System and method for discarding of peeled covers of pharmaceutical materials tubs under aseptic conditions

Abstract

A tub cover depository and associated method of use within a sterilizable controlled environment enclosure are provided for retaining covers peeled from tubs holding pharmaceutical materials. The depository comprises a frame comprising a plurality of cover retention tabs disposed within an upper portion of the frame; a vertically translatable platen comprising a plurality of platen fingers contactlessly interlacing with the tabs in a horizontal plane; and a plurality of elastically deformable structures each extending from a lower portion of the frame to the platen. The platen is vertically depressed when a peeled tub cover is forced onto the platen by a depressing force, elastically deforming the elastically deformable structures. Upon removal of the depressing force, a portion of any received tub cover is trapped between the platen fingers and the cover retention tabs as the platen repositions upward under the action of a restoring force in the elastically deformable structures.

Description

System and method for discarding of peeled covers of pharmaceutical materials tubs under aseptic conditionsCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is an original provisional application. Later filed applications based on this filing may be a continuation / continuation-in-part / National Stage of [PCT International] Patent Application Serial Number , filed MONTH date, YEAR, which claims priority under 35 U.S.C. §119[(e)] of Patent Application Serial Number xx / yyy,yyy, filed MONTH date, YEAR, the disclosures of which are incorporated by reference herein.FI ELD OF TH E I NVENTION

[0002] This present disclosure relates to the medical field as exemplified by IPC class A61 and more particularly to apparatus and associated methods for sterilization of and sterile handling of pharmaceutical materials and containers for pharmaceuticals, including bringing pharmaceuticals into form for administration to medical or veterinary patients. In one aspect, it relates to maintaining proper aseptic conditions in conjunction with the efficient processing with such equipment and systems.DESCRIPTION OF RELATED ART

[0003] The subject of filling pharmaceuticals into pharmaceutical containers is a major aspect of the Pharmaceuticals Industry. The subject is heavily controlled by various governmental and official bodies in various countries. Technologically, the subject is a challenge in that the pharmaceutical products need to be filled into the containers under very strict aseptic conditions. Very specific procedures are specified for this task to a degree that makes the handling of pharmaceuticals profoundly different from the handling of any other industrial product, including specifically semiconductors, which also demand extreme and consistent environmental conditions. Indeed, the parallels between the handling of semiconductors in semiconductor "clean laboratories" and the handling of pharmaceuticals in aseptic isolators are superficial. They share the use of such "clean laboratories", but there is no inherent aseptic requirement associated with semiconductor manufacture and the semiconductor field lacks the extreme focus on biologically viable particulates that is so crucially necessary for success in the pharmaceutical field.

[0004] The recent experience with the SARS-CoV-2 pandemic has heightened the industrial awareness of the need to maintain aseptic conditions in pharmaceutical processing equipment. It has also gone some distance toward making this clear to the ordinary citizen. This awareness, along with pressures to produce vaccine doses numbering in the hundreds of millions, has also put immense pressure on pharmaceutical companies to streamline operations and increase throughput in the pharmaceutical filling area.

[0005] The filling process specifically requires the aseptic handling of both the containers and the fluid pharmaceutical itself within a controlled environment enclosure such as an aseptically sealed pharmaceutical isolator. The controlled environment enclosure is used to limit exposure to viable particulates such as bacteria, fungi, and viruses. This leads to complex mechanisms and procedures, many of which may be automated to one degree or another. Such automated equipment may include machines for manipulation of containers, including test tubes, roller bottles, cell culture dishes, bottles, vials, ampoules and syringes. Typical examples of such manipulations are inspection, filling and capping. The parts to be manipulated in controlled environment enclosures may be packaged in a container such as a tub. The container may be closed with a cover consisting of a sheet of flexible material, which generally is heat sealed to the container. The sealed container and contents are decontaminated using a chemical agent, plasma or radiation, including, for example, ultraviolet radiation.

[0006] Decontamination may be done thermally using steam or chemically using chemical agents. Suitable chemical agents known in the art include hydrogen peroxide, ozone, betapropiolactone, aziridine, formaldehyde, chlorine dioxide, ethylene oxide, propylene oxide, and peracetic acid. In most cases the decontamination and sterilization operations have to be preceded by a cleaning process. Such cleaning processes have the function of removing major contamination by simple mechanical and chemical action. The surfaces and materials inside the controlled environment enclosures therefore have to be resistant to the decontamination procedures and chemicals.

[0007] One particular manipulation is the removal of covers from tubs holding pharmaceutical materials such as pharmaceutical containers, or container nests holding the containers. A similar consideration holds for the closures of the containers. Such closures may also be supplied in nests inside of tubs sealed with covers. When the covers are removed from the tubs, the peeled covers have to be deposited somewhere for later removal. Since the controlled environment enclosure is aseptically closed during the cover removal and deposition processes, the coversare discarded within the closed enclosure and then later removed in bulk. Given that the covers in their peeled state are no longer planar in two dimensions and have curled three-dimensional shapes, they consume considerable three-dimensional space.

[0008] In existing systems, the peeled and discarded covers may consume so much space that filling runs have to be interrupted, the discarded covers removed, and the controlled environment enclosure and all its contents decontaminated all over again, before the filling process may be continued. This has major process and financial implications for a pharmaceutical filling organization. Furthermore, attempts to increase the size of the pharmaceutical filling machine so as to accommodate more discarded covers merely puts expensive clean laboratory space under pressure and renders the filling machines unwieldy, expensive, and complicated to install.

[0009] The above makes it clear that there is a great need in industry for a solution for the controlled and space-efficient handling of peeled tub covers within pharmaceutical filling apparatus. Any such solution has to recognize the challenges of establishing and maintaining aseptic conditions within the pharmaceutical filling apparatus during any handling and internal discarding of peeled tub covers.SUMMARY OF THE INVENTION

[0010] A tub cover depository is provided for receiving and retaining peeled tub covers within a sterilizable controlled environment enclosure, the tub cover depository comprising: a tub cover depository frame comprising a plurality of cover retention tabs disposed within an upper portion of the tub cover depository frame; a vertically translatable platen comprising a plurality of platen fingers contactlessly interlacing with the cover retention tabs in a horizontal plane; and a plurality of elastically deformable structures each extending from a lower portion of the tub cover depository frame to the platen, wherein the platen is disposed within the tub cover depository frame so as to be vertically depressible relative to the cover retention tabs upon receiving a peeled tub cover forced onto the platen by a depressing force and so as to trap a portion of the received tub cover between the platen fingers and the cover retention tabs when the depressing force is relieved to allow the platen to reposition upward under the action of an elastic restoring force induced in the elastically deformable structures by the depressing force, and wherein the tub cover depository is capable of being sterilized by a sterilizing agent comprising at least one of sterilizing radiation, a sterilizing plasma, a sterilizing gas, and a sterilizing vapor.

[0011] The elastically deformable structures may comprise elastically deformable torsion springs. All spaces between the contactlessly interlacing platen fingers and the cover retention tabs may be sized to remain accessible to the sterilizing agent. The tub cover depository frame, the platen, and the plurality of elastically deformable structures may be monolithically integrated. The tub cover depository may be composed of a polymer. The tub cover depository may be injection molded. The tub cover depository may be injection moulded using one of polycarbonates, polyether ether ketones, polypropylene, polyvinyl chloride, polyvinylidene difluoride, polychlorotrifluoroethylene, chlorinated polyvinyl chloride, and acrylonitrile butadiene styrene. In some embodiments, the tub cover depository may be manufactured from one of 316 stainless steel and medical grade stainless steel. The transfer stage may be configured to provide the depressing force.

[0012] An apparatus is also provided disposed inside an aseptically sealable controlled environment enclosure capable of being internally sterilized and capable of maintaining an aseptic condition in its interior, the filling apparatus comprising within the controlled environment enclosure: a remotely controlled tub manipulation apparatus configured for holding and moving tubs containing pharmaceutical materials, the tubs being sealed with tub covers; a remotely controlled gripper configured for gripping a fixed gripping area of a tub cover and holding the tub cover by the gripping area while the tub cover is peeled from the tub; a remotely controlled transfer stage configured for engaging the peeled tub cover while the peeled cover is held by the gripper; and a tub cover depository configured to receive the peeled tub cover from the transfer stage and to retain the peeled tub cover in the tub cover depository on the basis of an elastic restoring force once the tub cover is released by the transfer stage, the apparatus further comprising external to the controlled environment enclosure a controller for controlling at least the tub manipulation apparatus, the gripper, and the transfer stage.

[0013] The transfer stage may comprise an end portion configured for engaging the tub cover while the gripping area of the cover is gripped by the transfer stage; and the end portion of the transfer stage may be rotatable about a horizontal axis to transfer the peeled cover to the tub cover depository. The end portion of the transfer stage may be configured to engage the cover using one of vacuum, magnetic force and electrostatic force.

[0014] A method is provided for discarding within an aseptically sealed controlled environment enclosure a tub cover sealing a tub holding pharmaceutical materials, the method comprising: providing within the controlled environment enclosure a remotely controlled transfer stage anda tub cover depository comprising a tub cover depository frame mechanically communicating with a vertically translatable platen via a plurality of elastically deformable structures; peeling the tub cover from the tub within the controlled environment enclosure; engaging the peeled tub cover with the transfer stage; operating the transfer stage to press the peeled cover onto the platen; and operating the transfer stage to displace the platen and thereby elastically deform the elastically deformable structures so as to trap the peeled tub cover between the displaced platen and an upper portion of the tub cover depository frame.The method may comprise providing within the controlled environment enclosure a remotely operable articulated arm apparatus and a gripper wherein peeling the tub cover from the tub comprises holding a fixed gripping area of the tub cover stationary with the gripper while moving the tub using the articulated arm apparatus. The engaging the peeled tub cover with the transfer stage may comprise: engaging the peeled tub cover with the transfer stage while the gripper grips the fixed gripping area of the peeled tub cover after the peeling; and then operating the gripper to release the fixed gripping area of the peeled cover. The operating the transfer stage may comprise rotating an end portion of the transfer stage about a horizontal axis.

[0015] The operating the transfer stage to displace the platen may comprise: depressing the peeled tub cover and platen to downward displace the platen and elastically deform the elastically deformable structures to induce in the elastically deformable structures a restoring force; and raising the end portion of the transfer stage to allow the restoring force to trap the peeled tub cover between the displaced platen and the upper portion of the tub cover depository frame.BRI EF DESCRI PTION OF DRAWINGS

[0016] The above mentioned and other features and objects of this invention, and the manner of attaining them, will become more apparent and the invention itself will be better understood by reference to the following description of an embodiment of the invention taken in conjunction with the accompanying drawings, wherein:

[0017] Figure 1 is a schematic drawing of a pharmaceutical filling apparatus.

[0018] Figure 2A shows a pharmaceutical materials tub with a sealed tub cover in place.

[0019] Figure 2B is a blown-up section of the tub in Figure 2A including the part of the tub cover which is gripped during removal of the tub cover.

[0020] Figures 3A, 3B, and 3C show the apparatus at three different stages of removing and discarding a tub cover.

[0021] Figure 4A shows an isometric view of an empty elastically compressible tub cover depository for peeled pharmaceutical container tub covers.

[0022] Figure 4B shows detail of a Lower frame portion of the elastically compressible tub cover depository of Figure 4A.

[0023] Figure 4C shows an isometric view of the tub cover depository of Figure 4A with peeled tub covers deposited and held in the tub cover-depository.

[0024] Figure 5 is a flow diagram of a method for discarding peeled covers of pharmaceutical materials tubs under aseptic conditions.

[0025] Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of the present invention, the drawings are not necessarily to scale and certain features may be exaggerated in order to better illustrate and explain the present invention. The exemplification set out herein illustrates an embodiment of the invention, in one form, and such exemplifications are not to be construed as limiting the scope of the invention in any manner.DETAI LED DESCRI PTION OF TH E I NVENTION

[0026] The embodiments disclosed below is / are not intended to be exhaustive or limit the invention to the precise form disclosed in the following detailed description. Rather, the embodiment is chosen and described so that others skilled in the art may utilize its teachings.

[0027] Figure 1 is a schematic drawing of a pharmaceutical filling apparatus 100 disposed inside controlled environment enclosure 110. Controlled environment enclosure 110 may be an aseptically sealable medical or pharmaceutical isolator capable of being internally sterilized and capable of maintaining an aseptic condition in its interior. Controlled environment enclosure 110 includes at least one access door which allows an operator access into controlled environment enclosure 110 during set-up, trouble-shooting, maintenance, etc. Sterilization of controlled environment enclosure 110 is obtained with the access door sealed closed and treatment with a sterilizing agent as further described hereinbelow. Enclosure 110 may be equipped with an air pressure control subsystem (not shown) for controlling air pressure inside enclosure 110. The air pressure control subsystem may comprise suitable pumps and valves. Suitable pressure control subsystems are well-known to practitioners of the art. Controlled environment enclosure 110 may house various intricate mechanical and servo-mechanicaldevices used to manipulate materials such as pharmaceutical containers, closures for the containers, tubs for holding pluralities of the containers or closures, and for the covers of such tubs. Enclosure 110 may also house various mechanical and servo-mechanical devices for manipulating at least one pharmaceutical fill needle 130 used for dispensing the pharmaceutical. These various devices will be described in more detail below. The pharmaceutical may typically, though not exclusively, be a fluid provided along supply path 132 from a reservoir (not shown) of the pharmaceutical. Electronic control systems to control or program activities inside enclosure 110 may also be in communication with the various pieces of apparatus inside enclosure 110. To this end, Figure 1 shows generic controller 120 connected to enclosure 110 and to various elements of apparatus 100 inside of enclosure 110. In the interest of clarity, the various electrical and control connections are not shown in Figure 1.

[0028] Pharmaceutical fill needle 130 may be arranged in filling station 140 controlled by controller 120 to fill pharmaceutical containers (not shown) located on filling station 134. Filling station 140 may comprise a robotic arm, as shown in Figure 1. The pharmaceutical containers may be supplied in tubs 150, tubs 150 being aseptically sealed with tub covers 156. The empty pharmaceutical containers may be housed in container nests (not shown) inside container tubs 150. Pharmaceutical container closures may similarly be provided in closure nests corresponding one-to-one with the pharmaceutical containers in the container nests. These container and container closure materials, including the various nests, are described in detail in US patent US10,781,002B2, the disclosures of which are hereby incorporated in full herein.

[0029] Apparatus 100 may further comprise within controlled environment enclosure 110 an articulated robotic arm apparatus 160 for holding and moving tubs 150. Suitable articulated robotic arms 160 for holding and moving tubs 150 are described in detail in US patent US11,O65,759 the disclosures of which are hereby incorporated in full herein. Automated articulated robotic arm is controlled by controller 120. In other embodiments, an alternative remotely controlled tub manipulation apparatus configured for holding and moving tubs containing pharmaceutical materials may be employed instead of articulated robotic arm apparatus 160. Suitable alternative remotely controlled tub manipulation apparatus include the rotary stage tub holding apparatus described in US patent 10,524,980 the disclosures of which are hereby incorporated in full herein.

[0030] Apparatus 100 may further comprise, within controlled environment enclosure 110, remotely controlled gripper 170 for gripping a fixed gripping area on tub covers 156 and, inconjunction with articulated robotic arm 160, for removing tub covers 156 from tubs 150. Gripper 170 may be controlled via controller 120. Suitable remotely controlled grippers are described in more detail in US patent US10081527B2, the disclosures of which are hereby incorporated in full herein. The tub cover removal process may comprise holding the fixed gripping area of tub cover 156 with gripper 170 while moving tub 150 using articulated robotic arm apparatus 160.

[0031] Apparatus 100 may further comprise, within controlled environment enclosure 110, remotely controlled vacuum transfer stage 180 comprising suction cups 182 and disposed for engaging and transferring peeled tub covers 156 from gripper 170 with suction cups 182, once tub covers 156 are fully peeled from tubs 150. Vacuum may be provided via vacuum line 184 from a suitable vacuum source (not shown) that may, in some embodiments, be located outside controlled environment enclosure 110. Transfer stage 180 may have an end portion configured to rotate about horizontal axis 188, as discussed later with respect to Figure 3C and is remotely controllable via controller 120. In other embodiments, transfer stage 180 may be based on techniques, technologies or mechanisms other than vacuum, for example without limitation, electrostatic, magnetic or purely mechanical holding arrangements.

[0032] Apparatus 100 may further comprise, within controlled environment enclosure 110, tub cover depository 190 disposed to allow the remotely controlled vacuum transfer stage 180 to deposit peeled tub cover 156 in tub cover depository 190. Tub cover depository 190 is configured to receive peeled tub cover 156 from vacuum transfer stage 180 and to retain peeled tub cover 156 once tub cover 156 is released by transfer stage 180. Tub cover depository 190 will be described in greater detail below.

[0033] The terms "aseptic" and "sterilize" and their derivatives are to be understood as follows for the purposes of the present specification. Establishing an aseptic condition in the interior of an enclosure shall be understood to mean establishing that condition throughout the internal atmosphere of the enclosure as well as on substantially all exposed interior surfaces of the enclosure. The sterilization may be achieved by treatment with a sterilizing agent comprising at least one of sterilizing radiation, a sterilizing plasma, a sterilizing gas, and a sterilizing vapor.

[0034] This shall include the surfaces of all items, containers, subsystems and the like exposed to the interior atmosphere of the enclosure. To the extent that extremely tight crevices or microscopic crevices may exist in the interior of the enclosure, a sterilizing agent may not perfectly penetrate into such tight regions. The degree of sterilization in practical cases maytherefore not be total. This is acknowledged in both the industry and in the standards set for the industry. The action of establishing an aseptic condition within the interior of the enclosure and "sterilizing the interior of the enclosure" shall have the same meaning in this specification.

[0035] Introducing into the interior of an enclosure with an aseptic condition an item of which the surfaces are not suitably sterilized destroys the existing aseptic condition within the enclosure. Conversely, introducing an aseptic or sterilized item into an interior of an enclosure that does not have an aseptic condition within that interior does not render that interior aseptic. In fact, all it does is to destroy the aseptic condition of the surface of the item so introduced. Similarly, introducing filtered air, even with all biological entities filtered out, into an unsterilized enclosure does not in any way sterilize the enclosure or render it aseptic to a degree acceptable in the pharmaceutical industry. The reason is that the interior surfaces of the enclosure are not sterilized by the introduction of such air. All that is achieved is to contaminate the filtered air with active biological species resident on the interior surfaces of the unsterilized enclosure.

[0036] In the interest of clarity and completeness, it should also be recorded that in the art the term "aseptic" is also sometimes used in association with the introduction of pharmaceutical fluids along aseptic tubes into bodies within controlled enclosures. In such cases the term in the art refers to the condition inside the tube or to the fact that the pharmaceutical fluid may be filtered to a suitable degree. This in no way sterilizes or renders aseptic the interior of the enclosure in question. The aseptic condition in such cases is confined to the interior of the tube bearing the pharmaceutical stream. Such streams are often filtered to a high degree, but such filtering affects only the interior of the particular tube and does not in any way sterilize the interior of the enclosure.

[0037] In some prior art systems, containers introduced into an enclosure for the purposes of being filled with a pharmaceutical are routed through sterilizing subsystems. This kills biological species on the containers. When such sterilized containers are introduced into the enclosure when the enclosure itself is not aseptic the containers lose their aseptic condition, as biological species contained within the enclosure will deposit on the previously aseptic containers.

[0038] It should also be pointed out that pharmaceutical or semiconductor clean rooms of any quality level, including "Class 100", "Class 10" or "Class 1", even when employing laminar flow hoods and the like or any quality of HEPA (High Efficiency Particulate Air) filters or ULPA (Ultra Low Particulate Air) filters, cannot constitute an aseptic enclosure because they do not have anassurable means to render the surfaces of the room sterile or aseptic. Standards for clean rooms exist from both the United States Food and Drug Administration and ISO (International Standards Organization). These specify in great detail to different standards the allowed particulate content of a cubic volume of air in such a clean room facility. None of these standards address the matter of biological species present on surfaces in the room. This serves to make the point that an enclosure cannot be rendered aseptic by the management of its atmosphere or airflow only. Nor, conversely, may the enclosure be rendered aseptic by the sterilization of only the surfaces of its interior.

[0039] The text "Guideline for Disinfection and Sterilization in healthcare Facilities, 2008" by Rutala et al from the Center for Disease Control lists a compendium of mechanisms and methods for sterilization and is hereby incorporated by reference in full as if fully disclosed in the present description. Our concern in this specification is specifically with those mechanisms for sterilizing the interior of an enclosure; that is, sterilizing both the interior surfaces and the atmosphere within the enclosure. Given the requirements, vapor base methods are most appropriate to the task. These include, but are not limited to, treatment with heated water vapor, hydrogen peroxide vapor, ozone, nitrogen dioxide, ethylene oxide, glutaraldehyde vapor or other suitable sterilizing gases and vapors. In one suitable method appropriate to the present invention, the sterilization is by means of hydrogen peroxide vapor which is then flushed using ozone before the enclosure is employed in the filling of pharmaceutical containers.

[0040] The term "decontamination" as used herein denotes a process for removing or inactivating contamination, including without limitation viruses, bacteria, spores, prions, molds, yeasts, proteins, pyrogens and endotoxins, to acceptable levels. "Decontamination" as used herein includes both sterilization (that is, the destruction of all microorganisms, including bacterial spores to a probability of surviving organisms of typically less than 1:106) and disinfection (that is, the destruction and removal of specific types of micro-organisms).

[0041] To achieve suitable levels of sterilization, enclosure 110 may be hermetically sealed. In one embodiment, the hermetic sealing provided by enclosure 110 is sufficient to satisfy predetermined requirements according to ISO standard ISO10648-2, entitled "Containment Enclosures Part 2 - Classification According to Leak Tightness and Associated Checking Methods." Specifically, the sealing is preferably sufficient to satisfy Class 3, or more preferably Class 2, or even more preferably Class 1. In another embodiment, the hermetic sealing provided by enclosure 100 is sufficient to satisfy predetermined requirements according to PDA Journal ofPharmaceutical Science and Technology Technical Report no. 34, entitled "Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products" (Sept / Oct 2001). The disclosures of both of these documents are herein incorporated by reference in full as if fully disclosed herein.

[0042] Figure 2A shows a bottom view of an example of tub 150. Tub 150 may be made of a metal, glass, plastic or a composite material, but typically tub 150 is a single use thin-walled container. Thin-walled single use tubs are typically made by a low-cost process, such as thermoforming or injection molding. As shown in Figure 2A, tub 150 may have features such as tapered sidewalls that assist in manufacturability, but are more difficult to hold than an object with rigid parallel walls. All four walls forming the sides of tub 150 may have step 152.

[0043] Figure 2B shows a detail view of a portion of tub 150. The kind of tub 150 typically employed in the pharmaceutical industry is characterized by top lip 154 that provides a surface area for a sealed connection to tub cover 156. The term "cover" is used here to describe any surface material, including but not limited to a flexible sheet made of plastic material, a polymeric membrane or laminated foil impermeable to bacteria.

[0044] Tub cover 156 may extend outside the outline of top lip 154 of tub 150 in at least one location, and typically extends outside the outline of top lip 154 in a plurality of locations. At least one area of tub cover 156 extends outside the outline of top lip 154 and provides fixed gripping area 158 that may be used as access for clamping. Clamping on gripping area 158 may be complicated by the flexibility of the material of tub cover 156. Gripping area 158 may be level, bent upwards, or bent downwards.

[0045] Figure 3A schematically shows gripper 170 peeling tub cover 156 off tub 150. Gripper 170 grips gripping area 158 of tub cover 156. One method for peeling tub cover 156 is by holding tub cover 156 still while moving tub 150 by operating articulated robotic arm apparatus 160. Since all the elements of Figure 3A have already been labeled in Figure 1, only those elements of system 100 directly involved in this step of the aseptic handling of tub cover 156 are labeled in Figure 3A.

[0046] Figure 3B schematically shows peeled tub cover 156 held by gripper 170 while suction cups 182 of remotely controlled vacuum transfer stage 180 engage peeled cover 156. When transfer stage 180 has fully engaged peeled tub cover 156, gripper 170 may be operated to release fixed gripping area 158 of tub cover 156 allowing transfer stage 180 to take over management of peeled tub cover 156 from gripper 170. Since all the elements of Figure 3B havealready been labeled in Figure 1, only those elements of system 100 directly involved in this step of the aseptic handling of tub cover 156 are labeled in Figure 3B.

[0047] Figure 3C schematically shows vacuum transfer stage 180 depositing tub cover 156 into tub cover depository 190 by rotating an end portion of transfer stage 180 about horizontal axis 188 as indicated by arrow 186. Since all the elements of Figure 3C have already been labeled in Figure 1, only those elements of system 100 directly involved in this step of the aseptic handling of the tub cover 156 are labeled in Figure 3C.

[0048] Tub cover depository 190 will now be described in more detail with reference to Figures 4A, 4B, 4C and 3C and the other elements of system 100 already described with reference to Figure 1. In one embodiment, tub cover depository 190 is desirably a monolithic polymeric structure, manufactured by, for example without limitation, injection molding or additive manufacturing, including 3D printing, to consist of a single portion of the polymeric material, having no constituent parts requiring assembly to make tub cover depository 190. This allows tub cover depository 190 to have no crevices and few if any right angle or acute angle portions potentially exploitable by biologically viable species. Suitable materials from which to manufacture tub cover depository 190 include, but are not limited to polycarbonates, polyether ether ketones (PEEK), polypropylene, polyvinyl chloride (PVC), polyvinylidene difluoride (PVDF), polychlorotrifluoroethylene (PCTFE or "Kel-F"), Chlorinated polyvinyl chloride (CPVC), and acrylonitrile butadiene styrene (ABS). Tub cover depository 190 may also be manufactured from 316 or medical grade stainless steel. Tub cover depository 190 comprises tub cover depository frame 192 mechanically communicating with vertically translatable platen 196 via a plurality of elastically deformable structures 194, which in the implementation shown here may be torsion springs 194. In a more general implementation, elastically deformable torsion springs 194 may be replaced by other elastically deformable structures and tub cover depository 190 may be assembled from constituent components as will be readily apparent to those of ordinary skill without departing from the teachings of the present invention. The platen comprises platen fingers 195 having vertical surfaces 197.

[0049] Lower frame portion 192a of frame 192 supports a plurality of upstanding pillars 193 to either side of platen 196, with each of pillars 193 supporting at a distal end thereof tab 198 extending towards platen 196 when springs 194 are undeflected. Each tab 198 includes oppositely-facing lower surface 198a and upper surface 198b. As seen in Figure 4A, the spaced interlacing of platen fingers 195 with tabs 198 may be described as tabs 198 extend intocrenulations formed between adjacent platen fingers 195 without contacting each other. Additionally, corresponding vertical surfaces 197 of platen 196 and surfaces 198c of tabs 198 are at least partially in facing spaced opposition such that top surface 196a of platen 196 is urged to extend past lower surface 198a of tab 198 in the direction of upper surface 198b. It is contemplated that top surface 196a of platen 196 may be co-planar with top surfaces 198b of the tabs 198 or may extend beyond surface 198b from 198a so long as top surface 196a extends at least beyond lower surfaces 198a in the direction towards upper surfaces 198b. Such arrangement is also noted to provide platen 195 substantially co-planar with tabs 198 in that platen 196 must be urged against the spring forces so as to move surface 196a past surface 198a when providing a cover to be retentively pinched and held therebetween by the spring forces urging platen 196 back towards its undeflected, at-rest position.

[0050] It bears repeating that frame 192, torsion springs 194 and platen 196 are desirably all monolithically part of one portion of polymeric material. Due to the entire structure of tub cover depository 190 being created in one process, the plurality of elastically deformable torsion springs 194 are created such as to locate platen 196 substantially co-planar cover retention tabs 198 as will be described further below. Cover retention tabs 198 are created in the same monolithic manufacturing step as the rest of tub cover depository 190. In this way, there is substantially zero tension or compression in the plurality of elastically deformable torsion springs 194 when tub cover depository 190 is empty of tub covers 156.

[0051] When tub cover depository 190 is empty of tub covers 156, vertical surfaces 198c of tabs 198 and vertical surfaces 197 of platen fingers 195 are biased by springs 194 to be at least partially in facing opposition to one another. Care is specifically taken to ensure that such mutually facing surfaces 197 and 198c have a spacing therebetween that is wide enough to ensure that no crevices potentially exploitable by biologically viable species are formed between cover retention tabs 198 and platen fingers 195. This ensures that the spaces between cover retention tabs 198 and platen fingers 195 are sterilizable by sterilizing vapors employed in rendering the pharmaceutical filling apparatus 100 and the interior of controlled environment enclosure 110 aseptic.

[0052] Figure 4B shows a detailed side-on view of lower frame portion 192a of elastically compressible tub cover depository 190 of Figure 4A. In some embodiments, lower frame portion 192a may comprise on its lower surface a plurality of sloped protrusions 192b arranged for contacting a surface that tub cover depository 190 may be placed on within enclosure 110. Thecontacting surface area of the plurality of protrusions 192b is much smaller than the area of the lower surface of lower frame portion 192a in the absence of protrusions 192b. This arrangement allows for sterilization of the lower surface regions of lower frame portion 192a by sterilizing vapors employed in rendering pharmaceutical filling apparatus 100 and the interior of controlled environment enclosure 110 aseptic.

[0053] Turning now to Figures 3C and 4C specifically, vacuum transfer stage 180 is operated as shown in Figure 3C to push a tub cover 156 held by suction cups 182 into tub cover depository 190 by pressing tub cover 156 down on platen 196 of tub cover depository 190. In this process, platen 196 with the tub cover 156 in contact and in tandem are moved down and the plurality of torsion springs 194 are elastically deformed. Two opposing perimeter portions of tub cover 156 are deformed by the cover retention tabs 198 until the platen 196 and tub cover 156 are pushed down far enough for the perimeter portions of tub cover 156 to slip below the cover retention tabs 198. As the vacuum in the suction cups 182 is relieved, the end portion of transfer stage 180 is rotated back to its original position so that platen 196 and cover 156 are restored in a vertical direction due to the now unopposed elastic compression in the plurality of torsion springs 194. The vertical travel of platen 196 and cover 156 ceases when the perimeter portions of tub cover 156 engage with the bottoms of the cover retention tabs 198 and the tension thus generated in the perimeter portions of tub cover 156 is enough to match the upward restoration force due to the elastic compression of the plurality of torsion springs 194.

[0054] This process may be repeated for a plurality of covers 156 peeled from a corresponding plurality of tubs 150 until peeled covers 156 fill the space between platen 196 in its maximally depressed position and the lower surfaces of cover retention tabs 198. Due to peeled covers 156 being stored nominally laminarly within tub cover depository 190, they do not consume much vertical space. As a result, large numbers of peeled covers 156 may be deposited into tub cover depository 190. During operation of tub cover depository 190, as many as 130 peeled tub covers have been stored in one tub cover depository 190. This stands in marked contrast to prior art systems in which a mere handful of peeled tub covers discarded by a gripper into a container inside a controlled environment enclosure have forced operators of the pharmaceutical filling apparatus to terminate operations and open the system to remove the peeled covers, only to have to then re-sterilize the entire system in order to be able to proceed with filling pharmaceuticals into pharmaceutical containers under sterile conditions. The present invention further contemplates that, should operation of apparatus 100 be halted andoperator access into enclosure 110 be required, tub cover depository 190 may be removed and emptied of retained covers and returned to enclosure 110 and re-sterilized as described for rendering enclosure 110 as sterile or asceptic hereinabove.

[0055] In one aspect, shown in the flow chart of Figure 5, method

[0200] is provided for discarding within aseptically sealed controlled environment enclosure 110 tub covers 156 sealing tubs 150 holding pharmaceutical materials, the method comprising: providing

[0210] within controlled environment enclosure 110 remotely controlled transfer stage 180 and tub cover depository 190, comprising tub cover depository frame 192 mechanically communicating with vertically translatable platen 196 via a plurality of elastically deformable structures 194; peeling

[0220] tub cover 156 from tub 150 within the controlled environment enclosure; engaging

[0230] peeled tub cover 156 with transfer stage 180; transferring

[0240] peeled cover 156 onto platen 196; and operating

[0250] transfer stage 180 to displace platen 196 and elastically deform the torsion springs 194 so as to trap peeled cover 156 between displaced platen 196 and a portion of the tub cover depository frame 192.

[0056] Peeling

[0220] the tub cover 156 from tub 150 may be by using remotely controlled gripper 170. Peeling

[0220] tub cover 156 from tub 150 may comprise holding stationary fixed gripping area 158 of cover 156 with gripper 170 while moving tub 150. Moving tub 150 may comprise moving tub 150 with remotely operated articulated robotic arm 160.

[0057] Engaging

[0230] peeled tub cover 156 with transfer stage 180 may comprise engaging peeled tub cover 156 with transfer stage 180 while gripper 170 grips the fixed gripping area of peeled tub cover 156 after peeling

[0220] ,

[0058] Operating

[0250] transfer stage 180 to displace platen 196 may comprise rotating an end portion of transfer stage 180 about horizontal axis 188. Operating transfer stage

[0250] to displace platen 196 may comprise depressing peeled tub cover 156 and platen 196 to downward displace platen 196 and elastically deform elastically deformable structures 194 to induce in elastically deformable structures 194 a restoring force; and raising the end portion of transfer stage 180 to allow the restoring force to trap peeled tub cover 156 between displaced platen 196 and the upper portion of tub cover depository frame 192.

[0059] Method

[0200] may further comprise repeating steps

[0220] to

[0250] for further tub covers 156 on further tubs 150 in order to trap those further tub covers 156 between displaced platen 196 and a portion of tub cover depository frame 192. The entire process of steps

[0220] to

[0250] may be performed automatically under control of controller 120.

[0060] The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention may be practiced. These embodiments are also referred to herein as "examples." Such examples may include elements in addition to those shown and described. However, the present inventors also contemplate examples in which only those elements shown and described are provided.

[0061] All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the event of inconsistent usages between this document and those documents so incorporated by reference, the usage in the incorporated reference(s) should be considered supplementary to that of this document; for irreconcilable inconsistencies, the usage in this document controls.

[0062] In this document, the terms "a" or "an" are used, as is common in patent documents, to include one or more than one, independent of any other instances or usages of "at least one" or "one or more." In this document, the term "or" is used to refer to a nonexclusive or, such that "A or B" includes "A but not B," "B but not A," and "A and B," unless otherwise indicated. In the appended claims, the terms "including" and "in which" are used as the plain-Engl ish equivalents of the respective terms "comprising" and "wherein." Also, in the following claims, the terms "including" and "comprising" are open-ended, that is, a system, device, article, or process that includes elements in addition to those listed after such a term in a claim are still deemed to fall within the scope of that claim. Moreover, in the following claims, the terms "first," "second," and "third," etc. are used merely as labels, and are not intended to impose numerical requirements on their objects.

[0063] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments may be used, such as by one of ordinary skill in the art upon reviewing the above description. The Abstract is provided to comply with 37 C.F.R. §1.72(b), to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less thanall features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separate embodiment. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

[0064] While this invention has been described as having an exemplary design, the present invention may be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, 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 invention pertains.

Claims

What Is Claimed Is:

1. A tub cover depository for receiving and retaining peeled tub covers within a sterilizable controlled environment enclosure, the tub cover depository comprising: a tub cover depository frame comprising a plurality of cover retention tabs disposed within an upper portion of the tub cover depository frame; a vertically translatable platen comprising a plurality of platen fingers contactlessly interlacing with the cover retention tabs in a horizontal plane; and a plurality of elastically deformable structures each extending from a lower portion of the tub cover depository frame to the platen, wherein the platen is disposed within the tub cover depository frame so as to be vertically depressible relative to the cover retention tabs upon receiving a peeled tub cover forced onto the platen by a depressing force and so as to trap a portion of the received tub cover between the platen fingers and the cover retention tabs when the depressing force is relieved to allow the platen to reposition upward under the action of an elastic restoring force induced in the elastically deformable structures by the depressing force, and wherein the tub cover depository is capable of being sterilized by a sterilizing agent comprising at least one of sterilizing radiation, a sterilizing plasma, a sterilizing gas, and a sterilizing vapor.

2. The tub cover depository of claim 1, wherein the elastically deformable structures comprise elastically deformable torsion springs.

3. The tub cover depository of claim 1, wherein all spaces between the contactlessly interlacing platen fingers and the cover retention tabs are sized to remain accessible to the sterilizing agent.

4. The tub cover depository of claim 1, wherein the tub cover depository frame, the platen, and the plurality of elastically deformable structures are monolithically integrated.

5. The tub cover depository of claim 4, wherein the tub cover depository is composed of a polymer.

6. The tub cover depository of claim 5, wherein the tub cover depository is made by a process of injection molding.

7. An apparatus disposed inside an aseptically sealable controlled environment enclosure capable of being internally sterilized and capable of maintaining an aseptic condition in its interior, the apparatus comprising:a remotely controlled tub manipulation apparatus configured for holding and moving tubs containing pharmaceutical materials, the tubs being sealed with tub covers; a remotely controlled gripper configured for gripping a fixed gripping area of a tub cover and holding the tub cover by the gripping area while the tub cover is peeled from the tub; a remotely controlled transfer stage configured for engaging the peeled tub cover while the peeled cover is held by the gripper; a tub cover depository configured to receive the peeled tub cover from the transfer stage and to retain the peeled tub cover in the tub cover depository on the basis of an elastic restoring force once the tub cover is released by the transfer stage, wherein the tub manipulation apparatus, the gripper, and the transfer stage are disposed within the controlled environment enclosure; and the apparatus further comprising a controller for controlling at least the tub manipulation apparatus, the gripper, and the transfer stage, the controller disposed external to the controlled environment enclosure.

8. The apparatus of claim 7, wherein the tub manipulation apparatus is an articulated arm apparatus.

9. The apparatus of claim 7, wherein the tub cover depository comprises: a tub cover depository frame comprising a plurality of cover retention tabs disposed within an upper portion of the tub cover depository frame; a vertically translatable platen comprising a plurality of platen fingers contactlessly interlacing with the cover retention tabs in a horizontal plane; and a plurality of elastically deformable structures each extending from a lower portion of the tub cover depository frame to the platen, wherein the platen is disposed within the tub cover depository frame so as to be vertically depressible relative to the cover retention tabs upon receiving a peeled tub cover forced onto the platen by a depressing force and so as to trap a portion of the received tub cover between the platen fingers and the cover retention tabs when the depressing force is relieved to allow the platen to reposition upward under the action of an elastic restoring force induced in the elastically deformable structures by the depressing force, and wherein the tub cover depository is capable of being sterilized by a sterilizing agent comprising at least one of sterilizing radiation, a sterilizing plasma, a sterilizing gas, and a sterilizing vapor.

10. The apparatus of claim 9, wherein the elastically deformable structures comprise elastically deformable torsion springs.

11. The apparatus of claim 9, wherein the transfer stage is configured to provide the depressing force.

12. The apparatus of claim 9, wherein all spaces between the contactlessly interlacing platen fingers and the cover retention tabs are sized to remain accessible to the sterilizing agent.

13. The apparatus of claim 9, wherein the tub cover depository frame, the platen, and the plurality of elastically deformable structures are monolithically integrated.

14. The apparatus of claim 13, wherein the tub cover depository is composed of a polymer.

15. The apparatus of claim 14, wherein the tub cover depository is injection molded.

16. The apparatus of claim 15, wherein the tub cover depository is made by a process of injection molding using one of polycarbonates, polyether ether ketones, polypropylene, polyvinyl chloride, polyvinylidene difluoride, polychlorotrifluoroethylene, chlorinated polyvinyl chloride, and acrylonitrile butadiene styrene.

17. The apparatus of claim 13, wherein the tub cover depository is manufactured from one of 316 stainless steel and medical grade stainless steel.

18. The apparatus of claim 7, wherein the transfer stage comprises an end portion configured for engaging the tub cover while the gripping area of the cover is gripped by the transfer stage; and the end portion of the transfer stage is rotatable about a horizontal axis to transfer the peeled cover to the tub cover depository.

19. The apparatus of claim 17, wherein the end portion of the transfer stage is configured to engage the cover using one of vacuum, magnetic force and electrostatic force.

20. A method for discarding within an aseptically sealed controlled environment enclosure tub covers sealing tubs holding pharmaceutical materials, the method comprising: providing within the controlled environment enclosure a remotely controlled transfer stage and a tub cover depository comprising a tub cover depository frame mechanically communicating with a vertically translatable platen via a plurality of elastically deformable structures; peeling a tub cover from a tub within the controlled environment enclosure; engaging the peeled tub cover with the remotely controlled transfer stage; transferring the peeled cover onto the platen; andoperating the transfer stage to displace the platen and thereby elastically deform the elastically deformable structures so as to trap the peeled tub cover between the displaced platen and an upper portion of the tub cover depository frame.

21. The method of claim 19, comprising providing within the controlled environment enclosure a remotely operable articulated arm apparatus and a remotely controllable gripper wherein peeling the tub cover from the tub comprises holding a fixed gripping area of the tub cover stationary with the gripper while moving the tub using the articulated arm apparatus.

22. The method of claim 20, wherein engaging the peeled tub cover with the remotely controlled transfer stage comprises: first engaging the peeled tub cover with the transfer stage while the gripper grips the fixed gripping area of the peeled tub cover after the peeling; and then operating the gripper to release the fixed gripping area of the peeled cover.

23. The method of claim 19, wherein operating the transfer stage to displace the platen comprises rotating an end portion of the transfer stage about a horizontal axis.

24. The method of claim 22, wherein operating the transfer stage to displace the platen comprises: depressing the peeled tub cover and platen to downward displace the platen and elastically deform the elastically deformable structures to induce in the elastically deformable structures a restoring force; and raising the end portion of the transfer stage to allow the restoring force to trap the peeled tub cover between the displaced platen and the upper portion of the tub cover depository frame.

25. The method of claim 19, comprising repeating the peeling, engaging, transferring and operating steps for further tub covers on further tubs in order to trap the further tub covers between the displaced platen and the upper portion of the tub cover depository frame.