Method, device and system for filling pharmaceutical containers

Abstract

In one general aspect, a method for filling multiple containers with a pharmaceutical product is disclosed, which comprises decontaminating sealed nested materials in a transfer chamber, removing from the sealed nested materials one or both of a container nest holding the multiple containers and a closure nest holding multiple closures, transferring from the transfer chamber to a controlled environment enclosure the removed nest, aseptically filling the containers with the pharmaceutical product, and closing the containers with the multiple closures. The nests are configured to allow multiple closures and containers to be simultaneously aligned concentrically, and closed simultaneously. Spring-loaded retaining structures on the closure nest allow it to releasably retain multiple closures above the corresponding multiple containers. In some embodiments the spring-loaded features are monolithically integrated with the closure nest. The product may be lyophilized in partially sealed containers while the sealing closures are releasably retained by the closure nest.

Claims

1. A method for aseptically closing a pharmaceutical product in a plurality of containers, the method comprising: a. providing a first plurality of sterilized containers in a container nest, the sterilized containers having an upper portion with an opening and the container nest retaining the first plurality of sterilized containers, in a controlled environment enclosure; b. providing a plurality of sterilized aseptic closures releasably suspended from a closure nest into the controlled environment enclosure, wherein each closure comprises a stopper, a cap, and a holding feature above and extending radially outward relative to the cap, and wherein the releasably suspended comprises releasably retaining the holding feature of each of the plurality of aseptic closures with a spring-loaded retaining structure of the closure nest; c. establishing an aseptic condition in the controlled environment enclosure; d. after the establishing, filling at least a first portion of the first plurality of containers with the pharmaceutical product inside the controlled environment enclosure; and e. after the filling, at least partially closing, simultaneously, containers of a second portion of the first plurality of containers with a portion of the plurality of aseptic closures while releasably retaining the plurality of aseptic closures in the closure nest such that at least one aseptic closure engages the upper portion of one of the plurality of containers.

2. The method of claim 1, wherein the releasably retaining with the holding feature comprises elastically retaining with the holding feature.

3. The method of claim 2, wherein the elastically retaining with the holding feature comprises retaining the holding feature with the spring-loaded retaining structure portion of the closure nest.

4. The method of claim 1, wherein the portion of the plurality of the aseptic closures is all the closures of the plurality of closures.

5. The method of claim 4, wherein the first portion of the first plurality of containers equals, in number, the number of closures in the plurality of closures.

6. The method of claim 4, wherein the number of closures in the plurality of closures is all the closures the closure nest is configured to releasably retain.

7. The method of claim 1, wherein filling at least the first portion of the first plurality of containers comprises filling two or more containers simultaneously.

8. The method of claim 1, further comprising lyophilizing the pharmaceutical product in the second portion of the first plurality of containers while releasably retaining the plurality of aseptic closures in the closure nest.

9. The method of claim 1, wherein the at least partially closing simultaneously takes place while at least the second portion of the first plurality of containers is in the container nest.

10. The method of claim 1 further, including automatically aligning the first plurality of containers in the container nest and the plurality of closures in the closure nest after the filling and before the at least partially closing.

11. A method for aseptically closing a pharmaceutical product in a plurality of containers, each of the containers having an upper portion, the method comprising: a. providing a first plurality of sterilized containers in a container nest in a controlled environment enclosure; b. providing a plurality of sterilized aseptic closures releasably suspended from a closure nest into the controlled environment enclosure, wherein each closure comprises a stopper, a cap, and a holding feature above and extending radially outward relative to the cap, the closure nest having a plurality of retention features wherein each retention feature comprises a spring-loaded retaining structure for releasably retaining at least one of the aseptic closures, wherein the releasably suspended comprises releasably retaining the holding feature of each of the at least one of the plurality of aseptic closures with the spring-loaded retaining structure of the closure nest; c. establishing an aseptic condition in the controlled environment enclosure; d. after the establishing, filling at least a first portion of the first plurality of containers with the pharmaceutical product inside the controlled environment enclosure; and e. after the filling, at least partially closing, simultaneously, containers of a second portion of the first plurality of containers with a portion of the plurality of aseptic closures within the closure nest while releasably retaining the plurality of aseptic closures within the closure nest with the retention feature of the closure nest such that at least one aseptic closure engages the upper portion of one of the plurality of containers.

12. The method of claim 11, wherein the releasably retaining with the retaining feature comprises elastically engaging the retention feature with the holding feature of the asepetic closure.

13. The method of claim 12, wherein the elastically engaging comprises retaining the holding feature with the spring-loaded retaining structure of the closure nest.

14. The method of claim 11, wherein the portion of the plurality of the aseptic closures is all the closures in the plurality of closures.

15. The method of claim 14, wherein the first portion of the first plurality of containers equals, in number, the number of closures in the plurality of closures.

16. The method of claim 14, wherein the number of closures in the plurality of closures is all the closures the closure nest is configured to retain.

17. The method of claim 11, wherein filling at least the first portion of the first plurality of containers comprises filling two or more containers simultaneously.

18. The method of claim 11, further comprising lyophilizing the pharmaceutical product in the second portion of the first plurality of containers while releasably retaining the plurality of aseptic closures in the closure nest.

19. The method of claim 11, wherein the at least partially closing simultaneously takes place while at least the second portion of the first plurality of containers is in the container nest.

20. The method of claim 11, further including automatically aligning the first plurality of containers in the container nest and the plurality of closures in the closure nest after the filling and before the at least partially closing.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

(2) FIG. 1 shows a system for filling pharmaceutical containers.

(3) FIG. 2 shows from bottom to top the arrangement and contents of a sealed nested container package as employed in the present invention.

(4) FIG. 3 shows from bottom to top the arrangement and contents of a sealed nested closure package as employed in the present invention.

(5) FIG. 4 shows an alternative embodiment of a system for filling pharmaceutical containers.

(6) FIGS. 5A and 5B show two views of a pharmaceutical container and its key dimensions.

(7) FIG. 6A and FIG. 6B show two embodiments of closures for pharmaceutical containers

(8) FIG. 7A and FIG. 7B show two embodiments of closure retaining structures for closure nests.

(9) FIG. 8 shows an arrangement for closing the container of FIG. 5 with the closure of FIG. 6A using the closure retaining structures of FIG. 7A.

DETAILED DESCRIPTION

(10) A method and associated system for filling pharmaceutical containers is described at the hand of the schematic depiction in FIG. 1, as well as FIG. 2 and FIG. 3. A filling system 10 for filling pharmaceutical containers 90 with a pharmaceutical product is disposed within a controlled environment enclosure 20. Controlled environment enclosure 20 is configured for maintaining an aseptic condition. In some embodiments, in particular that 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 potentially be toxic or otherwise harmful. As will be described in more detail below, the filling system 10 can be configured to locate, target, and fill containers 90 held in a container nest 70 within a container tub 80 (see FIG. 2). Many types of containers 90 are contemplated herein, including, but not limited to vials, syringes, bottles, and ampoules.

(11) 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. Frequently vials are used that have one or more additional custom specifications. In some cases these specifications may deviate from the standards.

(12) Glass has traditionally been the only choice for container material but problems with glass breakage, delamination, particulates due to glass-on-glass collisions, and stability of some products resulted in development and usage of suitable polymeric materials. One example of such polymeric material is TOPAS(R) cyclic olefin polymer. Vials made of polymeric materials are commercially available in size ranges and dimensions that typically closely mimic those of glass vials.

(13) Polymeric materials are significantly less scratch resistant than glass and existing aseptic processing equipment has not been redesigned to mitigate the risks of scratching. Scratched surfaces of containers are a serious concern for the perceived quality of the product, but also severely limits the inspection of the containers for particulates. Such inspection is typically a regulated requirement for good manufacturing practice.

(14) Processing of vials in nests can be an effective solution to prevent scratching of vials such as typically occurs during singulated handling of vials or during simultaneous handling of rows of vials. Handling of vials in nests avoids all vial-tooling and vial-vial collisions. The nests are particularly well suited for processing of polymeric vials but may be used equally well for processing of glass vials.

(15) Nests for syringes have been commercially available for some decades, but they are a comparatively new concept for the management of pharmaceutical containers beyond syringes. Suitable container nests 70 are available from Nuova Ompi of Newtown, Pa. and from Afton Scientific of Charlottesville, Va.

(16) The containers 90, tub 80, and container nest 70 are shown in more detail in FIG. 2 in which the packaging of the containers 90 is depicted in stages of completeness from bottom to top. The container nest 70 and container tray or tub 80 may be, for example without limitation, of the polystyrene EZ-FILL type provided by Nuovo Ompi of Newtown, Pa. These are supplied with a sealing Tyvek cover 82 permeable to ethylene oxide for purposes of sterilization. The cover 82 may comprise of a permeable Tyvek sheet 84 and a Tyvek lid 86 over the permeable Tyvek sheet 84. In the present specification we refer to the combination of tub 80, sealed with cover 82 and containing the nest 70 with containers 90 as sealed nested container materials 88. Sealed nested container materials 88 may be supplied packaged in a steri-bag 92. In the present specification we refer to this entire combination, as shown in FIG. 2, as a sealed nested container package 94.

(17) The closures 120 for the containers 90 may be supplied in similar fashion to the containers 90, as shown in FIG. 3. The closures may comprise caps 130 with integrated stoppers 140 and are described in more detail below at the hand of FIG. 6 and FIG. 7. The closures 120 are supplied arrayed within a closure nest 100 in a closure tub 110 with a sealing Tyvek cover 112 permeable to ethylene oxide for purposes of sterilization. The cover 112 may comprise of a Tyvek sheet 114 and a Tyvek lid 116 over the permeable Tyvek sheet 114. In the present specification we refer to the combination of tub 110, sealed with cover 112 and containing the closure nest 100 with closures 120 as sealed nested closure materials 118. Sealed nested container materials 118 may be supplied packaged in a steri-bag 122. In the present specification we refer to this entire combination, as shown in FIG. 3, as a sealed nested closure package 124. In the present specification sealed nested container materials 88 and sealed nested closure materials 118 are collectively referred to as sealed nested materials.

(18) Tubs 80, 110 may be handled within controlled environment enclosure 20 by an articulated arm apparatus 22 disposed within controlled environment enclosure 20. Articulated arm apparatus 22 comprises an end of arm tool 24 configured to hold tubs and nests. Articulated arm apparatus 22 may be, without limitation, a robotic articulated arm. Suitable robotic articulated arms are described in US Patent Application Publication US 2009/0223592A1 and in WIPO PCT Application Publication Number WO 2013/016248A1, both wholly incorporated herein by reference.

(19) In contrast to prior art conveyor belt systems, the sealed nested closure packages 92, 122, the tubs 80, 110 and nests 70, 100 are gripped and held by end of arm tool 24, which can be capable of gripping or holding. Furthermore, as described in co-pending patent application US2009/0223592A1, titled Robotic filling systems and methods the articulated arm apparatus 22 allows environment enclosure 20 to be cleanable to a much greater degree than a conveyor belt system. Articulated arm apparatus 22 lends itself to being fully automated and this allows a greater degree of automation of the entire container-filling process within the controlled environment enclosure 20 than what is otherwise attainable under such decontaminated or sterilized conditions as pertain within controlled environment enclosure 20. The use of articulated arm apparatus 22 eliminates some of the difficulties described in the background to this specification. In particular, the articulated arm apparatus 22 allows the relevant nest to be held in a single action until processing is completed and the container or closure 90, 120 itself is not held, as all handling operations may be carried out by means of nests 70, 100 or tubs 80, 110.

(20) As regards method, the sealed nested container- or closure package 94, 124 may be opened outside filling system 10. The cover 82, 112 may be highly permeable to the atmosphere and therefore the step of removing sealed tub 80, 110 from its packaging 88, 118 may expose not only the sealed tub 80, 110 but also its contents to ambient atmosphere.

(21) With the inner door 26 between transfer chamber 30 and controlled environment enclosure 20 closed, the outer door 32 of transfer chamber 30 may be opened. Sealed tub 80, 110 containing the nest 70, 100 with containers or closures 90, 120 may then be transferred via outer door 32 of transfer chamber 30 onto shelves 34 of transfer chamber 30. Shelves 34 may be, without limitation, carousel shelves.

(22) In a next step, sealed tub 80, 110 may be decontaminated inside transfer chamber 30. Suitable decontamination includes, but is not limited to exposure to hydrogen peroxide gas or ozone. Other suitable means of decontamination may include, without limitation, electron beam irradiation and ultraviolet irradiation. Transfer chamber 30 may be any isolatable and decontaminatable vessel, including without limitation, an autoclave or a radiation based decontaminatable vessel that is configured to be placed in spatial communication with controlled environment enclosure 20. In the present specification, the term transfer chamber is used to describe any such vessel that is decontaminatable and which may be placed in spatial communication with controlled environment enclosure 20. Further examples of vessels suitable for use as transfer chamber 30 are provided below.

(23) In some cases it can be advantageous to decontaminate transfer chamber 30 together with controlled environment enclosure 20. When decontaminated simultaneously, the seals on inner door 26 will be decontaminated. In some other cases the seal area of door 26 may be negligible.

(24) The covers 82, 112 may be highly permeable to gases and decontamination agents. Certain materials can be susceptible to significant sorption of decontamination agents during decontamination of the transfer chamber. Exposure of pre-sterilized materials of tub 80, 110 to decontamination agents can be prevented by use of an impermeable cover instead of cover 82, 112, or by addition of an impermeable layer on top of the cover 82, 112. Suitable methods for adding such an impermeable layer includes, without limitation adhesive film and heat seals.

(25) In another aspect of this invention, the transfer chamber 30 may be a vacuum chamber; and is configured to sterilize the contents of the tub 80, 110. Thermal and fast non-thermal sterilization cycles are well known in the art. The fast cycle time of non-thermal sterilization cycles may be particularly advantageous. Such cycles are typically used in hospital settings, for example for sterilization of surgical instruments. Gaseous sterilization agents can be hydrogen peroxide, ozone and combinations thereof.

(26) The transfer chamber 30 may be equipped with a plasma generator for rapid activation and removal of sterilization agents. The addition of non-thermal sterilizing transfer chamber 30 to controlled environment enclosure 20 is particularly well suited for processing of nested pharmaceutical container materials.

(27) When tub 80, 110 has been decontaminated, inner door 26 may be opened to place the interior of transfer chamber 30 in communication with the interior of controlled environment enclosure 20 and articulated arm apparatus 22 may be employed to remove the sealed nested materials 88, 118 from transfer chamber 30 into controlled environment enclosure 20 through inner door 26. Since the articulated arm apparatus 22 is a decontaminated or sterilized structure, and it is gripping the tub 80, 110 in a decontaminated environment, the gripping of the tub 80, 110 by the articulated arm apparatus 22 is referred to in the present specification as aseptically gripping. By way of contrast, other methods of transfer may not involve gripping or may not be aseptic, requiring the controlled environment enclosure 20 to be sterilized or decontaminated after transfer.

(28) Articulated arm apparatus 22 may be employed to remove one or both of lid 86, 116 and sheet 84, 114 within controlled environment enclosure 20. A suitable method for using articulated arm apparatus 22 to remove lid 86/116 is described in copending Patent Application PCT/US 13/39455, which is hereby incorporated in full. Sheet 84, 114 may alternatively be removed using suitable suction. Articulated arm apparatus 22 may then remove the nests 70, 100 with containers or closures 90, 120 from the tubs 80, 110.

(29) Controlled environment enclosure 20 comprises a filling station 60. In one embodiment, shown in FIG. 1, the filling station 60 comprises fill needle system 62 supplied with liquid product via fluid path 64 from fluid reservoir 50 under the action of a suitable pump 52. Pump 52 may be, without limitation, a peristaltic pump. The liquid product may be filtered via a suitable filter 54. The fluid may enter into controlled environment enclosure 20 along fluid path 64 via a suitable fluid path connector 56.

(30) In one embodiment of the method, shown in FIG. 1, articulated arm apparatus 22 may move an opening of each container 90 one after the other under fill needle system 62. Fill needle system 62 may comprise a single fill needle, or may comprise a plurality of fill needles. If fill needle system 62 comprises a single fill needle, the containers 90 are filled one after the other by moving the container nest 70 and operating the fill needle system 62 to fill the containers 90. If fill needle system 62 comprises a plurality fill needles, the containers 90 are filled one plurality after another by moving the container nest 70 and operating the fill needle system to fill the containers 90. The end of arm tool 24 can be rotated to align containers 90 with the fill needle(s) of fill needle system 62.

(31) In another embodiment, shown in FIG. 4, the container nest 70 with containers 90 is placed in a fixed position on a pedestal 28 and the fill needle system 62 is spatially manipulated by a suitable second articulated arm apparatus 22 to place the fill needle system 62 above the openings of the containers 90. The containers 90 are thus filled by moving and operating the fill needle system. The second articulated arm apparatus may be of the same type as articulated arm apparatus 22. It may have an end of arm tool 24 configured for manipulating the fill needle system 62. Having a second articulated arm apparatus dedicated to filling, frees up the articulated arm apparatus 22 for handling of a second tub 80, 110 and nest 70, 100 while a first tub 80, 110 is being filled.

(32) Filling system 10 comprises a stoppering 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 is in communication with an interior of stoppering apparatus 40 via stoppering system door 42. In the embodiment depicted in FIG. 1, stoppering apparatus 40 is shown as being contained within controlled environment enclosure 20. In other embodiments stoppering apparatus 40 may be arranged in a separate chamber from controlled environment enclosure 20 and may communicate with controlled environment enclosure 20 via a suitable stoppering system door.

(33) A container nest shelf 46 and a closure nest shelf 48 are disposed within the interior of stoppering apparatus 40. Container nest shelf 46 and a closure nest shelf 48 are disposed to allow closures 120 in closure nest 100 to be centered on the openings of containers 90 in container nest 70 when closure nest 100 and container nest 70 are placed on respectively container nest shelf 46 and closure nest shelf 48.

(34) In one embodiment of the method, shown in FIG. 1, stoppering system door 42 is opened and articulated arm apparatus 22 moves container nest 70 with filled containers 90 to place it on container nest shelf 46. Articulated arm apparatus 22 may be used to move closure nest 100 with closures 120 to place it on closure nest shelf 48. Each filled container 90 thereby has a closure concentrically positioned directly above it. Closure nest 100 with closures 120 may be placed on closure nest shelf 48 either before or after container nest 70 with filled containers 90 is placed on container nest shelf 46. To this end the container nest 70 and closure nest 100 may have mutually matching geometries to arrange a closure 120 concentrically with the opening of a container 90.

(35) After the container nest 70 with containers 90 and closure nest 100 with closures 120 have been located on their respective shelves 46 and 48 within stoppering apparatus 40, stoppering system door 42 is closed. To the extent that some stoppering procedures need to be performed under vacuum conditions or under inert atmosphere, the required vacuum or inert atmosphere may then be established within the interior of stoppering apparatus 40.

(36) Stoppering apparatus 40 is configured close all containers simultaneously using an actuated ram 44. For some subsequent operations, such as freeze-drying, the stoppers are required to be only partially inserted and actuated ram 44 may be configured to only partially insert the stoppers 140. After insertion of the stoppers 140, the articulated arm apparatus 22 removes nest 70 with containers 90 from stoppering apparatus 40.

(37) In another embodiment of the articulated arm apparatus 22 loads nested containers 90 and nested caps 130 with integrated stoppers 140 into stoppering apparatus 40. As described above, apparatus 40 can simultaneously stopper and cap a nest 70 of containers 90.

(38) After completion of the stoppering and capping, the articulated arm apparatus 22 moves the nested containers 90 back into transfer chamber 30. In other embodiments, the articulated arm apparatus 22 may move the filled, stoppered, and capped nest 70 with containers 90 to an adjacent controlled environment enclosure (not shown) through a suitable communicating door (not shown). The capped nest 70 with containers 90 may be moved to the adjacent controlled environment enclosure with the containers only partially stoppered or partially closed.

(39) FIGS. 5A and 5B show the generic shape of a pharmaceutical 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 container 90 is shown in enlarged view on the right. Typically, the d.sub.2 neck diameter 98 of the container 90 is only slightly smaller than the d.sub.1 main diameter 99 of container 90. This allows the placement of a cap 130 on the vial without reducing the packing density of containers 90 in nest 70 of FIG. 2. Therefore the densest circle packing density of the caps is closely the same as the packaging of the containers. It is particularly advantageous for the cap nest to have exactly same packaging geometry as the vial nest; so that cap nest can be overlayed on the vial nest and caps be applied without movement of the nest. Caps can be applied one at the time, multiples in a row, or all at once.

(40) In another aspect, this specification provides a nest for holding closures. We consider first the generic closure 120 provided in FIG. 6A. Closure 120 comprises cap 130 and stopper 140. Stopper 140 has a thinner septum 142 that is piercable by an extraction needle such as that of a syringe. Cap 130 comprises a cylindrical cap body 132, at least a first set of barbed retention features 134, and a tamper-evident flip-off cover 136. In the example of FIG. 6A two sets of barbed retention features 134 are shown and these may be arranged in a pattern around the inner perimeter of the cap 130. The tamper-evident flip-off cover 136 is manufactured as an integral part of cap 130 such that, when cover 136 is removed, it cannot be replaced. This serves as verification that septum 142 of stopper 140 has been exposed. Cover 136, in this particular example, has a larger diameter than body 132 of the cap 130. This may serve as a holding feature 138 for cap 130 and thereby for closure 120, which may be exploited for holding closure 120 in nest 100.

(41) In FIG. 6B another example closure 120. Closure 120 comprises cap 130 and stopper 140. Stopper 140 has a thinner septum 142 that is piercable by an extraction needle such as that of a syringe. Cap 130 comprises a cylindrical cap body 132, at least a first set of barbed retention features 134, and a tamper-evident flip-off cover 136. In the example of FIG. 6A two sets of barbed retention features 134 are shown and these may be arranged in a pattern around the inner perimeter of the cap 130. The tamper-evident flip-off cover 136 is manufactured as an integral part of cap 130 such that, when cover 136 is removed, it cannot be replaced. This serves as verification that septum 142 of stopper 140 has been exposed. Cover 136, in this particular example, has the same diameter as body 132 of the cap 130. However, a dimple 138 is provided at the join between the cover 136 and the cap body 132. This may serve as a holding feature 138 for cap 130 and thereby for closure 120, which may be exploited for holding closure 120 in nest 100.

(42) In the prior art these vial caps have been made from aluminum with polymeric flip-off covers. Capping of aluminum caps typically generates considerable amounts of non-viable particles and this has tended to make aluminum caps unacceptable in recent times. Caps made of polymeric material are now commercially available. The polymeric caps are particularly well suited for use with polymeric containers, but can also be used for glass containers.

(43) The most optimal geometry of containers 90 in a nest 70 follows the mathematical theories of equal sized circle packing, leading typically to hexagonal, triangular, square, elongated triangular; snub square and other related geometrical patterns of container positions in nest 70.

(44) In this specification, a closure nest 100 is presented in which the geometrical arrangement of the closures 120, 120 closely matches the geometrical patterns of container positions in nest 70. In some embodiments, closure nest 100 has exactly same packaging geometry as the container nest 70, with the distribution of closure centers in closure nest 100 lining up within a working tolerance with the distribution of container centers in container nest 70. This allows closure nest 100 to be overlayed on container nest 70, and closures 120, 120 to be applied to containers 90 so that all the closures 120, 120 in closure nest 100 may be applied to all the containers 90 in container nest 70 without any substantial movement of either nest 70 or nest 100. Closures 120, 120 may be applied one at a time, one row at a time, or all at substantially the same time.

(45) In FIG. 7A a part of closure nest 100 is shown schematically, depicting a closure retaining structure for a single cap 130 of closure 120 of FIG. 6A. In FIG. 7A the associated stopper 140 is contained within cap 130 and is therefore not visible. It is to be understood that the part of closure nest 100 shown in FIG. 7A is descriptive of a plurality of such parts, and that the parts are arranged two dimensionally to concentrically align a plurality of containers 90 in container nest 70 center-to-center with a plurality of closures 120 held by closure nest 100. The closure retaining structure comprises a spring-loaded retaining structure 102, arranged to engage with holding feature 138 on cover 136 of cap 130, thereby holding cap 130 vertically suspended. The closure retaining structure further comprises a stop structure 104 against which cap 130 can push when cap 130 and closure nest 100 are pushed together vertically. The cap 130 of FIG. 6B may similarly be held by its specific holding feature 138.

(46) In FIG. 7B a part of another closure nest 100 is shown schematically, depicting a closure retaining structure for a single cap 130 of closure 120 of FIG. 6A. In FIG. 7B the associated stopper 140 is contained within cap 130 and is therefore not visible. It is to be understood that the part of closure nest 100 shown in FIG. 7B is descriptive of a plurality of such parts, and that the parts are arranged two dimensionally to concentrically align a plurality of containers 90 in container nest 70 center-to-center with a plurality of closures 120 held by closure nest 100. The closure retaining structure comprises a spring-loaded retaining structure 102, arranged to engage with the bottom of cap 130, thereby holding cap 130 vertically suspended. In this arrangement, the bottom of cap 130 therefore serves as generic holding feature. The closure retaining structure further comprises a stop structure 104 against which cap 130 can push when cap 130 and closure nest 100 are pushed together vertically.

(47) The spring-loaded retaining structure may be implemented in different ways. One non-limiting example spring-loaded retaining structure 102 is an elastically flexible retaining structure. Spring-loaded retaining structure 102 may be a separate structure from closure nest 100 that is fastened to closure nest 100. In other embodiments, spring-loaded retaining structure 102 is an integral part of closure nest 100 and may be manufactured to be monolithically integrated with closure nest 100. One non-limiting way of manufacturing spring-loaded retaining structure 102 as a monolithically integrated part of closure nest 100, is by injection molding of a suitable polymer.

(48) Spring-loaded retaining structure 102 holds cap 130, 130 in place during handling and transport; and can flex open without risk of removing the tamper evident cover 136, 136 when the cap 130, 130 is being pushed or pulled out of the closure nest 100, 100. The direction of capping force can be upwards, downwards or both. Sections of the closure nest 100, 100 can be reinforced by structural features such as honeycombs to distribute the capping force and to prevent bowing during handling.

(49) The integrity of the container 90 and closure 120, 120 is achieved by deforming the elastomeric stopper 140, 140 by compressing the elastomeric stopper 140, 140 against the container 90 and permanently holding it in this compressed state by the cap 130, 130. The radial compression of stopper 140, 140 by the interference fit inside of the neck of container 90, as indicated with diameter d4 in FIG. 5 may well create a seal, but that seal is generally considered no more than a secondary seal. In fact some stopper designs for cap 130, 130 may go without any plug shape surrounding septum 142, 142.

(50) It is the vertical compression of the flange part of stopper 140, 140 against the top of the container 90, on the area of container 90 indicated with diameters d4 and d2 in FIG. 5, that creates the primary seal. Typically a high residual sealing force is required to guarantee a robust container seal and provides a wide safety margin for changes in stopper 130, 130, such as compression set. The compression force required for final sealing has to be conveyed through the top surface of cap 130, 130. Therefore an annular shape may be one non-limiting employed for stop structure 104, 104 to apply the compression force to the area of cap 130, 130 directly above the primary seal. Moreover an annular shape for stop structure 104, 104 allows for removal of the capped vial from nest by insertion of a push rod through the opening.

(51) Different shapes may be employed for stop structures 104, 104, depending on the particular design of the cap. The stop structures 104, 104 also determine the length of the spring-loaded retaining structure 102, 102 and therefore its spring retention and opening force. The spring-loaded retaining structure 102, 102 may be substantially linear and orthogonal to the closure nest 100, 100. In yet other examples the height of stop structures 104, 104 and spring-loaded retaining structure 102, 102 can be reduced by curling radially. In those cases where steam sterilization is required of the caps 130, 130 in the closure nest 100, 100, the contact area between stop structure 104, 104 and cap 130, 130 can be reduced to a series of point contacts to allow for good accessibility of steam.

(52) The spring-loaded retaining structure 102, 102 may be sized and shaped such that, when cap 130, 130 is secured on the container 90, spring-loaded retaining structure 102, 102 is automatically pushed out of the way by container 90, thereby releasing the cap 130, 130. The close packing of closure retaining structures on closure nest 100, 100 implies that there is limited space for lateral motion of spring-loaded retaining structures 102, 102. For example, in a hexagonal close packed arrangement, each closure retaining structure is surrounded by six nearest neighbor closure retaining structures, each requiring space for its spring-loaded retaining structures 102, 102 to open in order to release a corresponding cap 130. Each spring-loaded retaining structure 102, 102 is sized and positioned to allow caps 130, 130 on neighboring closure retaining structures to be applied simultaneously to containers 90 correspondingly arranged in container nests 70.

(53) In one embodiment, caps 130, 130 are each held by at least three spring-loaded retaining structures 102, 102 in order to geometrically restrain the cap in its position. In general each closure retaining structure on closure nest 100, 100 implies has a plurality of spring-loaded retaining structures 102, 102. In concept, there can be a single annular spring-loaded retaining structure 102, 102 for each single closure retaining structure, arranged to grip around the entire perimeter of the cap 130, 130. The most general embodiment of closure nest 100, 100 therefore has at least one spring-loaded retaining structure 102, 102 for each closure retaining structure.

(54) In operation, a plurality of closures 120, 120 is releasably retained in a closure nest 100, 100 through being held by spring-loaded retaining structures 102, 102 being engaged with holding features 138 of closures 120, 120, the closure bottoms being a special kind of holding feature. To engage the closures 120, 120 in this fashion, the closures 120, 120 are pushed into the closure retaining structures, during which action the spring-loaded retaining structures 102, 102 are elastically displaced by the caps 130, 130 of the closures 120, 120 until spring-loaded retaining structures 102, 102 click into position on the holding features 138, 138. The closures are then supplied to the filling process in this configuration.

(55) FIG. 8 shows the configuration for the closing of a single container 90, being one of a plurality of containers held in container nest 70 of FIGS. 1, 2 and 4. For closing, the closure 120, being one of a corresponding plurality of closures 120 releasably retained by closure nest 100, is concentrically aligned with container 90 by virtue of the geometries of nests 70 and 100 corresponding center-to-center with each other in two dimensions. The closure holding structure is that of FIG. 7A and the closure detail is that of FIG. 6A, with a limited number of elements of the closure 120 labeled for clarity. When elements are not numbered, the numbers of FIG. 6A pertain.

(56) During the closing of container 90 with closure 120, container 90 and closure 120 are vertically forced together. This may be done to a degree that merely causes the top of container 90 to engage with barbed retention features 134 (See FIG. 6A). This constitutes partial closing. The application of further force pushes stopper 140 via stop structures 104 deeper into container 90 to seal it. In a final step, container 90, duly capped and closed with closure 120, may be disengaged from the closure holding structure of closure nest 100 by pushing downward on the cover 136 of cap 130 of closure 120 with rod 106 attached to platen 108. The platen 106 may extend over the whole surface of closure nest 100 or may extend over part of it. There may be the same number of rods as the number of closures held by closure nest 100, or the rods 106 may be fewer. This action forces open the spring-loaded retaining structures 102, 102 and releases the capped container 90 from the closure holding structure of closure nest 100. This process or method may be conducted simultaneously for a plurality of closure holding structures of closure nest 100. All the closures in all the closure holding structures of closure nest 100 may undergo this procedure simultaneously.

(57) In a most general description, this specification provides a closure nest 100, 100 for releasably retaining a plurality of closures 120, 120 for pharmaceutical containers, the closure nest 100, 100 comprising a plurality of closure retaining structures each comprising at least one spring-loaded retaining structure 102, 102 and a stop structure 104, 104, the spring-loaded retaining structure 102, 102 configured to engage with a holding feature 138 on one of the plurality of closures 120, 120 and the stop structure 104, 104 configured to exert force on and confine the one of the plurality of closures 120, 120. The closure retaining structures may be arranged in a geometric pattern, which geometric pattern may be a close packed pattern and which may match center-to-center a corresponding a pattern of container-holding structures on a container nest. The spring-loaded retaining structure 102, 102 may be a flexible structure and may be manufactured from a polymer. The spring-loaded retaining structure 102, 102 may be monolithically integrated with the closure nest 100, 100.

(58) Associated with the closure nest 100, 100 a method for holding a plurality of closures 120, 120 comprises releasably retaining each closure 120, 120 by releasably suspending each closure 120, 120 by a holding feature 138 on closure 120, 120, the holding feature being a specifically designed holding feature 138 or the bottom of a closure as in FIG. 7B. The releasably suspending can be spring-loaded retaining, which is achieved by flexibly deforming or spring-wise deforming a spring-loaded retaining structure 102, 102. The term spring-loaded is used in this specification to describe any form of spring loading, whether by mechanical spring or by a flexible member, or by any other means that will produce a suitable spring or elastic action.

(59) The method provided here for aseptically sealing a pharmaceutical product into a plurality of containers comprises: introducing a first plurality of containers into a controlled environment enclosure; releasably suspending from a closure nest in the controlled environment a plurality of aseptic closures; 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 aseptic closures while releasably retaining the aseptic closures in the closure nest. The method may further comprise lyophilizing the pharmaceutical product in the second portion of the first plurality of containers while releasably retaining the aseptic closures in the closure nest.

(60) The releasably suspending and releasably retaining may comprise releasably engaging with a holding feature of each of the plurality of aseptic closures. The releasably engaging with the holding feature may comprise elastically engaging with the holding feature. The elastically engaging with the holding feature may comprise engaging the holding feature with a spring-loaded retaining structure portion of the closure nest.

(61) Some or all of the plurality of the aseptic closures retained by the closure nest may be used to either fully or partially seal the pharmaceutical product into the containers. The plurality of containers may be equal in number to the number of aseptic closures releasably suspended by the closure nest. Two or more containers may be filled simultaneously.

(62) As regards benefits, the closure nest 100, 100, with its spring-loaded retaining structures 102, 102 and stop structures 104, 104 described in this specification, lends itself to the simultaneous capping and stoppering, both partially and completely, of pluralities of containers 90. More specifically, it lends itself to the simultaneous capping, both partially and completely, of rows of containers 90. Yet more specifically, it lends itself to the simultaneous capping, both partially and completely, of complete two-dimensional arrays of containers 90 in container nests 70. There is no direct contact between the closure nest 100, 100 and any parts that will contact the pharmaceutical product. All handling of the closures 120, 120 by the articulated arm apparatus 22 is by means of the closure nest 100, 100. All contact with the closure nest 100, 100 within the aseptic environment of controlled environment enclosure 20 is by means of devices and surfaces that may be sterilized.

(63) The drawings and the associated descriptions are provided to illustrate embodiments of the invention and not to limit the scope of the invention. Reference in the specification to one embodiment or an embodiment is intended to indicate that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least an embodiment of the invention. The appearances of the phrase in one embodiment or an embodiment in various places in the specification are not necessarily all referring to the same embodiment. As used in this disclosure, except where the context requires otherwise, the term comprise and variations of the term, such as comprising, comprises and comprised are not intended to exclude other additives, components, integers or steps.

(64) Also, it is noted that the embodiments are disclosed as a process that is depicted as a flowchart, a flow diagram, a structure diagram, or a block diagram. Although a flowchart may disclose various steps of the operations as a sequential process, many of the operations can be performed in parallel or concurrently. The steps shown are not intended to be limiting nor are they intended to indicate that each step depicted is essential to the method, but instead are exemplary steps only. In the foregoing specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawing are, accordingly, to be regarded in an illustrative rather than a restrictive sense. It should be appreciated that the present invention should not be construed as limited by such embodiments.

(65) From the foregoing description it will be apparent that the present invention has a number of advantages, some of which have been described herein, and others of which are inherent in the embodiments of the invention described or claimed herein. Also, it will be understood that modifications can be made to the device, apparatus and method described herein without departing from the teachings of subject matter described herein. As such, the invention is not to be limited to the described embodiments except as required by the appended claims.