130 hangs from the closure nest 100' as it is positioned and suspended within the closure retention structure 103'. By appropriate selection of the dimensions of the cap 130 and the closure engagement structure 105', the cap 130 can be suspended completely independently of friction, allowing the cap 130 to be held within the closure nest 100' substantially without friction. As in FIG. 7A, the term "friction-free suspension" is used herein to refer to suspension of the closure 120 by the closure retention structure 103' without the need for friction anywhere between the cap 130 of the closure 120 and any part of the closure retention structure 103'.Each closure engagement structure 105' further comprises a plug structure 104' against which the cap 130 can bear when the cap 130 and closure nest 100' are pressed together in a vertical direction.

[0078] The closure engagement structure 105 comprising the spring-loaded arm 102 may be implemented in different ways. One non-limiting example of the spring-loaded arm 102 is a resiliently flexible arm. The spring-loaded arm may be a separate structure from the closure nest 100 that is fastened to the closure nest 100. In other embodiments, the spring-loaded arm 102 may be an integral part of the closure nest 100 and manufactured to be integrally integrated with the closure nest 100. One non-limiting method of manufacturing the spring-loaded arm 102 as an integrally integrated part of the closure nest 100 is by injection molding of a suitable polymer.

[0079] The closure engagement structures 105, 105' hold the caps 130, 130' (see FIG. 6B) in place during handling and shipping, allowing the caps 130, 130' to flex open when pushed or pulled out of the closure nest 100, 100' without risk of removing the tamper-evident covers 136, 136'. The direction of the associated capping force can be upward, downward, or both. Areas of the closure nest 100, 100' can be reinforced with structural features, such as honeycomb, to distribute the capping force and prevent flexing during handling.

[0080] Integration of the container 90 and closure 120, 120' is achieved by deforming the elastomeric plug 140, 140' against the container 90 and permanently holding it in compression by the cap 130, 130'. Radial compression of the plug 140, 140' by an interference fit inside the neck of the container 90, as indicated by diameter d4 in FIG. 5B, can also create a seal, but that seal is generally considered only a secondary seal. In fact, some plug designs for the cap 130, 130' may not involve any form of plug surrounding the septum 142, 142'.

[0081] Creating the primary seal is vertical compression of the flange portion of the plug 140, 140' against the top of the container 90 in the region of the container 90 indicated by diameters d4 and d2 in FIG. 5B. Typically, a large residual sealing force is required to ensure a robust container seal, providing a wide safety margin for changes in the plug 140, 140', such as compression set. The compression force required for final sealing must be transmitted through the top surface of the cap 130, 130'. Therefore, an annular shape may be one non-limiting embodiment used for the plug structure 104, 104' to apply a compression force to the cap 130, 130' just above the primary seal. Furthermore, the annular shape for the plug structure 104, 104' allows for removal of the capped container from the closure nest 100 by insertion of a push rod (not shown) through the opening 107, 107' in the planar support structure 109, 109' of the closure nest 100, 100'.

[0082] As previously discussed, the radial dimensions of the containers 90 and their corresponding caps 130 should ideally be equal or nearly equal to optimize the planar density of the containers in the container nest 70 and the planar density of the corresponding closures in the closure nest 100 of FIG. 7A. This places a constraint on the diameter of the openings 107, relative to the radial separation of the suspended shelves 101. This planar density constraint forces the retention features 138 to be narrow in radial extent. The inner diameter c of the annular arrangement of the suspended shelves 101 is close to, but slightly smaller than, the diameter of the cover 136. Despite these limitations on the dimensions of the various components of the cap 130, a sufficiently strong plug structure 104 of limited radial diameter is required to exert a closing force on the cap 130, as previously discussed. These substantial plug structures 104 must also be received in the closure nest 100 and positioned annularly around the underside of the opening 107 so as to engage the upper surface of the cap 130. As a result, the opening 107 in the planar support structure 109 will have a maximum dimension r that is less than the inner diameter c of the annular arrangement of the suspended shelf 101. On the same basis, the opening 107' in the planar support structure 109' of FIG. 7B will have a maximum dimension r' that is less than the inner diameter c' of the annular arrangement of the suspended shelf 101'.

[0083] Different shapes may be used for the stopper structure 104, 104' depending on the specific design of the cap. The stopper structure 104, 104' also determines the length of the spring-loaded arms 102, 102', and thus its spring retention and opening forces. The spring-loaded arms 102, 102' may be substantially linear and perpendicular to the closure nest 100, 100'. In yet another example, the height of the stopper structure 104, 104' and spring-loaded arms 102, 102' may be reduced by radially rolling. If steam sterilization of the cap 130, 130' is required in the closure nest 100, 100', the contact area between the stopper structure 104, 104' and the cap 130, 130' may be reduced to a series of contact points to allow for better steam distribution.

[0084] The spring-loaded arms 102, 102' can be sized and shaped so that when the caps 130, 130' are secured to the container 90, the spring-loaded arms 102, 102' are automatically pushed out by the container 90, thereby releasing the caps 130, 130'. The close packing of the closure retention structures 103 in the closure nest 100, 100' means that there is limited space for lateral movement of the spring-loaded arms 102, 102'. For example, in a hexagonal close-packed arrangement, each closure retention structure 103 is surrounded by its six nearest neighbors, each of which requires space for its spring-loaded arms 102, 102' to open in order to release the corresponding cap 130, 130'. Each spring-loaded arm 102, 102' is sized and positioned to simultaneously apply the caps 130, 130' on the adjacent closure retention structure 103 to the corresponding containers 90 positioned in the container nest 70.

[0085] In one embodiment, the caps 130, 130' are each retained by at least three annularly arranged spring-loaded arms 102, 102' to geometrically restrain each cap in its position. Generally, each closure retention structure in the closure nest 100, 100' has a plurality of annularly arranged spring-loaded arms 102, 102'. Each closure retention structure 103, 103' can include at least three closure engagement structures 105, 105' arranged annularly about a cylindrical axis 111, 111', each closure engagement structure 105, 105' including a suspended shelf 101, 101' extending toward the cylindrical axis 111, 111'. At least one of the at least three closure engagement structures 105, 105' can include a spring-loaded arm 102, 102' extending substantially perpendicularly from a planar support structure 109, 109'. Conceptually, there can be a single annular spring-loaded arm 102, 102' for each one closure retention structure 103 that is positioned to grip around the entire circumference, or alternatively, around a majority of the circumference, of the cap 130, 130'. Thus, the most common embodiment of the closure nest 100, 100' has at least one spring-loaded arm 102, 102' for each closure retention structure 103.

[0086] In operation, a plurality of closures 120, 120' are releasably retained in the closure nest 100, 100' through frictionless suspension by the closure engagement structures 105, 105' engaging the retention features 138 of the closures 120, 120', the bottoms of the closures being a type of retention feature. To engage the closures 120, 120' in this manner, the closures 120, 120' can be pushed into the closure retention structures 103, 103' while the actuating spring-loaded arms 102, 102' are resiliently displaced by the caps 130, 130' of the closures 120, 120' until the suspended shelves 101, 101' move into position in the retention features 138, 138'. The closures are then fed into the filling process in this configuration.

[0087] While the closure engagement structures provide an initial frictional resistance through lateral forces when the closures 120, 120' are pressed into the closure retention structures 103 as part of the installation process of the closure nests 100, 100' with closures 120, 120', the subsequent retention of the closures 120, 120' is independent of any lateral friction-inducing forces perpendicular to the axial movement of the closures 120, 120' to the nested state. The suspension shelves 101, 101' of the spring-loaded arms 102, 102' act as a barrier to downward movement of the closures 120, 120', causing the closures 120, 120', now with the containers 90 engaged, to suspend in the closure engagement structures 105, 105'.

[0088] Figure 8 illustrates an arrangement for closing a single container 90, which is one of a plurality of containers held in the container nest 70 of Figures 1, 2, and 4. For closure, a closure 120, which is one of a corresponding plurality of closures 120 releasably held by the closure nest 100, is concentrically aligned with the container 90 by virtue of the shapes of the nests 70 and 100, which correspond center-to-center in two dimensions. The closure holding structure is that of Figure 7A, and the closure details are that of Figure 6A, with a limited number of elements of the closure 120 labeled for clarity. When elements are not labeled, the numbers from Figure 6A are included.

[0089] During closure of the container 90 with the closure 120, the container 90 and closure 120 are forced together vertically. This may occur only to the extent that the top of the container 90 engages the barbed retention feature 134 (see FIG. 6A ). This constitutes a partial closure. Application of additional force forces the plug 140 deeper into the container 90 via the plug structure 104 to seal the container 90. In a final step, the container 90, now properly capped and closed with the closure 120, can be disengaged from the closure retention structure 103 of the closure nest 100 by, in one embodiment, using a rod 106 attached to a platen 108 to press downward on the cover 136 of the cap 130 on the closure 120. The platen 108 can extend over the entire surface of the closure nest 100 or over a portion of its surface. There may be as many rods 106 as there are closures retained by the closure nest 100, or there may be fewer rods 106. This actuation force opens the spring-loaded arms 102, 102', releasing the capped container 90 from the closure retention structures of the closure nest 100. This process or method may be performed simultaneously on multiple closure retention structures of the closure nest 100. All closures in all closure retention structures of the closure nest 100 may undergo this procedure simultaneously.

[0090] In its most general description, the present disclosure provides a closure nest 100, 100' for releasably retaining a plurality of closures 120, 120' for a drug container, the closure nest 100, 100' including a plurality of closure retention structures 103, each including at least one closure engagement structure 105, 105'. The at least one closure engagement structure includes a spring-loaded arm 102, 102' and a plug structure 104, 104'. The spring-loaded arm 102, 102' is configured to engage a retention feature 138 on one of the plurality of closures 120, 120', and the plug structure 104, 104' is configured to trap one of the plurality of closures 120, 120' and exert a force on the one of the plurality of closures when the closures and the closure nest are pressed together in a vertical direction. The closure engaging structures can be arranged in a geometric pattern, which can be a closely spaced pattern, and can be center-to-center aligned with a corresponding pattern of container retaining structures on the container nest. The spring-loaded arms 102, 102' can be flexible and fabricated from a polymer. The spring-loaded arms 102, 102' can be integrally integrated with the closure nest 100, 100'.

[0091] In connection with the closure nest 100, 100′, a method for retaining multiple closures 120, 120′ includes releasably suspending each closure 120, 120′ by a retention feature 138 on the closure 120, 120′, which may be a specifically designed retention feature 138 or the bottom of the closure, as in FIG. 7B . The releasable suspension may be a frictionless suspension. The releasable suspension may be a spring-loaded retention achieved by flexibly or spring-like deformation of the spring-loaded arms 102, 102′. The term “spring-loaded” is used herein to describe any form of spring loading, whether by a mechanical spring or flexible member, or by any other means that creates a suitable spring or elastic actuation.

[0092] wherein a method for aseptically sealing a pharmaceutical product into a plurality of containers includes the steps of introducing a first plurality of containers into a controlled environment enclosure, releasably suspending a plurality of sterile closures from a closure nest in the controlled environment, filling at least a first portion of the first plurality of containers with the pharmaceutical product, and simultaneously sealing at least partially a second portion of the first plurality of containers with a portion of the plurality of sterile closures while releasably retaining the sterile closures in the closure nest. The method may further include lyophilizing the pharmaceutical product in the second portion of the first plurality of containers while releasably retaining the sterile closures in the closure nest.

[0093] The releasable suspension may be a friction-free suspension.

[0094] The releasably suspending and releasably retaining may include releasably engaging a retention feature of each of the plurality of sterile closures. The releasably engaging with the retention feature may include resiliently engaging the retention feature. The resiliently engaging with the retention feature may include engaging the retention feature with a spring-loaded arm portion of the closure nest.

[0095] Some or all of the plurality of sterile closures held by the closure nest can be used to either fully or partially seal a pharmaceutical product into a container. The number of containers can be equal to the number of sterile closures releasably suspended by the closure nest. Two or more containers can be filled simultaneously.

[0096] In terms of convenience, the closure nest 100, 100', along with its spring-loaded arms 102, 102' and stopper structures 104, 104' described herein, allows itself to simultaneously cap and simultaneously stopper multiple containers 90, both partially and completely. More specifically, the closure nest 100, 100' allows itself to simultaneously cap rows of containers 90, both partially and completely. Even more specifically, the closure nest 100, 100' allows itself to simultaneously cap complete two-dimensional arrays of containers 90 in the container nest 70, both partially and completely. There is no direct contact between the closure nest 100, 100' and any components that come into contact with the pharmaceutical product. All handling of the closures 120, 120' by the articulating arm device 22 uses the closure nest 100, 100'. All contact with the closure nests 100, 100' within the sterile environment of the controlled environment enclosure 20 is with devices and surfaces that can be sterilized. As is apparent from Figures 6A, 6B, 7A, 7B, and 8, all portions of each of the plurality of closure retention structures 103, 103' are positioned to remain free of contact with the bungs 140, 140' of the corresponding closures 120, 120' when the corresponding closures 120, 120' are engaged by the at least one closure engagement structure 105, 105'.

[0097] 1 and 4, it can be seen that the actuation driver 44' in the embodiment is shown as being positioned above the closure nest 100. In other embodiments described below with reference to FIGS. 9-15, the actuation driver 44' can instead be positioned below the container 90 and configured to move upward (as provided by the arrow in those figures) when actuated to plug the container 90 into the closure 120. The closure nest 100, and thus the closure 120, are prevented by the fixed upper plate 47 from moving upward beyond a fixed height due to the upward force exerted by the container 90 in the closure 120 due to actuation of the driver 44'. The direction of movement of the driver 44' and the direction of the force exerted by the driver 44' during the plug installation operation are provided by the arrows in FIGS. 9-15.

[0098] It is worth repeating here that for some drugs, closure 120 may be engaged with the container during the stopper installation process without fully pushing stopper 140 (see FIGS. 6A, 6B, and 8) into container 90. Such partial closure is used for subsequent lyophilization. Final, complete closure may be performed after lyophilization.

[0099] One of the difficulties during the process of closing multiple containers 90 held in nest 70 with corresponding center-to-center aligned closures 120 held in closure nest 100 is that any set of containers may not have exactly the same height dimensions, as shown in FIGS. 9-15 . ISO standards, namely, ISO 8362-1, "Injection containers and accessories -- Part 1: Injection vials made of glass tubing," exist to limit the amount of variation allowed. However, with the closures 120 and containers 90 under pressure from both the top and bottom during closure, longitudinal pressure along the closure direction can potentially be unevenly distributed even among containers conforming to ISO 8362-1, resulting in uneven fit of the closures 120 with the containers 90 and even the possibility of breakage. For some taller containers 90, compression / stoppering may begin before the closures 120 begin this flow into the lower ones of the containers 90. As the closure 120 fully closes on the taller containers 90, the force of the driver 44' can increase rapidly, and the stopper applicator 40 can reach its torque limit before all of the containers 90 in the container nest 70 have been successfully closed. This problem is particularly significant for containers 90 such as 2R (2 ml, Φ16.0 mm x 35 mm x 1.00 mm) crimp-neck injection vials manufactured from clear, tubular borosilicate glass of Class 1 hydrolytic resistance in accordance with ISO 8362. The ISO 8362-1 specification allows for height dimensions to vary between 34.5 mm and 35.5 mm, and even a variation from 34.55 mm to 35.35 mm can create problems of the nature described above.

[0100] With the ever-increasing cost of specifically engineered drugs, the loss of a single batch of nested drug samples can result in catastrophic downtime problems and consequent severe cost implications. To address this problem, several embodiments of solutions are described with reference to Figures 9-15.

[0101] All of these solutions have in common a resilient, compliant element between at least one of the nested containers 90 and its corresponding aligned closures 120, on the one hand, and either the actuating driver 44' or the fixed upper plate 47, on the other. In this way, there is always a resilient, compliant element in the series between the actuating driver 44' and the fixed upper plate 47. The resilient, compliant element is positioned and configured to absorb excess pressure in a container 90 with a height dimension greater than the container 90 with the smallest vertical dimension. Each of Figures 9-17 shows a different arrangement of the resilient, compliant member.

[0102] 9 shows an embodiment of the plug attachment device 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 aligned center-to-center in a closure nest 100 by means of an actuation driver 44' and an opposing fixed upper plate 47. The plug structure 104 (see FIGS. 7A and 7B) of the closure nest 100 can be a resilient, compliant element in the system. In this embodiment, the closures 120, which are pushed upward by the actuation of the actuation driver 44', are pressed against the compliant plug structure 104. The resilient compliance of the compliant plug structure 104 is sufficient to compensate for the difference between the container 90 with the largest height dimension and the other containers 90 with the smallest height dimension in the same nest 70.

[0103] FIG. 10 illustrates an embodiment of the bung applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 aligned center-to-center in a closure nest 100 by means of an actuating driver 44' and an opposing fixed upper plate 47. The resiliently compliant element in this embodiment is the top surface of the closure cap 130 (see FIGS. 6A and 6B) itself for each closure 120 and corresponding container 90. Specifically, the resiliently compliant element may be a tamper-evident flip-off cover 136 (see FIGS. 6A and 6B) for some closures 120. The top surface of the closure 120 (which in some cases is the top surface of the cap 130 of the closure 120) may be made of an appropriately resiliently compliant material to undergo sufficient elastic deformation to equalize the pressure difference between the container 90 with the largest height dimension and the container 90 with the smallest height dimension in the same nest 70. The opposing fixed upper plate 47 may include a plurality of fixed, non-compliant pins 48, one for each closure 120 in the nest 100, that are aligned centrally with the closures 120 in the nest 100. In this embodiment, actuation of the actuation driver 44' causes the non-compliant pins 48 to pass through the closure nest openings 107 and engage the tops of the closures 120.

[0104] 11 illustrates an embodiment of the bung applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 aligned center-to-center in a closure nest 100 by means of an actuating driver 44' and an opposing fixed upper plate 47. The resiliently compliant element in this embodiment is one resiliently compliant pad 45 for each corresponding container 90, with the pad 45 positioned on a surface of the actuating driver 44' facing the containers 90, aligned center-to-center with the corresponding container 90, and configured to engage each container 90 under actuation of the actuating driver 44'.

[0105] 12 illustrates an embodiment of the bung applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 aligned center-to-center in a closure nest 100 using an actuating driver 44' and an opposing fixed upper plate 47. The resiliently compliant element in this embodiment is a single resiliently compliant pad 45' disposed on a surface of the driver 44' facing the containers 90, the resiliently compliant pad 45' configured to engage the plurality of containers 90 under actuation of the actuating driver 44'.

[0106] 13 shows an embodiment of the bung applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 aligned center-to-center in a closure nest 100 by means of an actuating driver 44' and an opposing fixed upper plate 47. The resiliently compliant element in this embodiment is a single resiliently compliant pad 45" disposed on the surface of the driver 44' facing the containers 90, the resiliently compliant pad 45" configured to engage with the plurality of containers 90 under actuation of the actuating driver 44'. In this embodiment, the resiliently compliant element can be a sheet 45" with an arrangement of tops of the resiliently compliant material on the surface facing the containers 90, the tops being capable of engaging the bottoms of the containers 90.

[0107] FIG. 14 shows that the embodiment of FIG. 13 can be used with a container held in a container cup nest 70′. The top of the sheet 45″ can engage the bottom of the container 90 through openings 72 in the bottom of the cups of the container cup nest 70′.

[0108] 15 shows an embodiment that is a variation on the embodiment of FIG. 13. In this embodiment, the resilient conformable element may be a pad 45" that is again positioned on the surface of the driver 44' facing the container 90, but the pad 45" is mounted with the top arrangement of conformable material facing the top surface of the working driver 44'. This makes the conformable pad 45" more easily cleanable while still providing sufficient conformance to compensate for differences in the height of the container 90.

[0109] 16 illustrates an embodiment of the stopper applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 that are center-to-center aligned in a closure nest 100 using an actuating driver 44' and a corresponding fixed upper plate 47. The resiliently compliant element in this embodiment is a resiliently compliant tip 49 disposed at the lower end of a pin 48 for each closure 120 and corresponding container 90, positioned to pass through an opening 107 and engage the upper surface of the closure 120. The pin 48 is disposed on the lower surface of the corresponding fixed upper plate 47 in the same manner as in the embodiment of FIG. 10. Under actuation of the actuating driver 44', the resiliently compliant tip 49 of the pin 48 engages the upper surface of the closure nest 120 and resiliently compresses to absorb any differences in vertical force acting on the plurality of containers 90 among the plurality of containers 90. In a variation on this embodiment, the resiliently compliant portion of the pin 48 is not located at the tip of the pin 48, but instead is located at another location along the length of the pin 48, such as, but not limited to, at the base of the pin 48 where the pin 48 is coupled to the opposing fixed upper plate 47.

[0110] FIG. 17 illustrates an embodiment of the stopper applicator 40 for closing a plurality of nested containers 90 in a container nest 70 with a plurality of nested closures 120 that are center-to-center aligned in a closure nest 100 using an actuating driver 44' and a corresponding fixed upper plate 47. The resiliently compliant element in this embodiment is a spring-loaded, retractable pin 48' that is positioned for each closure 120 and corresponding container 90, passing through an opening 107 and engaging the upper surface of the closure 120. The spring-loaded, retractable pin 48' is positioned on the lower surface of the corresponding fixed upper plate 47 in the same manner as in the embodiment of FIGS. 10 and 15. Under actuation of the actuating driver 44', the spring-loaded, retractable pin 48' engages the upper surface of the closure 120 and is resiliently compressed to absorb any differences in vertical force acting on the plurality of containers 90 among the plurality of containers 90. Under the action of the actuating driver 44', the lower section of any one of the spring-loaded telescoping pins 48' is pushed upward toward the upper section of the spring-loaded telescoping pin 48', causing the lower section to compress the spring inside the upper section, thereby creating a resilient compression of the entire spring-loaded telescoping pin 48'.

[0111] With the exception of the embodiment described with respect to FIG. 17, the material of the resiliently compliant members 45, 45′, 45″, 130 should be compatible with the internal environment of the stopper attachment device 40. Because the stopper attachment system door 42 can be opened during operation of the system 10, 10′, the interior of the stopper attachment device 40 is generally the same as the interior of the system 10, 10′, and the same conditions apply with respect to sterilization and maintaining aseptic conditions. This places limitations on the types of resiliently compliant materials that may be incorporated into the stopper attachment device 40. Suitable resiliently compliant materials include, but are not limited to, ethylene propylene diene monomer (EPDM), silicone, and Viton® fluoroelastomer. Materials for the non-compliant parts of the pin 48 include, but are not limited to, 316 stainless steel and polyether ether ketone (PEEK).

[0112] The various embodiments of the plug mounting device 40 described above may be combined such that each individual one of the plug mounting devices 40 may have one or more resiliently compliant members disposed between the actuating driver 44' and the opposing fixed upper plate 47.

[0113] The drawings and associated descriptions are provided to illustrate embodiments of the invention, not to limit the scope of the invention. References herein to "one embodiment" or "an embodiment" are intended to indicate that the particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase "in one embodiment" or "an embodiment" in various places herein are not necessarily all referring to the same embodiment. As used in this disclosure, unless the context otherwise requires, the term "comprising" and variations of that term, such as "comprising" and "comprised on," are not intended to exclude other additives, components, integers, or steps.

[0114] It is also noted that the embodiments are disclosed as processes that are depicted as flowcharts, flow diagrams, structure diagrams, or block diagrams. While a flowchart may disclose various steps of an operation as a sequential process, many of the operations can be performed in parallel or simultaneously. The steps shown are not intended to be limiting, nor are they intended to indicate that each depicted step is essential to the method, but rather are exemplary steps only. In the foregoing detailed description, the present invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and changes can be made therein without departing from the broader spirit and scope of the present invention. Accordingly, the specification and drawings are to be interpreted in an illustrative, and not a restrictive, sense. It is to be understood that the present invention should not be interpreted as limited by such embodiments.

[0115] It will be apparent from the foregoing that the present invention has several advantages, some of which are described herein and others of which are inherent in the embodiments of the invention described or claimed herein. It is also to be understood that changes can be made in the devices, apparatus, and methods described herein without departing from the teachings of the subject matter described herein. Consequently, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this application pertains, and the invention is not to be limited to the described embodiments except as required by the appended claims. [Explanation of symbols]

[0116] 10, 10' Filling system, 20 Controlled environment enclosure, 22 Articulated arm device, 22' Second articulated arm device, 24 Arm tool, 26 Inner door, 28 Table, 30 Transfer chamber, 32 Outer door, 34 Shelf, 40 Plug attachment device, 42 Plug attachment system door, 44, 44' Actuating driver, 45, 45', 45" Pad, sheet, 46 Container nest shelf, 47 Fixed upper plate, 48 Closure nest shelf, pin, 48' Spring-loaded telescoping pin, 49 Resilient, compliant tip, 50 Fluid reservoir, 52 Pump, 54 Filter, 56 Fluid connector, 60 Filling station, 62 Filling needle system, 64 Fluid line, 70 Container nest, 70' Container cup nest, 72 Opening, 80 Container tab, 82 Cover, 84 Sheet, 86 Lid, 88; Sealed and nested container material, packaging, 90; Pharmaceutical container, 92; Steribag, sealed and nested closure package, 94; Sealed and nested container package, 96; Container body, 97; Neck, 98; Neck diameter, 99; Main diameter, 100, 100'; Closure nest, 101, 101'; Hanging shelf, 102, 102'; Spring-loaded arm, 103, 103'; Closure retention structure, 104, 104'; Plug structure, 105, 105'; Closure engagement structure, 106; Rod, 107, 107'; Opening, 108; Platen, 109, 109'; Planar support structure, 110; Closure tab, 111, 111'; Cylindrical shaft, 112; Cover, 114; Sheet, 116; Lid, 118 Sealed and nested closure material, packaging, 120, 120' closure, 122 Steribag, sealed and nested closure package, 124 sealed and nested closure package, 130, 130' cap, 132, 132' cap body, 134, 134' barb retention feature, 136, 136' tamper-evident flip-off cover, 138, 138' retention feature, recess, 140, 140' stopper, 142, 142' septum, c inner diameter of hanging shelf portion 101, c' inner diameter of hanging shelf portion 101', d1 diameter of main portion of container 90, d2 diameter of neck of container 90, d3 diameter of container 90, d4 inside diameter of neck of container 90, h1, h2, h3 height of container 90, r maximum dimension of opening 107, r' Maximum dimension of the opening 107', s1 wall thickness of the container body 96, s2 bottom thickness of the container body 96

Claims

1. 1. A stopper application device for closing a plurality of drug containers held in a container nest with a corresponding plurality of closures held in a closure nest, comprising: a controlled environment enclosure capable of maintaining sterility; an actuation driving machine having an upwardly facing horizontal driving surface, the actuation driving machine configured to move along a vertical path within the controlled environment enclosure; a fixture plate disposed within the controlled environment enclosure above the driving machine, the fixture plate having a lower horizontal surface parallel to and facing the horizontal driving surface; at least one resiliently compliant element compressibly disposed between at least one of the containers and the horizontal impact surface; A plug mounting device comprising:

2. 2. The plug attachment device of claim 1, wherein at least one of said resiliently compliant elements is a single resiliently compliant pad compressibly positioned between all of said containers and said horizontal striking surface.

3. at least one of the resilient compliant elements further comprises a plurality of resilient compliant pads; 2. The plug attachment device of claim 1, wherein each of the pads is center-to-center aligned along a vertical axis with a corresponding container in the container nest and positioned to be compressible between the corresponding container and the horizontal striking surface.

4. 2. The bung attachment device of claim 1, wherein at least one of the resiliently compliant elements comprises a single resiliently compliant pad, the surface of the pad facing the lower horizontal surface of the fixed plate being shaped to provide a distribution of top portions of resiliently compliant material that are arranged to be resiliently compressible between the container and the horizontal striking surface.

5. 5. The plug attachment device of claim 4, wherein a portion of the top of the resiliently compliant material is positioned to pass through an opening in a lowermost surface of the container nest for engaging the container.

6. 2. The bung fastener of claim 1, wherein at least one of the resiliently compliant elements comprises a single resiliently compliant pad, the surface of the pad facing the horizontal driving surface being shaped to provide a distribution of peaks of the resiliently compliant material that are arranged to be resiliently compressible when the pad is pressed against the container under the action of the actuating driving tool.

7. 1. A stopper application device for closing a plurality of drug containers held in a container nest with a corresponding plurality of closures held in a closure nest, comprising: a controlled environment enclosure capable of maintaining sterility; an actuation driving machine having an upwardly facing horizontal driving surface, the actuation driving machine configured to move along a vertical path within the controlled environment enclosure; a fixture plate disposed within the controlled environment enclosure above the driving machine, the fixture plate having a lower horizontal surface parallel to and facing the horizontal driving surface; a plurality of pins attached to the horizontal lower surface of the stationary plate, the pins being center-to-center with the plurality of closures along a vertical axis; Equipped with the pins are positioned and configured to pass through openings in the closure nest to engage with tops of the closures when the actuation driver drives the containers into the corresponding closures; The bung applicator is configured such that the pin resiliently compresses the closure top under the action of the actuation driver.

8. 1. A stopper application device for closing a plurality of drug containers held in a container nest with a corresponding plurality of closures held in a closure nest, comprising: a controlled environment enclosure capable of maintaining sterility; an actuation driving machine having an upwardly facing horizontal driving surface, the actuation driving machine configured to move along a vertical path within the controlled environment enclosure; a fixture plate disposed within the controlled environment enclosure above the driving machine, the fixture plate having a lower horizontal surface parallel to and facing the horizontal driving surface; a plurality of pins attached to the horizontal lower surface of the fixed plate, the pins being centered along a vertical axis and corresponding to the plurality of closures, the pins being positioned and configured to pass through openings in the closure nest to engage with tops of the closures when the actuation driving tool drives the plurality of containers into the corresponding plurality of closures; Equipped with Each of the pins includes a resiliently compliant element disposed at a point along its length, the resiliently compliant element being made from a resiliently compliant material, the resiliently compliant element being arranged and configured to be resiliently compressible.

9. 1. A stopper application device for closing a plurality of drug containers held in a container nest with a corresponding plurality of closures held in a closure nest, comprising: a controlled environment enclosure capable of maintaining sterility; an actuation driving machine having an upwardly facing horizontal driving surface, the actuation driving machine configured to move along a vertical path within the controlled environment enclosure; a fixture plate disposed within the controlled environment enclosure above the driving machine, the fixture plate having a lower horizontal surface parallel to and facing the horizontal driving surface; a plurality of resiliently compressible telescoping pins attached to the horizontal lower surface of the fixed plate and centered along a vertical axis with the plurality of closures, the plurality of pins being positioned and configured to pass through openings in the closure nest to engage tops of the closures when the actuation driving tool drives the plurality of containers into the corresponding closures; A plug mounting device comprising:

10. 1. A stopper application device that provides a controlled environment for receiving a nest of drug containers and a nest of closures, and for closing an array of drug containers held in said container nest with a corresponding array of closures held in said closure nest, comprising: first and second opposing rigid plates defining a space therebetween for receiving the array of closures in overlapping registration with the openings of the array of containers, the rigid plates being arranged for relative movement toward and away from one another to drive the array of containers and the array of closures together to seal the openings of each of the containers in the array of containers with a corresponding closure in the array of closures, the second plate being in overlapping registration with the first plate; at least one resiliently compliant element positioned between the array of containers and the first rigid plate, the at least one resiliently compliant element being locally deformable by each container of the array of containers during driving of the containers into sealing engagement with the closure; A plug mounting device comprising:

11. 11. The bung attachment device of claim 10, wherein at least one of the resiliently compliant elements is a single resiliently compliant pad compressibly disposed between all of the containers and the first of the opposing rigid plates.

12. at least one of the resilient compliant elements further comprises a plurality of resilient compliant pads; 11. The plug attachment device of claim 10, wherein each of the pads is center-to-center aligned with a corresponding container in the container nest along a vertical axis and positioned so as to be compressible between the corresponding container and the first of the opposing rigid plates.

13. 11. The bung attachment device of claim 10, wherein at least one of the resiliently compliant elements comprises a single resiliently compliant pad shaped to provide a distribution of tops of resiliently compliant material such that a surface of one of the rigid plates facing the other of the rigid plates is resiliently compressible between the container and a surface of the first of the rigid plates.

14. 14. The plug attachment device of claim 13, wherein a portion of the top of the resiliently compliant material is positioned to pass through an opening in a lowermost surface of the container nest for engaging the container.

15. 11. The bung fastener of claim 10, wherein at least one of the resiliently compliant elements comprises a single resiliently compliant pad, the surface of the pad facing the first of the opposing plates being shaped to provide a distribution of peaks of the resiliently compliant material that is arranged to be resiliently compressible when the pad is pressed against the container under the action of the actuation driver.

16. 1. A stopper application device that provides a controlled environment for receiving a nest of drug containers and a nest of closures, and for closing an array of drug containers held in said container nest with a corresponding array of closures held in said closure nest, comprising: first and second opposing rigid plates defining a space therebetween for receiving the array of closures in overlapping registration with the openings of the array of containers, the rigid plates being arranged for relative movement toward and away from one another to drive the array of containers and the array of closures together to seal the openings of each of the containers in the array of containers with a corresponding closure in the array of closures, the first plate being in overlapping registration with the second plate; a plurality of pins disposed on a surface of the first plate, the pins being centered relative to the closures, each pin extending along an axis parallel to the longitudinal axis of the corresponding container; Equipped with The pin is positioned and configured to pass through a corresponding opening in the closure nest to engage a top of the closure during driving of the container into sealing engagement with the closure.

17. 17. The plug attachment device of claim 16, wherein the pin is configured to resiliently compress the top portion of the closure.

18. 17. The plug attachment device of claim 16, further comprising a resiliently compliant element disposed within or on the end of each of a plurality of said pins and arranged to be resiliently compressed during driving of said container into sealing engagement with said closure.

19. 17. The plug attachment device of claim 16, wherein each said pin comprises a resiliently compressible telescoping pin arranged to be compressed during driving of the container into sealing engagement with the closure.

20. 1. A method of operating a stopper application device for closing a plurality of pharmaceutical containers held in a container nest with a corresponding plurality of closures held in a closure nest, comprising: providing a controlled environment enclosure capable of maintaining sterility; providing an actuated driving tool within the controlled environment enclosure, the driving tool having an upwardly facing horizontal driving surface, the driving tool configured to move along a vertical path within the controlled environment enclosure; providing a fixture plate within the controlled environment enclosure, the fixture plate being positioned within the controlled environment enclosure above the driving machine, the fixture plate having a lower horizontal surface that is parallel to and faces the horizontal driving surface; attaching a plurality of pins to the lower horizontal surface of the stationary plate, the pins being centered along a vertical axis with the plurality of closures; the pins are positioned and configured to pass through openings in the closure nest to engage with tops of the closures when the actuation driver drives the containers into the corresponding closures; the pin is configured to resiliently compress the closure top under actuation of the actuation driver; a step of pushing the articulation tool and the fixing plate together; A method comprising:

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